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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: polycystic ovary syndrome ( pcos ) is a heterogeneous disease characterized by chronic oligoanovulation , clinical / biochemical hyperandrogenism , polycystic ovaries , and insulin resistance .
the pcos - related ovarian dysfunction has emerged as the main cause of anovulatory infertility .
although several approaches are available to induce ovulation in anovulatory pcos women , clomiphene citrate ( cc ) is still considered the first - line therapy , with lower risk of adverse effects and lower cost .
however , evidence has demonstrated that approximately 1540% of pcos patients do not respond to cc treatment , which is termed cc resistance .
it has been reported that pcos women with obesity , hyperandrogenism , and insulin resistance are less likely to respond to cc , suggesting these factors could be prominent causes of cc resistance [ 79 ] .
given the multifaceted pathogenesis of pcos and the great heterogeneity in the studied populations , the aforementioned factors can not fully explain the origin of cc resistance .
on the other hand , current strategies of augmenting therapy with insulin - sensitizing agents such as metformin are not proving to be sufficient .
recently , a growing body of evidence has demonstrated that pcos is a low - grade pro - inflammatory state .
some of the pro - inflammatory cytokines were found to be elevated in the peripheral circulation of pcos women [ 1214 ] .
cytokines have been shown to be directly involved in maintaining the delicate balance of the hypothalamo - pituitary - ovarian axis and in the maintenance of normal ovarian and menstrual cycles .
we thus hypothesized that the dysregulation of cytokines , a main feature of chronic inflammation in pcos , may be also associated with the blunted ovarian response to cc therapy .
the aim of this cross - sectional study was to identify the circulating cytokines that are expressed differently in cc - resistant and cc - sensitive pcos women .
at the department of reproduction health and infertility of the first affiliated hospital of chongqing medical university , between february 2013 and december 2014 , we recruited 44 anovulatory pcos women determined to no have response to ovulation induction by cc treatment and assigned them to the cc - resistant group .
we recruited 55 age- and body mass index ( bmi)-matched anovulatory pcos women who had ovulated after cc treatment and assigned them to the cc - sensitive group as control .
all the patients recruited met the following inclusion criteria : diagnosis of pcos ( with at least both oligo - amenorrhea and polycystic ovaries on ultrasonography ) based on the 2003 rotterdam consensus .
fasting blood glucose levels < 7.0 mmol / l and a 2-h glucose levels < 11.1 mmol / l following a 75-g oral glucose tolerance test ( ogtt ) ; follicle - stimulating hormone ( fsh ) and thyroid - stimulating hormone ( tsh ) levels within normal ranges ; no intake of the hormone medications ( including oral contraceptives ) within the past 2 months or of medicines that affect insulin sensitivity ( e.g. , metformin or thiazolidinediones ) within the past 3 months ; no male - related infertility or tubal causes of infertility .
the study was approved by the ethics committee of the first affiliated hospital of chongqing medical university .
all participants were induced to ovulate by giving 50 mg / day cc on day 5 to 9 of a spontaneous or a progestin - induced menstrual cycle .
ovulation was observed by vaginal b - ultrasound ( ge voluson e8 , zipf , austria ) on days 11 to 14 of the menstrual cycle , and progesterone level was measured on day 21 of the menstrual cycle .
if there was no dominant follicle ( size < 10 mm in diameter ) observed and the progesterone level was < 5 ng / ml after 1 cycle of cc treatment , 100 mg / day cc was used on the same days of subsequent cycles .
the maximum dose of cc used in our hospital was 100 mg / day due to the nature of the asian population .
the duration of follow - up for all patients was at least 3 treatment cycles .
the cc - resistant group was defined as those who failed to ovulate in response to cc treatment after 3 cycles .
the patients who ovulated after at least 1 of 3 cycles of cc treatment were defined as cc - sensitive .
bmi was calculated as the ratio between weight in kilograms and the square of height in meters ( kg / m ) .
a blood sample was collected from each patient on day 3 of the first menstrual cycle ( before the initiation of cc treatment ) , following overnight fasting .
plasma glucose was measured by the glucose oxidase method ( mindray , shenzhen , china ) .
fasting plasma insulin , total testosterone , fsh , and tsh were determined by chemiluminescence ( beckman , ca , usa ) .
the plasma levels of high - sensitivity c - reactive protein ( hscrp ) were measured by immunoturbidimetry on the autoanalyzer ( hitachi 7180 , ichige , japan ) . insulin resistance ( ir )
was estimated by homeostasis model assessment of ir ( homa - ir ) , which was calculated using the formula fpg ( mmol / l) fasting insulin ( iu / ml)/22.5
screening for circulating cytokines secreted by cc - sensitive or cc - resistant patients was performed by hybridizing plasma with antibody - coated glass slides according to the protocol supplied by the manufacturer [ raybio human cytokine antibody array g series 2000 , a kit combining glass slides of array g6 , g7 , and g8 and allowing the simultaneous detection of 174 cytokines ( cat .
aah - cyt-2000 ) , for details please refer to http://www.raybiotech.com/manual/antibody%20array/aah-cyt-2000.pdf ( raybiotech , inc , norcross ga , usa ) ] .
spots fluorescent signal intensities on slides were quantified by using a laser scanner [ genepix 4000b ( molecular devices , llc , ca , usa ) ] .
signals were normalized to internal positive controls present on each slide ( figure 1 ) , and then expressed as intensity units in each group .
the differentially secreted cytokines between the 2 groups as identified by cytokine antibody microarrays ( p<0.05 ) were further validated by elisa .
the assessment of circulating angiopoietin-2 , urokinase receptor ( upar ) , tissue inhibitor of metalloproteinase-1 ( timp-1 ) , soluble tumor necrosis factor receptor-2 ( stnf - r2 ) , adiponectin , cxcl-16 , and human epidermal growth factor receptor 3 ( erbb3/her3 ) were performed by using elisa kits from raybiotech according to the manufacturer s instructions .
statistical analysis was performed using sas 9.13 ( sas institute , cary , nc ) .
variables are presented as means sd or median ( interquartile ranges ) or number ( percentage ) .
means of continuous variables were compared using the unpaired t test or the wilcoxon 2-sample test .
the differences between groups were considered statistically significant at p<0.05 . for logistic regression analysis ,
the statistical significance was set as p<0.1 and the 95% wald confidence intervals ( ci ) did not include 1.0 .
at the department of reproduction health and infertility of the first affiliated hospital of chongqing medical university , between february 2013 and december 2014 , we recruited 44 anovulatory pcos women determined to no have response to ovulation induction by cc treatment and assigned them to the cc - resistant group .
we recruited 55 age- and body mass index ( bmi)-matched anovulatory pcos women who had ovulated after cc treatment and assigned them to the cc - sensitive group as control .
all the patients recruited met the following inclusion criteria : diagnosis of pcos ( with at least both oligo - amenorrhea and polycystic ovaries on ultrasonography ) based on the 2003 rotterdam consensus .
fasting blood glucose levels < 7.0 mmol / l and a 2-h glucose levels < 11.1 mmol / l following a 75-g oral glucose tolerance test ( ogtt ) ; follicle - stimulating hormone ( fsh ) and thyroid - stimulating hormone ( tsh ) levels within normal ranges ; no intake of the hormone medications ( including oral contraceptives ) within the past 2 months or of medicines that affect insulin sensitivity ( e.g. , metformin or thiazolidinediones ) within the past 3 months ; no male - related infertility or tubal causes of infertility .
the study was approved by the ethics committee of the first affiliated hospital of chongqing medical university .
all participants were induced to ovulate by giving 50 mg / day cc on day 5 to 9 of a spontaneous or a progestin - induced menstrual cycle .
ovulation was observed by vaginal b - ultrasound ( ge voluson e8 , zipf , austria ) on days 11 to 14 of the menstrual cycle , and progesterone level was measured on day 21 of the menstrual cycle .
if there was no dominant follicle ( size < 10 mm in diameter ) observed and the progesterone level was < 5 ng / ml after 1 cycle of cc treatment , 100 mg / day cc was used on the same days of subsequent cycles .
the maximum dose of cc used in our hospital was 100 mg / day due to the nature of the asian population .
the duration of follow - up for all patients was at least 3 treatment cycles .
the cc - resistant group was defined as those who failed to ovulate in response to cc treatment after 3 cycles .
the patients who ovulated after at least 1 of 3 cycles of cc treatment were defined as cc - sensitive .
bmi was calculated as the ratio between weight in kilograms and the square of height in meters ( kg / m ) .
a blood sample was collected from each patient on day 3 of the first menstrual cycle ( before the initiation of cc treatment ) , following overnight fasting .
plasma glucose was measured by the glucose oxidase method ( mindray , shenzhen , china ) .
fasting plasma insulin , total testosterone , fsh , and tsh were determined by chemiluminescence ( beckman , ca , usa ) .
the plasma levels of high - sensitivity c - reactive protein ( hscrp ) were measured by immunoturbidimetry on the autoanalyzer ( hitachi 7180 , ichige , japan ) . insulin resistance ( ir )
was estimated by homeostasis model assessment of ir ( homa - ir ) , which was calculated using the formula fpg ( mmol / l) fasting insulin ( iu / ml)/22.5
screening for circulating cytokines secreted by cc - sensitive or cc - resistant patients was performed by hybridizing plasma with antibody - coated glass slides according to the protocol supplied by the manufacturer [ raybio human cytokine antibody array g series 2000 , a kit combining glass slides of array g6 , g7 , and g8 and allowing the simultaneous detection of 174 cytokines ( cat .
aah - cyt-2000 ) , for details please refer to http://www.raybiotech.com/manual/antibody%20array/aah-cyt-2000.pdf ( raybiotech , inc , norcross ga , usa ) ] .
spots fluorescent signal intensities on slides were quantified by using a laser scanner [ genepix 4000b ( molecular devices , llc , ca , usa ) ] .
signals were normalized to internal positive controls present on each slide ( figure 1 ) , and then expressed as intensity units in each group .
the differentially secreted cytokines between the 2 groups as identified by cytokine antibody microarrays ( p<0.05 ) were further validated by elisa .
the assessment of circulating angiopoietin-2 , urokinase receptor ( upar ) , tissue inhibitor of metalloproteinase-1 ( timp-1 ) , soluble tumor necrosis factor receptor-2 ( stnf - r2 ) , adiponectin , cxcl-16 , and human epidermal growth factor receptor 3 ( erbb3/her3 ) were performed by using elisa kits from raybiotech according to the manufacturer s instructions .
statistical analysis was performed using sas 9.13 ( sas institute , cary , nc ) .
variables are presented as means sd or median ( interquartile ranges ) or number ( percentage ) .
means of continuous variables were compared using the unpaired t test or the wilcoxon 2-sample test .
the differences between groups were considered statistically significant at p<0.05 . for logistic regression analysis , the statistical significance was set as p<0.1 and the 95% wald confidence intervals ( ci ) did not include 1.0 .
as shown in table 1 , the 2 groups of participants were well matched in terms of age and bmi .
there were no significant differences between the 2 groups in terms of hormonal and metabolic parameters , as well the proportions of obesity , hyperandrogenism , and insulin resistance .
compared to the cc - sensitive patients , the cc - resistant patients displayed higher levels of hscrp , a pro - inflammatory marker .
fasting plasma from cc - sensitive and cc - resistant pcos patients were subjected to cytokine antibody microarray for profiling 174 human cytokines ( figure 1 ) .
angiopoietin-2 , upar , timp-1 , stnf - r2 , adiponectin , cxcl-16 , and erbb3 were differentially secreted between the 2 groups ( table 2 , p<0.05 ) .
these cytokines were further validated in 55 cc - sensitive and 44 cc - resistant individuals by elisa .
the elisa results confirmed that 2 of 7 candidate cytokines were altered in cc - resistant individuals .
compared to the cc - sensitive group , the secretion of angiopoietin-2 was significantly reduced in the cc - resistant group [ 1.64 ( 0.931.95 ) vs. 1.08 ( 0.851.34 ) , p<0.05 ] , while cxcl-16 was over - secreted by the cc - resistant group ( 9.102.35 vs. 10.412.82 , p<0.05 ) .
pearson correlation analysis showed that cxcl-16 was positively correlated with hscrp ( r=0.33 , p<0.01 ) .
univariate logistic regression analysis further showed that decreased angiopoietin-2 levels and increased cxcl-16 levels were significantly associated with the presence of cc resistance ( table 3 ) .
as shown in table 1 , the 2 groups of participants were well matched in terms of age and bmi .
there were no significant differences between the 2 groups in terms of hormonal and metabolic parameters , as well the proportions of obesity , hyperandrogenism , and insulin resistance .
compared to the cc - sensitive patients , the cc - resistant patients displayed higher levels of hscrp , a pro - inflammatory marker .
fasting plasma from cc - sensitive and cc - resistant pcos patients were subjected to cytokine antibody microarray for profiling 174 human cytokines ( figure 1 ) .
angiopoietin-2 , upar , timp-1 , stnf - r2 , adiponectin , cxcl-16 , and erbb3 were differentially secreted between the 2 groups ( table 2 , p<0.05 ) .
these cytokines were further validated in 55 cc - sensitive and 44 cc - resistant individuals by elisa .
the elisa results confirmed that 2 of 7 candidate cytokines were altered in cc - resistant individuals .
compared to the cc - sensitive group , the secretion of angiopoietin-2 was significantly reduced in the cc - resistant group [ 1.64 ( 0.931.95 ) vs. 1.08 ( 0.851.34 ) , p<0.05 ] , while cxcl-16 was over - secreted by the cc - resistant group ( 9.102.35 vs. 10.412.82 , p<0.05 ) .
pearson correlation analysis showed that cxcl-16 was positively correlated with hscrp ( r=0.33 , p<0.01 ) .
univariate logistic regression analysis further showed that decreased angiopoietin-2 levels and increased cxcl-16 levels were significantly associated with the presence of cc resistance ( table 3 ) .
some studies have suggested that serum androgen levels , bmi , blood glucose , and insulin resistance are associated with cc resistance .
other researchers have reported that fsh receptor polymorphism at position 680 and basal fsh levels predict the ovarian response to cc . however , in the present study , the cc - sensitive and cc - resistant groups had similar bmi , and showed no significant differences in blood glucose , insulin levels , total testosterone , or fsh levels before cc treatment . however , the cc - resistant group displayed a higher pro - inflammatory state , as shown by an increase in hscrp levels .
therefore , we then focused on investigating the correlation between circulating cytokines and cc resistance without the interference of obvious hormonal and metabolic confounding factors .
the regulation of cytokines in the ovary has been described as promoting processes of follicular growth , steroidogenesis , recruitment , and activation of leukocytes necessary for ovulation and tissue remodelling during ovulation , luteinization , and luteolysis .
ovulation is regarded as an inflammatory event that is followed by anti - inflammatory reactions ; these processes need the coordination of both pro - inflammatory and anti - inflammatory cytokines .
moreover , cytokines are involved in both the inhibition and stimulation of follicular responsiveness to gonadotrophins .
however , the involvement of cytokines in the ovulatory response to cc medication has not been thoroughly investigated .
serum levels of il-6 have been reported to be decreased in anovulatory pcos women resistant to cc when compared to ovulatory women , suggesting that low serum il-6 could be a marker of cc resistance .
another study found that circulating levels of leptin , an adipokine , were significantly higher in cc non - responders and could be used to predict cc resistance . using cytokine antibody microarray technology , we investigated 174 human cytokines , including the pro - inflammatory factors , growth factors , chemokines , anti - inflammatory factors , extracellular matrix factors , and adipokines . by subsequently performing elisa
, we ultimately identified 2 cytokines that had different circulating levels between the cc - sensitive and cc - resistant patients .
angiopoietin-2 , a growth factor , is decreased in cc - resistant women , and is also reversely correlated with the presence of cc resistance as determined by logistic regression analysis .
it is known that angiopoietin-1 is necessary for the recruitment of peri - vascular cells that lead to the maturation and stabilization of newly developed capillaries , while angiopoietin-2 acts as a natural antagonist of angiopoietin-1 , resulting in loosening of the supporting cell matrix and destabilization of existing vessels . in the physiological condition ,
angiopoietin-2 protein level in the ovary increases during follicular enlargement and decreases during maturation of follicles , suggesting that angiopoietin-2 may be critical for follicular development .
in contrast , in the pathological pcos condition , angiopoietin-2 level was decreased in the ovaries of pcos rats compared to the normal controls , resulting in higher ovarian vascularity and vessel stabilization .
the compromised angiopoietin-2 expression in cc - resistant pcos women suggest that defects of follicular development and ovulation may result from excessive ovary angiogenesis .
we also found that cxcl-16 was increased in cc - resistant women and was positively correlated with cc resistance .
although the function of cxcl-16 in the ovaries or hypothalamo - pituitary is still poorly documented , it is known that cxcl-16 plays an important role in initiating and shaping immune - inflammatory responses by attracting inflammatory mononuclear cells .
consistently , we have found a significant positive correlation between cxcl-16 and hscrp , indicating that cxcl-16-mediated pro - inflammation might also be involved in regulating cc sensitivity in pcos patients .
circulating cytokines are disturbed in cc - resistant pcos patients . altered angiopoietin-2 and cxcl-16 levels might impair the responsiveness of the ovaries to cc through up - regulating angiogenesis and inflammation .
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### Summary:
: backgroundpolycystic ovary syndrome ( pcos ) is a common gynecological disease characterized by chronic oligoanovulation , clinical / biochemical hyperandrogenism , polycystic ovaries , and insulin resistance .
accumulating evidence has shown that pcos - related ovarian dysfunction is the main cause of anovulatory infertility .
clomiphene citrate ( cc ) is the first - line therapy for pcos patients ; however , approximately 1540% pcos patients are resistant to cc treatment . it has been demonstrated that pcos is a chronic pro - inflammatory state , as some pro - inflammatory cytokines were elevated in the peripheral circulation of pcos patients , but whether altered inflammatory cytokines expression in pcos patients is associated with blunted response to cc remains unknown.material/methodswe recruited 44 cc - resistant pcos patients , along with 55 age and body mass index ( bmi)-matched cc - sensitive pcos patients .
ovulation was induced by administrating 50100 mg / day cc on days 5 to 9 of each menstrual cycle .
the cytokine profiles were detected by cytokine antibody microarrays and further validated by elisas.resultscc-resistant patients had higher levels of high - sensitivity c - reactive protein ( hscrp ) than the cc - sensitive individuals .
a growth factor , angiopoietin-2 , was significantly reduced [ 1.64 ( 0.931.95 ) vs. 1.08 ( 0.851.34 ) , p<0.05 ] , while a chemokine cxcl-16 was significantly increased ( 9.102.35 vs. 10.412.82 , p<0.05 ) in cc - resistant patients compared to the cc - sensitive subjects .
cxcl-16 was positively correlated with hscrp ( r=0.33 , p<0.01 ) .
logistic regression analysis showed that angiopoietin-2 and cxcl-16 are associated with cc resistance.conclusionscirculating cytokines are disturbed in cc - resistant pcos patients .
altered angiopoietin-2 and cxcl-16 levels might compromise the responsiveness of the ovary to cc through up - regulating angiogenesis and inflammation .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: wise and witter1 were the first to describe the use of argon laser trabeculoplasty ( alt ) for reducing intraocular pressure ( iop ) in glaucoma patients .
many studies have since shown the benefit of alt as either the initial approach for primary open angle glaucoma , or as an adjuvant to hypotensive medications .
latina and park2 later reported a neodymium : yttrium aluminum garnet laser ( q switched , frequency doubled , 532 nd : yag laser ) that selectively targets the pigmented trabecular meshwork ( tm ) cells as an alternative to alt.3 the selective laser trabeculoplasty ( slt ) approach uses a few thousand times less energy than is needed by alt , thereby maintaining the normal tm architecture and allowing the procedure to be repeatable.4 several published studies that were conducted over the past few years compared the efficacy of the two methods in their ability to reduce iop .
they all showed that slt and alt are similar in their biological effects , complication rates , and capabilities in their iop reduction potential among the investigated patient groups.511 a number of publications that reported the effect of prior cataract surgery on long - term outcomes demonstrated that clear cornea phacoemulsification carried out in normal subjects1215 as well as in primary open - angle glaucoma ( poag ) patients prior to cataract surgery1618 significantly reduces the iop for a sustained period of time through a mechanism not fully understood . in 2007 , werner et al19 compared the outcome of slt as a secondary treatment for glaucoma in pseudophakic versus phakic patients and found no significant difference between phakic and pseudophakic eyes in terms of decreased iop or success rates at any time point .
the aim of the current study was to compare the efficacy of slt and alt in reducing the iop of pseudophakic glaucoma patients who recently underwent successful cataract extraction surgery . towards that end , we evaluated and compared the iop - lowering effect of slt versus alt at 12 months by determining the percentage of patients from each group that had reached a reduction of 15% in iop from baseline .
all participants signed an informed consent form before enrollment into this prospective , randomized , controlled single center trial .
all the iop measurements , laser treatments , and follow - up evaluations were conducted by a single glaucoma specialist .
the patients had been diagnosed as having either poag , pseudoexfoliation glaucoma , pigmentary glaucoma , or ocular hypertension ( oht ) ( table 1 ) .
they were all receiving maximum tolerated glaucoma medical treatment and had an uncontrolled iop of 20 mmhg .
the primary outcome of this study was the iop - lowering effect of slt compared to alt at 12 months .
the secondary outcome was to obtain iop measurements at 1 week and 1 , 3 , and 6 months following each procedure .
surgical success was defined as having reached a decrease of 15% in iop from baseline by the time of the final follow - up at the first postoperative year .
each patient was randomly assigned to receive either the slt or alt treatment according to a note that was written , which specified the name of the designated treatment , and which was placed in an unmarked and closed envelope .
the inclusion criteria for the study were : being older than 18 years of age ; having a history of glaucoma with subtypes poag , pseudoexfoliation glaucoma , pigmentary glaucoma , or oht ; patients who underwent a successful phacoemulsification - assisted cataract excision surgery with intracapsular lens implantation ; and patients who underwent a laser treatment ( slt or alt ) not less then 3 months and not more then 6 months following the cataract surgery .
the reason for performing the laser treatment less than 3 months since the cataract extraction phacoemulsification was to allow for complete healing , such as intracapsular fibrosis and reduction in inflammatory response .
this interval would also enable the achievement of a stability in change of anterior chamber depth , an angle opening distance at 500 m anterior to the scleral spur , and reduction in iop at various time points ( 1 , 3 , and 6 months ) after cataract extraction , as shown by various studies , such as the one by huang et al.20 excluded from the study were patients who had a complicated cataract excision surgery ; those with an intraocular lens implantation other than an intracapsular lens ; an advanced visual field defect within 10 of fixation ; previous glaucoma surgery ( except for peripheral iridotomy or alt ) ; previous slt ; severe corneal disease that resulted in inaccurate applanation measurements , or that inhibited the adequate visibility of the tm on gonioscopy ; patients using systemic steroids ; and/or patients suffering from endophthalmitis or uveitic glaucoma .
a calibrated goldmann applanation tonometer was used for the baseline iop measurement , which was done approximately 1 hour prior to initiating the chosen laser treatment .
the follow - up schedule thereafter was as follows : 1 hour , 1 week , and 1 , 3 , 6 , and 12 months postlaser treatment .
changes in iop and significance of the differences in values were determined for each time point during the follow up period of up to 12 months .
the average decreases in iop for each group at each time point were compared statistically .
ocular assessment included corrected visual acuity , slit - lamp assessment of the anterior segment , and gonioscopy .
tm pigmentation was graded according to a standard scale from 0 to 4 + , where 0 indicated no pigmentation and 4 + indicated dense homogeneous pigmentation .
iop was measured with a goldmann applanation tonometer on approximately the same time of day ( plus or minus 1 hour ) at all follow - up visits to minimize diurnal variations of iop .
stereoscopic optic nerve examination was performed with a volk 90d lens ( volk optical , inc , mentor , oh ) . on the day of laser trabeculoplasty
, iop was measured , and one drop of 1% apraclonidine was instilled in the study eye , after which either slt or alt was undertaken .
alt was performed using 50 applications of a 50 m spot size with a 0.1 second duration , and an average power ranging from 400 to 600 mw directed through a volk magna view lens ( volk optical , inc ) to produce blanching or an occasional bubble formation in the anterior tm .
slt was performed with a laserex solo ( ellex medical pty , adelaide , sa , australia ) q switched , frequency doubled , 532 nd : yag laser using 5070 nonoverlapping applications , with a spot size of 400 m ( centered on the tm ) and a pulse duration of 3 ns .
the initial energy used was 0.8 mj , which was increased or decreased until a bubble formation appeared , when it was then decreased by 0.1 mj for the remainder of the treatment .
patients were instructed to instill dexamethasone in the treated eye three times a day for 7 days after treatment .
an attempt was made to keep the patient on the same glaucoma medications throughout the study , and the medications were changed only if the pressure worsened significantly from the preoperative status , or if there had not been an adequate drop in iop to reach the target iop as determined by the severity of the cup - to - disc ratio , and/or worsening of glaucomatous visual field defects and its parameters before treatment .
trabeculectomy was usually performed if the iop had not been successfully lowered to the target pressure .
this was regarded as treatment failure , and the subject s data were excluded from analysis .
fifty - two patients were enrolled in the study and randomly assigned to one of the two laser treatment procedures .
twenty - two patients were assigned to undergo slt and 30 were assigned to undergo alt ( one of the latter patients had already undergone an alt procedure ) .
table 1 summarizes the baseline characteristics of the patients , baseline iops , types and severity of the glaucoma based on iop values , severity of visual field defects , and cup - to - disc ratio severity .
there were no significant differences in iop - lowering effects between the two groups throughout the 12-month study period .
table 2 and figure 1 display the records of the mean iop values of the patients in the two groups during the entire follow - up period .
differences in iop - lowering values were observed twice during the follow - up period , although neither reached a level of significance . the biggest difference in the iop - lowering effect between the groups
was observed 1 week postoperatively , where the mean iop in the alt group was 22.66 mmhg and the mean iop of the slt group was 21.26 mmhg ( p = 0.072 ) . at the 3-month checkup ,
the mean iop in the alt group was 22.25 mmhg and the mean iop in the slt group was 20.93 mmhg ( p = 0.069 ) . at the final checkup , which was reached by 17 of 30 ( 56.6% ) patients from the alt group and 16 of 22 ( 72.2% ) patients from the slt group , the mean iop reduction from baseline was 3.23 mmhg in the alt group and 4.30 mmhg in the slt group ( p = 0.269 ) . at the final checkup ,
six of the 17 ( 35.3% ) patients in alt group and 12 of the 16 ( 75% ) patients in the slt group had a reduction of 15% from baseline iop ( the target iop ) .
at 12 months , the average reduction in iop was 12.8% in the alt group and 16.9% in the slt group . by reaching a 15% reduction in iop from baseline , which was the criterion for surgical success
a total of 15 patients , 12 in the alt group and three in the slt group , had an unsatisfactory reduction in iop after the laser treatment , resulting in failures which led to either adding or changing the type of an iop - lowering medication , or undergoing either a trabeculectomy or a repeat alt .
unsatisfactory reduction in iop was considered when there was a failure to reach the target iop of the eye based on baseline iop , clinical evaluation of cup - to - disc ratio and visual field damage , as well as the global indices .
the type of treatment used in case of failure was decided based on the iop and advancement in glaucoma severity .
statistical analyses showed no correlations between pigment severity and iop - lowering potential of the laser treatments .
several studies have favored slt over alt due to a number of benefits , such as targeting only the pigmented tm cells,3 low incidence of peripheral anterior synechia formation or collateral damage , and the potential of being a repeatable procedure.4 other studies claimed a clear advantage of alt over slt in certain glaucoma types , such as pseudoexfoliation and pigmentary glaucoma.21 a few investigations compared the iop - lowering effect of slt with alt in various glaucoma types,3,5,79,22 but , to the best of our knowledge , the current study is the first to compare the iop - lowering potential between these two laser approaches in glaucoma patients who recently underwent successful phacoemulsification cataract extraction surgery .
damji et al5 performed a randomized clinical trial comparing the effect of slt and alt over a period of 18 months .
holl22 prospectively studied 28 eyes from 14 patients , in which one eye was treated with alt and the fellow eye with slt , and the author found no significant difference in the decreasing of iop potential following either procedure .
juzych et al8 prospectively compared the iop - lowering effect of slt and alt in almost 200 eyes with poag patients over a 5-year follow - up period and found the procedures to be of similar benefit as well .
martinez - de - la - casa et al9 conducted a similar study , and they also found a comparable iop - lowering effect ( 20% reduction in iop in the alt group and 22% in the slt group ) for the two techniques .
popiela et al7 treated 27 open angle glaucoma patients by alt in one eye and slt in the other eye , and they achieved results similar to those of the other studies , with no benefit of one procedure over the other .
the efficacy of alt in aphakic and pseudophakic eyes was reviewed by schwartz et al.23 they found that eyes that were treated with alt had a success rate of up to 34% at 36 months posttreatment .
they also found that pseudophakic eyes had a better response rate than aphakic eyes , and that eyes with extracapsular surgery did better than the ones with intracapsular surgery .
werner et al19 retrospectively compared the iop - lowering effect of slt in phakic and pseudophakic patients ; the mean iop decreased from 18.1 to 15.5 mmhg in the phakic group , and from 18.3 to 15.2 mmhg in the pseudophakic group .
they concluded that there were no significant differences in decreased iop or success rates between phakic and pseudophakic eyes at any time point during their study . a recent study by shazly et al24 evaluated the iop - lowering effect of slt as primary treatment in poag or oht phakic patients to poag or oht pseudophakic patients in up to 30 months of follow - up .
they found the greatest reduction in iop at 3 months posttreatment , which is what we found in our current study .
their conclusion was that the response to slt treatment was delayed in the pseudophakic compared to the phakic patients , while the long - term effectiveness of slt was the same in both groups .
it is unclear why slt may be more effective in pseudophakic patients , but , as suggested by those authors,24 it is plausible that clear corneal phacoemulsification and slt may share a common pathway involving inflammation , prostaglandin release , and interleukin-1 release .
therefore , the iop response to slt may be different in pseudophakic eyes compared to phakic eyes due to partial or complete activation of pathways common to the slt response and to the clear cornea phacoemulsification mediated iop - lowering effect in those patients .
the findings of this study show no significant differences in the iop - lowering capabilities of alt and slt throughout 12 months of follow - up . the biggest differences between the two groups were evident at 1 week and 3 months post - treatment , but none reached a level of significance . only the slt group had surgical success , which was defined by achieving the study s target of a mean iop reduction from baseline of 15% ; the reduction in iop was 16.9% in the slt group , as compared to 12.8% in the alt group .
overall , both laser techniques acceptably reduced the iop from baseline until study closure at 12 months , and both were safe and effective for treating various types of glaucomas in our study population .
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### Summary:
: introduction : this study evaluated and compared the efficacy of selective laser trabeculoplasty ( slt ) and argon laser trabeculoplasty ( alt ) in terms of intraocular pressure ( iop)-lowering effects in pseudophakic patients at various time points after treatment .
the primary aim was to compare the efficacy of slt and alt in reducing the iop of pseudophakic glaucoma patients who recently underwent successful cataract extraction surgery .
the secondary endpoint was to determine the percentage of slt and alt patients whose iop was successfully reduced by at least 15% from baseline.patients and methods : this study was a follow - up of a prospective randomized clinical trial .
fifty - two eyes from 52 glaucoma patients with uncontrolled iop who had previously undergone successful phacoemulsification - assisted cataract excision surgery with intracapsular lens implantation were randomly assigned to treatment with either alt ( n = 30 ) or slt ( n = 22 ) .
fifteen patients were excluded due to adverse events encountered during the study , leaving a total of 18 and 19 patients in the alt and slt groups , respectively .
iop measurements were carried out at scheduled intervals until 12 months post - laser treatment.results:there were no significant differences in the iop - lowering effects between the two methods at any time point during the follow - up period .
the greatest differences between the two groups were observed at 1 week posttreatment and at the 3-month time point , but neither reached a level of significance . at the final checkup ,
the mean iop reduction from baseline was 3.23 mmhg in the alt group and 4.30 mmhg in the slt group ( p = 0.269 ) . at that visit , six ( 35.3% )
patients in the alt group and 15 ( 75% ) patients in the slt group had a reduction of 15% from their baseline iop.conclusion:slt and alt are equally effective in their iop - lowering capabilities in new pseudophakic glaucoma patients during the first 12 months after treatment .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: as laparoscopy in gynecologic surgery becomes more widely utilized , gynecologists continue to seek safer and more cosmetically acceptable techniques .
this step generally involves the blind insertion of a veress needle , followed by the blind insertion of a sharp trocar into the peritoneal cavity .
bowel and vascular injuries are rare but serious complications of this initial step in laparoscopy .
insufflation of the subcutaneous or preperitoneal space may also occur using this blind technique , the former creating subcutaneous emphysema , the latter complicating visibility during the subsequent procedure .
overall , combined incidences of veress needle- or trocar - related injury have been quoted at 2.7 to 2.9/1000 . in an attempt to avoid complications with the veress needle , direct trocar insertion before attaining pneumoperitoneum has also been advocated .
although it is possible to confirm intraabdominal placement of the trocar with the laparoscope before insufflation with carbon dioxide gas , the risk of vascular and bowel injuries still exists with potentially wider , more serious injuries . in light of these problems ,
open laparoscopic techniques have been developed , such as the hasson approach , first described in 1971 .
this involves a periumbilical laparotomy of at least 2 cm , dissecting down to the linea alba under direct visualization and suturing this fascial layer , exposing the peritoneum .
this has been the approach favored by general surgeons , and often used by gynecologists operating on patients with previous laparotomies , suspected adhesions , or cancer .
perhaps secondary to selection bias , when gynecologists have retrospectively compared complication rates between closed and open - entry techniques , the open techniques were associated with higher entry - related complications .
laparoscopic surgery offers shortened recovery time and improved cosmesis for a variety of pelvic surgeries yet involves the potential for risk during the initial blind trocar insertion .
prior to initiating this study , the author noted that intraumbilical skin incisions , if stretched , frequently lead to a small , visualized peritoneal opening in thin women .
we decided to study whether an intentional technique of 5-mm open entry could be applied to all our laparoscopic cases .
the same attending surgeon performed 65 consecutive diagnostic and/or operative laparoscopies through the 2-month rotations of 3 residents in 2004 through 2005 at st .
if peritoneal entry was not attained , a standard technique using a veress needle was performed .
the umbilicus just superior to the inferior margin of the umbilical fold is grasped with a tonsil clamp and elevated .
the assistant then injects 1 ml of a 0.25% bupivacaine local anesthesia into the umbilicus superior to the clamp . a number 11-blade scalpel
is then used to incise the skin 2 mm to 4 mm in a vertical direction within the umbilicus superior to the elevated tonsil clamp .
a second tonsil clamp is then used with a downward spreading motion to bluntly dissect the subcutaneous tissue until the fascial plane is reached .
further downward stretching with the tip of the tonsil clamp will generally separate the fascia and peritoneum , permitting visualization of the peritoneal cavity .
a 5-mm endopath bladeless trocar ( ethicon endo - surgery inc , cincinatti , oh ) is then gently inserted , requiring minimal downward pressure at a safe angle , into the peritoneal cavity under direct visualization with a 5-mm laparoscope ( figures 1 and 2 ) .
the umbilicus just superior to the inferior margin of the umbilical fold is grasped with a tonsil clamp and elevated .
the assistant then injects 1 ml of a 0.25% bupivacaine local anesthesia into the umbilicus superior to the clamp . a number 11-blade scalpel
is then used to incise the skin 2 mm to 4 mm in a vertical direction within the umbilicus superior to the elevated tonsil clamp .
a second tonsil clamp is then used with a downward spreading motion to bluntly dissect the subcutaneous tissue until the fascial plane is reached .
further downward stretching with the tip of the tonsil clamp will generally separate the fascia and peritoneum , permitting visualization of the peritoneal cavity .
a 5-mm endopath bladeless trocar ( ethicon endo - surgery inc , cincinatti , oh ) is then gently inserted , requiring minimal downward pressure at a safe angle , into the peritoneal cavity under direct visualization with a 5-mm laparoscope ( figures 1 and 2 ) .
in 46 of 65 patients ( 70.8% ) , the endopath bladeless trocar could be placed directly into the peritoneal cavity ( successful open entry ) .
there were no differences in age , body mass index ( bmi ) , or history of prior surgery between patients with a successful open entry ( group a ) and those requiring blind veress insertion ( group b ) ( table 1 ) .
because the overall rate of entry - related injuries during laparoscopy remains relatively low , no study of significant size exists that clearly demonstrates the superiority of one entry technique over another .
the 5-mm open - entry technique as described above is advantageous because it combines entry under direct visualization with the benefits inherent to a smaller fascial defect , along with the cosmetic appeal of a small incision hidden within the umbilicus .
the technique was successful at obtaining open - entry placement of a 5-mm endopath bladeless trocar in 71% of patients .
if entry was not obtained via this technique , a veress needle placement followed without difficulty through the same small umbilical incision .
overall , the characteristics between the 2 groups were similar , suggesting that neither a higher bmi nor a history of prior abdominal surgery is a contraindication to attempting the 5-mm open - entry trocar placement .
this technique was learned by successive residents during a brief rotation , suggesting the technique may be easily mastered .
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### Summary:
: background and objective : the rare but serious complications of blind veress needle insertion during laparoscopy include bowel and vascular injury .
to reduce these risks , a novel method of open laparoscopy was introduced into our clinical practice , and its efficacy was evaluated.methods:this is a retrospective evaluation of a novel 5-mm - open laparoscopic technique in a university hospital - based endoscopy practice in 65 consecutive patients undergoing laparoscopy with a single surgeon.result:a 71% success rate was achieved using the 5-mm open - entry laparoscopic technique .
no complications occurred during any of the laparoscopic procedures , but 29% reverted to a standard 5-mm veress needle technique .
the success of the open - entry technique was independent of prior abdominal surgery , subject age , or body mass index ( bmi).conclusion : the 5-mm open - entry technique is safe , fast , and cosmetic .
it is easily mastered and may be converted to a standard veress needle technique if peritoneal entry is not achieved .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: we aimed to determine the drug susceptibility of pandemic ( h1n1 ) 2009 in mexico .
we randomly selected 692 independent clinical samples ( 452 cell culture supernatants and 199 nasopharyngeal swab specimens [ nps ] ) or viral isolates , mostly from patients hospitalized in mexico and from a few symptomatic patients with highly suspected oseltamivir- resistant infections ( 31 nps and 10 lung biopsy specimens from patients who died ) .
all samples were received during may 2009april 2010 at the institute of epidemiologic diagnosis and reference ( indre [ mexico city , mexico ] ) ; all were positive for pandemic ( h1n1 ) 2009 by real - time reverse transcription
pcr ( rt - pcr ) , according to the procedure recommended by the centers for disease control and prevention ( atlanta , ga , usa ) and the world health organization .
patients did not differ significantly by sex , and persons 1029 years of age were most commonly affected , similar to the number of incident cases of acute respiratory infection in mexico ( table 1 ) .
viral rna was extracted by using either magna pure lc total nucleic acid isolation kit ( roche diagnostics , rotkreuz , switzerland ) or qiamp viral rna mini kit ( qiagen , hilden , germany ) .
an endpoint rt - pcr was performed for all 692 samples screened for the h275y molecular marker by using the superscript iii rt - pcr system ( invitrogen , carlsbad , ca , usa ) and fluan1721f and fluan1924r primers spanning position 275 of the na gene ( table 2 ) .
direct sequencing of these pcr products was performed by using a sequencing primer ( fluan1904r , table 2 ) and the bigdye terminator version 3.1 cycle sequencing reaction kit on an abi prism 3130xl dna analyzer ( applied biosystems , foster city , ca , usa ) . * na , neuraminidase ; utr , untranslated region .
all the sequences obtained indicated that the hy mutation at the na 275 residue was absent , except in 1 nps from an 8-month - old girl ( a / mexico / indre797/2010 ) .
she had no known history of travel , contact with a person treated with this drug , or diagnosed immunodeficiency .
her clinical record mentioned 2 respiratory events in the 2 months before the influenza diagnosis : broncholitis , which required hospitalization , and readmission to the hospital 2 weeks after discharge because of influenza - like illness and severe pneumonia .
in addition to oseltamivir , the child required other antimicrobial drugs ( ceftriaxone and vancomycin ) and mechanical ventilation .
the clinical specimen was collected , and pandemic ( h1n1 ) 2009 was laboratory confirmed on january 27 , 2010 . in this sample and in isolating the virus we further analyzed , we discarded any of the 9 previously described mutations ( 5,10 ) associated with resistance to nais ( v116 , i117 , e119 , q136 , k150 , d151 , d198 , i223 , and n295 [ n2 numbering ] ) by the full sequence of the na gene by using 2 overlapping rt - pcr products ( figure 1 , table 2 ) . the complete na sequence of the a / mexico / indre797/2009 virus obtained from nps and mdck isolate ( genbank accession no .
cy057074 ) confirmed the h275y substitution and showed no other na mutations known to be associated with nai resistance ( figure 2 , panel a ) . pyrosequencing analysis performed on the clinical specimen from the 8-month - old patient showed oseltamivir - resistant h275y and wild - type h275 virus variants ( figure 2 , panel b )
the a / mexico / indre797/2009 virus was tested at the centers for disease control and prevention by using an na inhibition assay ( na - star kit , applied biosystems ) and showed an 120-fold increase in oseltamivir 50% inhibitory concentration over that of a sensitive control ( 27.3
nmol / l vs. 0.23 nmol / l ; this result was consistent with h275y and h275 variants .
we also sequenced the m2 gene and confirmed the s31n substitution that confers m2 blocker resistance .
sequencing of the ha gene showed that the substitution d222 g , potentially associated with severe clinical outcome ( 12 ) , was not present in this isolate ( data not shown ) .
reverse transcription pcr ( rt - pcr)/sequencing primers scheme for the neuraminidase ( na ) gene .
b ) primer position and the 2 overlapping rt - pcr products for the complete na sequence .
a ) analysis of molecular markers ( v116 , i117 , e119 , q136 , k150 , d151 , d198 , i223 , h275 , and n295 ) for oseltamivir and/or zanamivir resistance among the pandemic ( h1n1 ) 2009 virus isolates . the oseltamivir resistance
conferring mutation cac ( histidine ) to tac ( tyrosine ) at position 275 was detected in the indre797 sample .
b ) detection of the h275y mutation in the na of the viruses by single - nucleotide polymorphism analysis at na275 position ( yellow area ) .
in addition , 24 virus isolates collected during december 2009january 2010 were tested in the na inhibition assay .
no other molecular markers of nai resistance , such as at residues q136 , k150 , or d151 , which might confer zanamivir resistance , were observed in the isolate from the 8-month - old girl .
the functional ni assay confirmed the oseltamivir resistance and susceptibility to zanamivir of the virus . both variants ( h275y and wild type ) were present in the clinical specimen and its matching virus isolate , which is not unusual ( 13 ) .
the proportion of resistant virus ( 1 [ 0.14% ] of 692 analyzed cases ) is lower than has been described , perhaps because of the limited analysis .
the m2 s31n substitution , the adamantane resistance marker , also was present , as is expected in this virus .
concern exists that an oseltamivir - resistant variant of pandemic ( h1n1 ) 2009 virus may emerge and spread in a manner similar to that of oseltamivir - resistant seasonal influenza a virus ( h1n1 ) ( 14 ) . because pandemic ( h1n1 ) 2009 virus is already resistant to adamantanes , oseltamivir resistance would leave zanamivir as the only antiviral treatment option . consequently , close monitoring of the antiviral susceptibility of pandemic ( h1n1 ) 2009 strains is critical for controlling the spread of this virus ( 15 ) .
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### Summary:
: during may 2009april 2010 , we analyzed 692 samples of pandemic ( h1n1 ) 2009 virus from patients in mexico .
we detected the h275y substitution of the neuraminidase gene in a specimen from an infant with pandemic ( h1n1 ) 2009 who was treated with oseltamivir .
this virus was susceptible to zanamivir and resistant to adamantanes and oseltamivir .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
:
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### Summary:
: investigations of the male reproductive toxicity of ethoxyethanol ( ethylene glycol monoethyl ether ) have been restricted exclusively to histopathological assessments of the testes .
the present study consisted of two experiments designed to document the spermatotoxicity of ethoxyethanol ( ee ) as reflected in evaluations of ejaculated rat semen . the basic strategy involved the evaluation of individual ejaculates recovered from the genital tract of a female rat prior to exposure of the males to ee . repeated assessments of the ejaculate were made during the experimental phase according to specified protocols .
adult long - evans hooded male rats received 0 , 936 , 1872 or 2808 mg / kg ( po ) of ee for five consecutive days .
semen evaluations were then conducted at weeks 0 , 1 , 4 , 7 , 10 and 14 after exposure .
males in the highest two dose groups showed declines in sperm counts by week 4 and were essentially azoospermic by week 7 . at this time
, males receiving the lowest dose of ee also exhibited decreases in ejaculated sperm counts .
an increase in abnormal sperm shapes was also observed . over the ensuing weeks all males exhibited varying degrees of recovery as reflected by increasing ejaculated sperm counts . in a second experiment , males were treated with 0 or 936 mg / kg of ee daily ( 5 days / week ) for 6 weeks with semen evaluations conducted weekly . by week 5 , sperm counts were significantly depressed and there was an increase in the number of abnormal shapes .
sperm motility was depressed by week 6 .
the temporal trends seen in these experiments suggested a differential sensitivity of the spermatocyte stage to ee toxicity.(abstract truncated at 250 words)imagesfigure 2 .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: attempting to predict the onset and progression of disease is one of the cornerstones of epidemiology .
accurate risk prediction can enable targeted preventative treatments , such as fitness regimens for patients at risk of cardiovascular disease , or increased mammogram frequency for patients with high breast cancer risk .
traditional epidemiological risk prediction incorporates a small number of environmental and clinical factors known to be associated with disease , such as body mass index and lipid levels for type 2 diabetes ( 1 ) or the various framingham risk scores for predicting cardiovascular outcomes ( 2 ) .
some of these predictions ( e.g. type 2 diabetes ) are accurate enough to be clinically useful , but for many diseases ( e.g. crohn 's ) the prediction is barely better than chance . evaluating the accuracy of environmental prediction is further complicated by recall - bias and the potential for reverse causality when
the importance of genetic factors in risk prediction has long been appreciated , and is exemplified in a simple form by the value of family history in predicting many complex diseases .
nevertheless , only a few specific molecular genetic variables have played an important role in historical risk predictions [ e.g. brca1 and brca2 in familial breast and ovarian cancer ( 3 ) ] .
the success of recent genome - wide association studies ( gwas ) , however , has rapidly changed the outlook for genetic risk prediction .
these studies have unlocked thousands of clearly validated genetic associations to complex diseases , but their generally weak effects have left their predictive value and clinical utility subject to hot debate .
the principal outputs of the gwas revolution have been the new insights into the biological mechanisms of disease ( 46 ) , but it is also possible to use the fruits of gwas extend genetic prediction from single large factors to aggregations of individually weak effects . in order to explore post - gwas risk prediction , we first discuss the relative merits of different statistical summaries of prediction .
we next consider the state of prediction from current gwas knowledge and consider possible insights from idealized models of prediction as well as their potential pitfalls .
the widespread interest in risk prediction has led to the development of an entire ecosystem of classification metrics .
the most appropriate statistics to use depend on the circumstances and the question being asked .
we discuss below the approaches to quantifying prediction that are most relevant to the subsequent discussion in this paper .
more detailed discussions of many of these metrics , how they are related and how they can be classified are available elsewhere ( 7,8 ) .
predictive tests can produce either a binary classification of each individual as high or low risk , or a quantitative risk score that represents the degree of risk for each individual .
optimally , such a risk score is equal to the posterior probability of developing the disease ( e.g. from logistic regression ) , although some widely used scores ( such as risk allele counting ) do not meet this criterion .
scores can be transformed into binary outcomes by defining high risk to be individuals with a score greater than a threshold t , and all others as low risk .
analysis of risk for quantitative traits is even more straightforward , as such transformations are unnecessary , and much of the discussion below is equally applicable to such non - categorical scenarios .
the simplest measures of classification accuracy are the sensitivity and specificity of the test , respectively defined as the proportion of individuals who develop the disease who were classified as high risk , and the proportion of healthy individuals classified as low risk .
these values vary with the choice of t , which represents the unavoidable trade - off between sensitivity and specificity : predicting everyone will become ill will guarantee complete sensitivity , but without any specificity .
a plot of the sensitivity against 1-specificity for all possible choices of t is known as a receiver - operating characteristic ( roc ) curve ( 9 ) .
the area under the roc curve ( the auc , sometimes called the c statistic ) has the pleasing property of being equal to the probability that a randomly selected individual with the disease has a higher score than a randomly selected healthy individual .
they are not dependent on the prevalence of the disease , with the result that even a high auc predictor of a very rare disease is often of little practical use .
for instance , consider a predictor of a disease with a prevalence of 1% : even with specificity and sensitivity of 0.93 ( typical of a test with an auc of around 0.98 ) only 12% of the individuals who test positive will go on to develop the disease .
alternate statistics such as the positive and negative predictive values account for prevalence . the positive predictive value ( ppv ) is the proportion of people who test positive for the disease who go on to develop it , and the negative predictive value ( npv ) is the proportion of people who test negative who remain healthy . note that , like sensitivity and specificity , the positive and negative predictive values are dependent on the risk score threshold t. these statistics can be used to tune the parameter t : for instance , while in the example above a test of a 1% disease with an auc of 0.98 had a ppv of 12% and a sensitivity of 93% , by raising the threshold we could also produce a test with a sensitivity of only 40% , but a ppv of 75% .
this test would miss a larger proportion of people with the disease , but would have much higher confidence that those it caught will go on to show symptoms .
the most basic means of incorporating genetic information in risk prediction is via family history , which has predictive accuracy proportional to both the heritability and prevalence of disease ( the auc of a single sibling family history is , where k is the prevalence and s the sibling relative risk , see supplementary methods for derivation ) .
the information from a single affected sibling , for instance , predicts crohn 's disease with auc of 0.56 ( 10 ) .
prediction based on molecular measurements of genotype began with common loci of unusually large effect , such as the hla effect in autoimmune diseases like type 1 diabetes [ which alone gives an auc of 0.85 ( 11 ) ] , rheumatoid arthritis and lupus or the effect of apoe in alzheimer 's .
many of these loci were identified in the pre - gwas era by linkage studies , which further mark them as exceptions in complex disease genetics .
rare high penetrance mutations ( such as brca1 and brca2 for breast cancer ) , while obviously very important to the families who carry them , are of surprisingly little value in population - level prediction ( 12,13 ) .
brca1/2 population screening has an auc of only 0.52 , assuming a mutation frequency of 1% ( 14 ) , a penetrance of 50% ( 15 ) and a breast cancer lifetime risk of 12% ( 16 ) ( see supplementary methods for derivation ) .
hundreds of gwas and ever - larger meta - analyses have discovered a lengthening list of variants associated with complex disease .
figure 1 shows the auc of predictors based on the current genetic knowledge of 18 diseases .
for example , good genetic prediction of age - related macular degeneration was quickly enabled by multiple large - effect variants identified by relatively small gwas . another notable gwas success story ( 17,18 ) , crohn 's disease , can be reasonably well predicted by a large number of weak effects .
note that the range of aucs for these diseases is very similar to the range found in classical prediction ( 1,1922 ) .
figure 1.the predictive accuracy of variants discovered by gwas , as a function of the effective sample size , adjusted for the number of stages in the study ( three stage studies have a smaller fraction of samples with gwas data , and thus have lower power ) .
risk prediction is performed using logistic regression evaluated on data sets simulated from allele frequencies and odds ratios taken from replication data .
pd : parkinson 's disease ( 45,46 ) , amd , age - related macular degeneration ( 47 ) ; t1d , type 1 diabetes ( 11 ) ; t2d , type 2 diabetes ( 48 ) ; uc , ulcerative colitis ( 49 ) ; cd , crohn 's disease ( 18,50 ) ; ra , rheumatoid arthritis ( 51 ) ; cad , coronary artery disease ( 52 ) ; brca , breast cancer ( 53 ) ; load , late - onset alzheimer 's disease ( 54,55 ) ; ms , multiple sclerosis ( 56 ) ; mdd , major depressive disorder ( 57 ) ; bp , bipolar disorder ( 58 ) ; sle , systemic lupus erythematosus ( 59 ) ; sz , schizophrenia ( 29 ) ; crca , colorectal cancer ( 60 ) ; prca , prostate cancer ( 61 ) ; ovca , ovarian cancer ( 62,63 ) .
the predictive accuracy of variants discovered by gwas , as a function of the effective sample size , adjusted for the number of stages in the study ( three stage studies have a smaller fraction of samples with gwas data , and thus have lower power ) .
risk prediction is performed using logistic regression evaluated on data sets simulated from allele frequencies and odds ratios taken from replication data .
pd : parkinson 's disease ( 45,46 ) , amd , age - related macular degeneration ( 47 ) ; t1d , type 1 diabetes ( 11 ) ; t2d , type 2 diabetes ( 48 ) ; uc , ulcerative colitis ( 49 ) ; cd , crohn 's disease ( 18,50 ) ; ra , rheumatoid arthritis ( 51 ) ; cad , coronary artery disease ( 52 ) ; brca , breast cancer ( 53 ) ; load , late - onset alzheimer 's disease ( 54,55 ) ; ms , multiple sclerosis ( 56 ) ; mdd , major depressive disorder ( 57 ) ; bp , bipolar disorder ( 58 ) ; sle , systemic lupus erythematosus ( 59 ) ; sz , schizophrenia ( 29 ) ; crca , colorectal cancer ( 60 ) ; prca , prostate cancer ( 61 ) ; ovca , ovarian cancer ( 62,63 ) . the wide spectrum of auc values shown in figure 1 is attributable to a number of factors .
three stage designs used in several cancer studies ) play important roles in the process of variant discovery which feeds into risk prediction .
clinical heterogeneity and the complexity of affected tissues likely contribute to the recalcitrance of psychiatric illness to genetic prediction ( and gwas more generally ) .
highly heritable diseases are unsurprisingly usually easier to predict [ a review of heritabilities is in wray et al .
these principles are exemplified in crohn 's disease , which has been subject to large gwas , is more heritable than the etiologically similar ( but harder to predict ) ulcerative colitis and has a definitive clinical diagnosis .
other differences are harder to explain using any of these arguments , such as the significantly greater predictive accuracy of type 2 diabetes compared with coronary artery disease , which is more heritable and has been subjected to larger gwas meta - analyses .
gwas - based predictions can be further improved by returning to first principles and incorporating family history conditional on genotype at known loci ( 10,24 ) .
for instance , auc from a [ now out - dated ( 18 ) ] list of 30 crohn 's loci is 0.71 ( 10 ) , much higher than the 0.56 mentioned above for family history alone , but less than the auc of 0.74 for family history and gwas combined . since collecting family history
is an important part of standard medical assessment , and can contribute independent genetic information beyond gwas variants , it seems sensible to incorporate it into genetic risk prediction . for diseases where non - genetic prediction is already well established , it is important to evaluate the information added by genetic loci .
clearly , if classical prediction is strong and genetic prediction is weak , little additional value is added .
for instance , if a risk variant increases the risk of developing a disease through increasing the level of a blood biomarker , and that blood biomarker is part of the classical test , then the genetic factor will substantially increase the predictive accuracy .
even this example is more complex than it may appear , as genetic variants that influence lipid levels do grant some increase in prediction even when lipid levels are measured ( 25 ) , likely due to the fact that they can predict lipid production over longer time periods than a blood lipid measurement at a single time point can .
prospective studies are required to disentangle these issues , and recent examples run the gamut from success stories , such as using common variants to increase the auc of risk prediction from 0.76 to 0.83 in age - related macular degeneration ( 21 ) , to negligible improvements for prediction of metabolic diseases ( 1,26 ) .
the predictive accuracies mentioned in the previous section are all based on replicated risk variants discovered by gwas to date . however , established gwas loci typically explain only a small fraction of the heritability of complex diseases [ an observation known as missing heritability ( 27 ) ] .
regardless of the explanation for this phenomenon , it raises questions about broader methods of risk prediction using the entire genome .
a number of approaches have been developed to address this issue , but the answers they provide depend on the assumptions inherent in different models of as - yet undiscovered genetic risk .
recent studies have estimated that a large proportion of heritability can be explained by common variation , based on identity - by - descent sharing of distantly related individuals ( 28 ) .
it has been shown that 3% of variance ( corresponding to an auc of 0.65 ) ( 23 ) in schizophrenia risk can be explained by a polygenic model , including a large number of loci that did not achieve genome - wide significance ( 29 ) .
various attempts have been made to use highly polygenic risk scores based on these non - significant loci for prediction in different diseases , with varying degrees of success ( 3032 ) .
a natural extension of considering genome - wide risk prediction is the theoretical accuracy one might achieve if the genetic architecture of a disease were completely described
. some diseases might be difficult to predict due to poor current understanding of the underlying genetics , whereas others might never be tractable to genetic prediction .
epidemiological estimates of heritability ( 23 ) can be used to create such theoretically complete risk models .
three models have been proposed ( 33 ) , each of which corresponds to a different assumption about the distribution of disease probability in the population .
one of these models ( the log model ) is an analytically tractable but relatively unrealistic , assuming that probabilities are log - normally distributed , which can create disease probabilities greater than 1 .
the other two models are more complex but also more realistic , with each making different but apparently equally valid assumptions .
the logit ( or logistic ) model assumes that odds ratios are log - normally distributed , and as a result has similar properties to , and is easy to integrate with , the logistic regression techniques used in gwas .
the probit ( or liability threshold ) model is a generalization of the variance component models used in quantitative trait modelling , and assumes a continuous distribution of a disease phenotype ( called the liability ) in the population , with heritable and non - heritable components .
an individual who develops the disease is assumed to have a liability value above a certain threshold .
clayton ( 11 ) derived expressions for the auc and the roc curves given the log model , which showed surprisingly small aucs for most scenarios .
however , wray and goddard ( 33 ) 's calculations based on the probit model showed very high aucs for a similar range of heritabilities .
similar expressions can not be easily derived for the logistic model , although they can be calculated numerically .
figure 2 shows the predicted roc curves for diseases with a prevalence of k = 1/200 and k = 1/20 , and a sibling relative risk of s = 9 and s =3 for the three models .
these values represent conservative parameter estimates for uncommon diseases , such as crohn 's disease or type 1 diabetes , and more common diseases such as cardiovascular disease . for the rarer disease ,
all the models give divergent answers , with the probit model giving an auc of 0.98 , a logit model an auc of 0.96 and the log model an auc of 0.89 . for the common disease ,
the logit and probit models agree on an auc of 0.93 , although with a different sensitivity specificity trade - off , and the log model gives a much lower auc of 0.84 .
part of this discrepancy is explained by an assumption in the log model that ks<<1 , to avoid troublesome risk probabilities > 1 ( 33 ) . in practice
, we have found that the log model is inaccurate if ks>0.01 ( supplementary material , fig .
s1 ) and therefore agree with wray and goddard ( 33 ) that this model should not be used for common diseases .
a plausible maximum auc for rare diseases therefore likely lies between 0.96 and 0.98 , and common diseases around 0.93 , as predicted by the logit and probit models . if future genetic studies are able to account for a significant proportion of the heritability of common diseases , then genetic prediction has the potential to become much more powerful .
figure 2.the roc curves for the log , logit and probit models of disease risk for a rare disease with a prevalence k = 1/200 and sibling relative risk of s = 9 , and a common disease with k = 1/20 and s =3 , given that has been explained .
the corresponding aucs are 0.89 , 0.96 and 0.98 , respectively , for the rare disease , and 0.84 , 0.93 and 0.93 for the common disease .
the roc curves for the log , logit and probit models of disease risk for a rare disease with a prevalence k = 1/200 and sibling relative risk of s = 9 , and a common disease with k = 1/20 and s =3 , given that has been explained .
the corresponding aucs are 0.89 , 0.96 and 0.98 , respectively , for the rare disease , and 0.84 , 0.93 and 0.93 for the common disease .
gwas results available today allow prediction for a large number of common diseases , with accuracies ranging from slight to moderately high , similar to the range of predictive accuracies found in classical prediction ( although the specific diseases that can be predicted well differ by method ) . indeed
, genetic prediction has already been incorporated into clinical practice in situations where relatively rare , but powerful predictors have been discovered , such as hla - b*701 mediated hypersensitivity reaction to the antiretroviral abacavir ( 34 ) . in addition , larger meta - analyses and future sequencing studies will identify further risk variants , possibly including lower frequency variants of large effect size .
such studies could bring risk prediction ever closer to the high - accuracy theoretical predictions described above .
irrespective of predictive power , there are a number of benefits of such genetic prediction over classical alternatives .
for instance , unlike classical risk prediction , genetic risk prediction is highly stable over time , as a person 's genetic sequence is essentially constant throughout their life . some currently used clinical biomarkers , in contrast , are powerful predictors of disease risk in the near term but less valuable in assessing lifetime risk .
a study in type 2 diabetes ( 35 ) showed that the auc for clinical predictors declines from 0.76 to 0.64 as mean follow - up time increases from 16 to 28 years , but genetic prediction improves from 0.57 to 0.62 over the same timescale ( see also the lipid level example above ) .
this allows risk prediction to be performed on a much longer time scale than is currently plausible .
such stable risk stratification could be especially important when the proposed interventions are more effective if started at an early age , or continued over a long time period .
the inherent value of any disease predictor , however , is a function not just of predictive power , but also the cost and invasiveness of the prediction procedure , and the cost and effectiveness of the interventions available .
this balance of practicality and predictive power is central to the incorporation of any predictor to routine medical practice , including genetics .
genetic risk prediction is currently not straightforward , as it requires obtaining a blood or saliva sample and ordering a bespoke genotyping assay for a locus of interest .
however , the marginal cost of prediction could be very low in the future if full genome sequences are available and infrastructure is developed to interpret it .
the continuing plunge in the cost of sequencing individual genomes ( 36 ) is making this scenario increasingly likely .
cheap and readily available genome sequencing is already being used in clinical genetics practice to diagnose genetic disease ( 37,38 ) , to guide cancer treatment ( 39 ) and as a cost - effective form of carrier testing ( 40 ) .
once a patient 's genome is on file , risk prediction can essentially be performed for free and can then be used to inform diagnostics , screening and preventative measures in an automated way .
attaching a patient 's genome to an electronic medical record will enable a variety of prediction scenarios dependent on disease aetiology , prevalence and prevention and treatment options .
for some diseases , such as age - related macular degeneration , the high accuracy of genetic prediction could be applied to entire populations so that regular ophthalmological examinations for at - risk individuals could allow early detection and treatment of this degenerative disease . for rarer diseases ,
population screening is less useful due to low positive predictive values , but genetic prediction could be applied when patients present with early symptoms .
for instance , while the rarity of crohn 's disease results in a low positive predictive value in the population , genetic data could aid in the diagnosis of a patient who presents with early symptoms such as abdominal pain , diarrhoea and weight loss .
complex risk prediction also interacts with clinical genetics because some diseases , such as diabetes , have similar presentation of both complex and monogenic forms ( 41 ) .
an accurate prediction of either must take into account the possibility of different underlying genetic models : conditional on disease symptoms , the probability of having a monogenic mutation increases as complex disease risk decreases .
widespread clinical incorporation of genetic risk prediction will also require development of sophisticated infrastructure to perform prediction and deliver interpretable results to patients and health care professionals .
such systems will need to be designed both to provide evidence at the bedside to doctors , and to enable communication of these results to patients in a maximally beneficial way .
furthermore , complete genome sequences will inevitably lead to potentially worrisome incidental findings , such as apoe homozygosity for a high alzheimer 's risk allele .
procedures will need to be put in place to handle such discoveries in a consistent manner which avoids unintended psychological harm . while early reports have not shown drastic behavioural consequences of genetic testing ( 4244 ) , a more detailed understanding of the psychological response to genetic risk prediction , and how best to communicate such predictions to patients ,
, clinical trials will be required to learn how effective these applications are at improving outcomes , as well as how much of a cost burden is associated with them .
the promise of risk prediction has ( sometimes ominously ) hovered over the study of disease genetics since the initial sequencing of the human genome .
genetic risk prediction has never become as powerful as some early hype suggested it would be , but neither is it as useless as some detractors claim .
genetic risk prediction can already improve upon classical prediction , in some cases substantially so .
however , as is true for classical predictors , the utility of genetic risk prediction is dependent not just on predictive accuracy , but also on cost and the ability of clinicians and patients to effectively use this information .
the falling cost of whole - genome sequencing will drive the marginal cost of prediction lower and lower , but further progress in gene - mapping research , infrastructure and medical practice will be needed to take full advantage of genetic risk prediction .
we also thank the wellcome trust for funding this work ( wt089120/z/09/z ) . funding to pay
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### Summary:
: attempting to classify patients into high or low risk for disease onset or outcomes is one of the cornerstones of epidemiology .
for some ( but by no means all ) diseases , clinically usable risk prediction can be performed using classical risk factors such as body mass index , lipid levels , smoking status , family history and , under certain circumstances , genetics ( e.g. brca1/2 in breast cancer ) .
the advent of genome - wide association studies ( gwas ) has led to the discovery of common risk loci for the majority of common diseases .
these discoveries raise the possibility of using these variants for risk prediction in a clinical setting .
we discuss the different ways in which the predictive accuracy of these loci can be measured , and survey the predictive accuracy of gwas variants for 18 common diseases .
we show that predictive accuracy from genetic models varies greatly across diseases , but that the range is similar to that of non - genetic risk - prediction models .
we discuss what factors drive differences in predictive accuracy , and how much value these predictions add over classical predictive tests .
we also review the uses and pitfalls of idealized models of risk prediction .
finally , we look forward towards possible future clinical implementation of genetic risk prediction , and discuss realistic expectations for future utility .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: open surgical removal of staghorn calculi was at one time considered the gold standard to which all other forms of stone removal were compared .
currently , open surgery is performed infrequently with the procedure being used in < 1% of patients undergoing stone removal .
a 65 year old man was taken up for open pyelolithotomy for large staghorn calculus by a urologist in a medical college .
i was called for help as the patient started having intractable bleeding after the removal of staghorn calculus .
i suggested to him to pack the renal fossa with roller gauzes as neither pre operative ivp nor b negative blood was not available in the blood bank .
the renal fossa was packed with three long roller gauze packs , as bleeding continued after approximation of pyelotomy incision with three interrupted 3 - 0 vicryl sutures .
one roll of gauze was placed over the pyelotomy bleeding or oozing site , second roll of gauze was placed on the medial side of the kidney and third roll of gauze was placed on the lateral side of kidney to fill the renal fossa .
all these rolls were tied together and brought out from the posterior end of the main wound .
one 30f tube drain was also kept which was brought out from a separate stab incision .
the patient was shifted to the high dependency unit ( hdu ) for post operative monitoring .
the patient had uneventful post operative course and was discharged on 10 post operative day after suture removal .
the renal functions were found to be normal at the time of discharge . a 45 year old male patient who presented with multiple calculi mimicking a large stag horn calculus in left kidney [ figure 1 ] .
the patient developed intractable bleeding when one of the two small stones was retrieved [ figure 3 ] , possibly due to injury to interlober / segmental vessels .
the patient was managed by packing of renal fossa with three long roller gauze packs as bleeding continued after approximation of pyelotomy incision with three interrupted 3 - 0 vicryl sutures .
all three packs were removed after 48 hrs in the post operative ward under sedation .
the patient 's recovery was uneventful.ivp/ivu done after six months showed good renal function [ figure 4 ] .
kub showing left stag horn calculi preoperative ivu showing kidney function removed left stag horn calculi ivu ( six months after 48 hours packing ) showing good renal function a 62 year old female patient had a large staghorn calculus .
the renal functions were normal even though packs were kept in renal fossa for more than 36 hrs .
a 65 year old man was taken up for open pyelolithotomy for large staghorn calculus by a urologist in a medical college .
i was called for help as the patient started having intractable bleeding after the removal of staghorn calculus .
i suggested to him to pack the renal fossa with roller gauzes as neither pre operative ivp nor b negative blood was not available in the blood bank .
the renal fossa was packed with three long roller gauze packs , as bleeding continued after approximation of pyelotomy incision with three interrupted 3 - 0 vicryl sutures .
one roll of gauze was placed over the pyelotomy bleeding or oozing site , second roll of gauze was placed on the medial side of the kidney and third roll of gauze was placed on the lateral side of kidney to fill the renal fossa .
all these rolls were tied together and brought out from the posterior end of the main wound .
one 30f tube drain was also kept which was brought out from a separate stab incision .
the patient was shifted to the high dependency unit ( hdu ) for post operative monitoring .
the patient had uneventful post operative course and was discharged on 10 post operative day after suture removal .
a 45 year old male patient who presented with multiple calculi mimicking a large stag horn calculus in left kidney [ figure 1 ] .
the patient developed intractable bleeding when one of the two small stones was retrieved [ figure 3 ] , possibly due to injury to interlober / segmental vessels .
the patient was managed by packing of renal fossa with three long roller gauze packs as bleeding continued after approximation of pyelotomy incision with three interrupted 3 - 0 vicryl sutures .
all three packs were removed after 48 hrs in the post operative ward under sedation .
the patient 's recovery was uneventful.ivp/ivu done after six months showed good renal function [ figure 4 ] .
kub showing left stag horn calculi preoperative ivu showing kidney function removed left stag horn calculi ivu ( six months after 48 hours packing ) showing good renal function
the renal functions were normal even though packs were kept in renal fossa for more than 36 hrs .
open pyelolithotomy constitutes less than 1% of all stone removal surgeries in the western countries .
prolonged packing of renal fossa has not been described before except for renal trauma . on the contrary two nephrectomies
have been reported to control intractable bleeding after open pyelolithotomy performed at a district hospital in pakistan .
moreover procedures like salvage nephrectomy especially for benign procedures are seldom reported because of its medico - legal implications .
bouboulis and others have described the role of packing of the chest after cardiac procedures for intractable bleeding as it allows a reasonable patient salvage rate .
perihepatic packing is also described in literature as an adjunct in obtaining hemostasis in coagulopathy patients sustaining major liver injuries .
survival was found to be good ( 83% to 90% ) in patients believed otherwise to be unsalvageable and in 77% , packing helped achieve hemostasis which was not otherwise possible . in unstable patients ,
packing of the renal fossa with laparotomy pads and transferring the patient to the surgical intensive care unit ( icu ) is best according to the european guidelines on urological trauma and a planned second - look laparotomy is better than time - consuming primary reconstruction .
packing of renal fossa is a simple and reproducible procedure which is worth trying for salvaging each and every kidney especially in surgery for benign renal disease .
rule of evidence does not apply in such case as aptly stated by meakins jl the development of surgical procedures and their introduction into practice has not depended upon the randomised control trials ( rct ) but rather upon an enthusiast performing a case series , sometimes with clearly defined results .
should all operations and procedures be evaluated by a randomized control trial ( rct ) ?
clearly not , and the levels of evidence support this quite clearly with the all or none research category as level 1c .
this relates to frequent clinical situations requiring a solution often immediate , e.g. , pus , a ruptured aneurysm , a sucking chest wound , that do not lend themselves to a trial , as the control regimen ( doing nothing ) would lead to death .
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### Summary:
: there is no documented study to indicate the role of prolonged packing of renal fossa ( 24 to 48 hours ) to control bleeding in life threating haemorrhage following open pyelolithotomy without compromise in the renal functions . on the contrary emergency nephrectomy
was performed for intractable bleeding during renal stone surgery in peripheral hospitals .
several studies have shown the usefulness of temporary packing to control bleeding in liver injuries and following open heart operations .
packing of the renal fossa with laparotomy pads in unstable patients , and transferring the patient to the surgical intensive care unit ( icu ) is also described in trauma but not in controlling bleeding after open pyelolithotomy .
this study comprises of three such patients whose kidneys were salvaged by a simple procedure of temporary packing of renal fossa for period of 24 - 48 hours who had developed life threatening haemorrhage after open pyelolithotomy .
this technique is simple and worth trying especially for surgeons who are contemplating nephrectomy as prolonged packing has not lead to any compromise in renal functions .
the aim of this manuscript is very limited and clear .
packing is not a licence to carry out open pyelolithotomy without proper expertise and local backup or resources .
principles of safe and ethical surgical practice should never be violated as it can lead to medico legal complications .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the study was approved by the institutional review board for human studies at baylor college of medicine .
twelve adults with uncontrolled type 2 diabetes ( a1c 810% ) and 12 nondiabetic control subjects matched for age , sex , and bmi were recruited .
all subjects were free of thyroid disorders , hypercortisolemia , liver or renal impairment and malignancy , and had no infections or major illnesses during the preceding 6 months .
all patients received diabetic management from their primary physicians . to prevent acute swings of blood glucose , and to achieve comparable glycemic levels before and after supplementation with cysteine and glycine , we excluded patients receiving insulin therapy and recruited only subjects who recently were diagnosed and were being treated with either lifestyle modification or oral antidiabetic agents .
subjects were studied in the adult general clinical research center ( gcrc ) of the baylor college of medicine .
after measurement of blood counts , glucose concentrations , glycosylated hemoglobin , and liver and renal profiles , subjects participated in the first infusion study . the gcrc protocol consisted of intravenous infusions of stable isotopes to measure gsh synthesis in the fasted state .
all subjects were studied under baseline conditions ; only the diabetic subjects were studied again after 14 days of dietary supplementation with 0.81 mmol / kg / day of cysteine ( given as n - acetylcysteine ) and 1.33 mmol / kg / day of glycine .
subjects were asked to consume their usual habitual diets from 2 weeks before beginning the study to the end of the study period .
sterile solutions of [ h2]glycine ( cambridge isotope laboratories , woburn , ma ) were prepared . after a 10-h fast , subjects were admitted to the gcrc for the study , where two intravenous catheters were inserted into superficial veins for continuous infusion of the tracer solutions and blood sampling . after a basal blood sample was drawn ,
a primed constant intravenous infusion of [ h2]glycine ( prime dose 20 mol / kg ; infusion dose 15 mol / kg / h ) was maintained for 8 h. additional blood samples were taken at 2 , 3 , 4 , 5 , 6 , 7 , and 8 h for measurement of erythrocyte gsh derived glycine isotopic enrichments .
the primary outcome variables were fractional and absolute synthesis rates of gsh within erythrocytes , erythrocyte gsh , cysteine , glycine and glutamate concentrations , plasma lipid peroxide levels , and plasma oxidative stress measured as reactive oxygen metabolites .
baseline plasma samples were aliquotted into tubes for the various assays , and stored at 80c for later analyses .
hemoglobin , reactive oxygen metabolites ( droms ) , ( diacron international , grosetto italy ) , plasma chemistries , and lipid peroxides were measured .
erythrocyte gsh concentration and isotopic enrichment of gsh were measured as described next ( 12 ) .
briefly , duplicate aliquots of 1 ml whole blood were centrifuged to separate packed cells and measure gsh and glutamate , cysteine , and glycine , respectively .
the first aliquot of packed erythrocytes was washed thrice with normal saline and 1 ml of monobromobimane ( mbb ) buffer ( 5 mmol / l mbb , 17.5 mmol / l na2edta , 50 mmol / l potassium phosphate , 50 mmol / l serine , and 50 mmol / l boric acid ) was added .
cells were immediately lysed by rapid freeze - thaw with liquid nitrogen , and the erythrocyte - mbb buffer mixture was shaken and left in the dark at room temperature for 20 min for development of the gsh - mbb derivative . after adding 0.5 ml of 20% perchloric acid ,
the sample was centrifuged , and the supernatant containing the mbb derivative was sealed and frozen at 80c for later analysis of gsh .
concentrations of gssg were measured by first converting oxidized glutathione to reduced glutathione with the addition of a reducing agent ( 5 mmol / l dithiothreitiol ) and measuring this as total gsh ; the calculated difference between total gsh and reduced gsh is the concentration of gssg .
erythrocyte gsh was isolated as an red blood cell - free aliquot , and the concentration measured high - performace liquid chromatography ( waters , milford , ma ) using a 717 plus autosampler complexed to a 2475 fluorescent detector and equipped with a reverse - phase ods hypersil column ( 5 m , 4.6 200 mm ; waters ) .
elution of gsh was accomplished with a 313.5% acetonitrile linear gradient in 1% acetic acid ( ph 4.25 ) at a flow rate of 1.1 ml / min .
the gsh eluate was collected using a fraction collector , dried , and hydrolyzed for 4 h in 4 mol / l hcl at 110c .
a 1-ml aliquot of blood was centrifuged , and erythrocytes were then washed thrice with 3 ml sodium chloride solution ( 9
rbcs were then lysed by freeze - thaw action with the use of liquid nitrogen , and cellular proteins were precipitated by using 10% perchloric acid solution .
after centrifugation , the supernatant fluid was used for erythrocyte free amino acid analysis . before derivatization for gas chromatographic
mass spectrometric analysis , erythrocyte - free glycine was isolated by cation - exchange ( dowex 200 ; bio - rad laboratories , hercules , ca ) chromatography .
samples of glycine derived from erythrocyte glutathione and plasma and erythrocyte - free glycine samples were converted to the n - propyl ester , heptafluorobutyramide derivative .
the tracer - to - tracee ratio for glycine in various samples was determined by negative chemical ionization gas chromatographic
mass spectrometric analysis with selective monitoring of ions at mass - to - charge ratios of 293295 on an agilent 6980 gas chromatograph complexed to a 5973 mass spectrometer ( agilent technologies , wilmington , de ) .
erythrocyte amino acid concentrations were determined by high - performace liquid chromatography analysis with a waters system ( millipore , milford , ma ) . to assess the level of oxidative stress , the derivatives of droms were determined in serum .
briefly , plasma is reacted with an acidic acetate buffer ( ph 4.8 ) , which liberates transition metal ions that catalyze the decomposition of the hydroperoxides to alkoxy and peroxyl radicals . these newly formed radicals in turn oxidize the spectrophotometric marker ( n , n - diethyl - p - phenylenediamine ) , which is detectable by absorption at 505 nm as ucarr ( where 1 ucarr is equal to 0.8
briefly , this was measured using freshly prepared buffers containing ammonium ferrous sulfate , xylenol orange , h2so4 , bht in 90% vol / vol methanol , and triphenylphosphine in methanol .
heparinized blood was centrifuged , and 10 l of 10 mmol / l tpp solution was added to 90 l of plasma ( control vials ) then 10 l of methanol was added ( test vials ) , and this solution was incubated at room temperature for 30 min . after adding appropriate buffers , each vial was incubated at room temperature for 30 min , centrifuged , and the absorbance of the supernatant was determined by spectrophotometry .
the hydroperoxide content was determined from test controls and assayed against the standard curve ( 13 ) .
the fractional synthesis rate ( fsr ) of erythrocyte gsh ( fsrgsh ) was calculated according to the precursor - product equation : fsrgsh ( % /day ) = ( irt7 irt5)/(irrbc 1,200/t7 t5 ) , where irt7 irt5 is the increase in the isotope ratio of erythrocyte gsh - bound glycine between the fifth and seventh hours of infusion , when the isotope ratio of erythrocyte - free glycine , irrbc , had reached a steady state .
the absolute synthesis rate ( asr ) of erythrocyte gsh per day was calculated as follows : asr = erythrocyte gsh concentration fsr .
the units of asr are expressed as micromols of gsh per gram of hemoglobin per day .
an independent unpaired t test was used to compute differences in means between the diabetic group presupplementation and the control group and also between the diabetic group postsupplementation and the control group .
differences in outcome measures in the diabetic patients studied pre- and postsupplementation was determined using a paired t test .
data analysis was performed with the statmate statistical software ( graphpad software , la jolla , ca ) .
baseline plasma samples were aliquotted into tubes for the various assays , and stored at 80c for later analyses .
hemoglobin , reactive oxygen metabolites ( droms ) , ( diacron international , grosetto italy ) , plasma chemistries , and lipid peroxides were measured .
erythrocyte gsh concentration and isotopic enrichment of gsh were measured as described next ( 12 ) .
briefly , duplicate aliquots of 1 ml whole blood were centrifuged to separate packed cells and measure gsh and glutamate , cysteine , and glycine , respectively .
the first aliquot of packed erythrocytes was washed thrice with normal saline and 1 ml of monobromobimane ( mbb ) buffer ( 5 mmol / l mbb , 17.5 mmol / l na2edta , 50 mmol / l potassium phosphate , 50 mmol / l serine , and 50 mmol / l boric acid ) was added .
cells were immediately lysed by rapid freeze - thaw with liquid nitrogen , and the erythrocyte - mbb buffer mixture was shaken and left in the dark at room temperature for 20 min for development of the gsh - mbb derivative . after adding 0.5 ml of 20% perchloric acid ,
the sample was centrifuged , and the supernatant containing the mbb derivative was sealed and frozen at 80c for later analysis of gsh .
concentrations of gssg were measured by first converting oxidized glutathione to reduced glutathione with the addition of a reducing agent ( 5 mmol / l dithiothreitiol ) and measuring this as total gsh ; the calculated difference between total gsh and reduced gsh is the concentration of gssg .
erythrocyte gsh was isolated as an red blood cell - free aliquot , and the concentration measured high - performace liquid chromatography ( waters , milford , ma ) using a 717 plus autosampler complexed to a 2475 fluorescent detector and equipped with a reverse - phase ods hypersil column ( 5 m , 4.6 200 mm ; waters ) .
elution of gsh was accomplished with a 313.5% acetonitrile linear gradient in 1% acetic acid ( ph 4.25 ) at a flow rate of 1.1 ml / min .
the gsh eluate was collected using a fraction collector , dried , and hydrolyzed for 4 h in 4 mol / l hcl at 110c .
baseline plasma samples were aliquotted into tubes for the various assays , and stored at 80c for later analyses .
hemoglobin , reactive oxygen metabolites ( droms ) , ( diacron international , grosetto italy ) , plasma chemistries , and lipid peroxides were measured .
erythrocyte gsh concentration and isotopic enrichment of gsh were measured as described next ( 12 ) .
briefly , duplicate aliquots of 1 ml whole blood were centrifuged to separate packed cells and measure gsh and glutamate , cysteine , and glycine , respectively .
the first aliquot of packed erythrocytes was washed thrice with normal saline and 1 ml of monobromobimane ( mbb ) buffer ( 5 mmol / l mbb , 17.5 mmol / l na2edta , 50 mmol / l potassium phosphate , 50 mmol / l serine , and 50 mmol / l boric acid ) was added .
cells were immediately lysed by rapid freeze - thaw with liquid nitrogen , and the erythrocyte - mbb buffer mixture was shaken and left in the dark at room temperature for 20 min for development of the gsh - mbb derivative . after adding 0.5 ml of 20% perchloric acid ,
the sample was centrifuged , and the supernatant containing the mbb derivative was sealed and frozen at 80c for later analysis of gsh .
concentrations of gssg were measured by first converting oxidized glutathione to reduced glutathione with the addition of a reducing agent ( 5 mmol / l dithiothreitiol ) and measuring this as total gsh ; the calculated difference between total gsh and reduced gsh is the concentration of gssg .
erythrocyte gsh was isolated as an red blood cell - free aliquot , and the concentration measured high - performace liquid chromatography ( waters , milford , ma ) using a 717 plus autosampler complexed to a 2475 fluorescent detector and equipped with a reverse - phase ods hypersil column ( 5 m , 4.6 200 mm ; waters ) .
elution of gsh was accomplished with a 313.5% acetonitrile linear gradient in 1% acetic acid ( ph 4.25 ) at a flow rate of 1.1 ml / min .
the gsh eluate was collected using a fraction collector , dried , and hydrolyzed for 4 h in 4 mol / l hcl at 110c .
a 1-ml aliquot of blood was centrifuged , and erythrocytes were then washed thrice with 3 ml sodium chloride solution ( 9 g / l ) .
rbcs were then lysed by freeze - thaw action with the use of liquid nitrogen , and cellular proteins were precipitated by using 10% perchloric acid solution .
after centrifugation , the supernatant fluid was used for erythrocyte free amino acid analysis . before derivatization for gas chromatographic
mass spectrometric analysis , erythrocyte - free glycine was isolated by cation - exchange ( dowex 200 ; bio - rad laboratories , hercules , ca ) chromatography .
samples of glycine derived from erythrocyte glutathione and plasma and erythrocyte - free glycine samples were converted to the n - propyl ester , heptafluorobutyramide derivative .
the tracer - to - tracee ratio for glycine in various samples was determined by negative chemical ionization gas chromatographic
mass spectrometric analysis with selective monitoring of ions at mass - to - charge ratios of 293295 on an agilent 6980 gas chromatograph complexed to a 5973 mass spectrometer ( agilent technologies , wilmington , de ) .
erythrocyte amino acid concentrations were determined by high - performace liquid chromatography analysis with a waters system ( millipore , milford , ma ) .
to assess the level of oxidative stress , the derivatives of droms were determined in serum .
briefly , plasma is reacted with an acidic acetate buffer ( ph 4.8 ) , which liberates transition metal ions that catalyze the decomposition of the hydroperoxides to alkoxy and peroxyl radicals . these newly formed radicals in turn oxidize the spectrophotometric marker ( n , n - diethyl - p - phenylenediamine ) , which is detectable by absorption at 505 nm as ucarr ( where 1 ucarr is equal to 0.8 mg / l hydrogen peroxide ) .
briefly , this was measured using freshly prepared buffers containing ammonium ferrous sulfate , xylenol orange , h2so4 , bht in 90% vol / vol methanol , and triphenylphosphine in methanol .
heparinized blood was centrifuged , and 10 l of 10 mmol / l tpp solution was added to 90 l of plasma ( control vials ) then 10 l of methanol was added ( test vials ) , and this solution was incubated at room temperature for 30 min . after adding appropriate buffers , each vial was incubated at room temperature for 30 min , centrifuged , and the absorbance of the supernatant was determined by spectrophotometry .
the hydroperoxide content was determined from test controls and assayed against the standard curve ( 13 ) .
the fractional synthesis rate ( fsr ) of erythrocyte gsh ( fsrgsh ) was calculated according to the precursor - product equation : fsrgsh ( % /day ) = ( irt7 irt5)/(irrbc 1,200/t7 t5 ) , where irt7 irt5 is the increase in the isotope ratio of erythrocyte gsh - bound glycine between the fifth and seventh hours of infusion , when the isotope ratio of erythrocyte - free glycine , irrbc , had reached a steady state .
the absolute synthesis rate ( asr ) of erythrocyte gsh per day was calculated as follows : asr = erythrocyte gsh concentration fsr .
the units of asr are expressed as micromols of gsh per gram of hemoglobin per day .
an independent unpaired t test was used to compute differences in means between the diabetic group presupplementation and the control group and also between the diabetic group postsupplementation and the control group .
differences in outcome measures in the diabetic patients studied pre- and postsupplementation was determined using a paired t test .
data analysis was performed with the statmate statistical software ( graphpad software , la jolla , ca ) .
the average ages of the control and diabetic subjects were 50.4 3.8 and 51.0 3.1 years , respectively ( table 1 ) .
there were no group differences in bmi , hematocrit and hemoglobin concentrations , renal functions , or liver enzymes .
the control subjects were euglycemic , whereas the diabetic subjects had significantly higher fasting glucose concentrations and glycosylated hemoglobin .
there were no differences in hematologic parameters , renal function , or liver enzymes before or after cysteine and glycine supplementation in the diabetic group .
clinical , hematological , and biochemical characteristics of nondiabetic control subjects and pretreatment and posttreatment data for subjects with type 2 diabetes * nondiabetic control subjects versus diabetic subjects : pre - treatment .
subjects with poorly controlled diabetes had 73.8% lower erythrocyte - reduced glutathione concentrations ( 6.75 0.47 vs. 1.65 0.16 mol / g hb ;
1a ) and higher concentrations of erythrocyte - oxidized gssg ( 0.10 0.01 vs. 0.33 0.07 mol / g hb ; p < 0.05 ) . compared with control subjects , total glutathione concentrations ( 6.75 0.47 vs. 1.65 0.16 mol / g hb ;
p < 0.001 ) and the ratio of gsh to gssg were both significantly lower in diabetic subjects ( 59.15 4.12 vs. 6.30 1.30 ; p < 0.001 ) .
diabetic subjects also had 43.4% slower gsh fsr ( 79.21 5.75 vs. 44.86 2.87%/day ; p < 0.001 ) and 85.5% slower asr ( 5.26 0.61 vs. 0.74 0.10 mol / g hb / day ; p < 0.001 ) ( figs .
diabetic subjects also had significantly lower rbc concentrations of glycine ( 514.7.7 33.1 vs. 403.2 18.2
mol / l ; p < 0.01 ) and cysteine ( 25.2 1.5 vs. 17.8 1.5 , mol / l ; p < 0.01 ) but not glutamate ( 530.1 88.3 vs. 451.5 120.7
diabetic subjects received treatment with cysteine and glycine supplementation for 14 days , and this led to 85.1% increase in erythrocyte gsh fsr ( 44.86 2.87 vs. 83.03 3.66%/day ; p < 0.001 ) , resulting in a 64.4% increase in erythrocyte gsh concentrations ( 1.65 0.16 vs. 2.72 0.15 mol / g hb ;
p < 0.001 ) and a 193.8% increase in gsh asr ( 0.74 0.10 vs. 2.17 0.17 mol gsh / g hb / day ; p < 0.001 ) .
precursor supplementation increased gsh fsr to the level of nondiabetic control subjects and led to significant increases in gsh concentrations and gsh asr .
however , when gsh concentrations and asr were compared between diabetic subjects and control subjects diabetic after supplementation , they remained at 59.7% ( 2.72 0.15 vs. 6.75 0.47 mol gsh / g hb ;
p < 0.001 ) and 58.7% ( 0.74 0.10 vs. 5.26 0.61 mol gsh / g hb / day ; p < 0.001 ) lower , respectively , in the diabetic subjects postsupplementation ( figs .
c ) . compared with presupplementation values , the post supplementation values of erythrocyte concentrations of gssg ( 0.33 0.07 vs. 0.28 0.07 mmol / g hb ;
p = ns ) and the ratio of gsh to gssg ( 6.30 1.30 vs. 12.63 3.15 ; p = ns ) did not change significantly .
the slower rates of gsh synthesis in the diabetic subjects at baseline were associated with significantly higher concentrations of markers of oxidative damage ( plasma droms and lipid peroxides ) ( table 1 ) than in control subjects .
after 14 days of cysteine and glycine supplementation , there was a significant fall in these parameters in the diabetic subjects , although not to the levels observed in the nondiabetic control subjects .
the average ages of the control and diabetic subjects were 50.4 3.8 and 51.0 3.1 years , respectively ( table 1 ) .
there were no group differences in bmi , hematocrit and hemoglobin concentrations , renal functions , or liver enzymes .
the control subjects were euglycemic , whereas the diabetic subjects had significantly higher fasting glucose concentrations and glycosylated hemoglobin .
there were no differences in hematologic parameters , renal function , or liver enzymes before or after cysteine and glycine supplementation in the diabetic group .
clinical , hematological , and biochemical characteristics of nondiabetic control subjects and pretreatment and posttreatment data for subjects with type 2 diabetes * nondiabetic control subjects versus diabetic subjects : pre - treatment .
compared with nondiabetic control subjects , subjects with poorly controlled diabetes had 73.8% lower erythrocyte - reduced glutathione concentrations ( 6.75 0.47 vs. 1.65 0.16 mol / g hb ;
1a ) and higher concentrations of erythrocyte - oxidized gssg ( 0.10 0.01 vs. 0.33 0.07 mol / g hb ; p < 0.05 ) . compared with control subjects , total glutathione concentrations ( 6.75 0.47 vs. 1.65 0.16 mol / g hb ;
p < 0.001 ) and the ratio of gsh to gssg were both significantly lower in diabetic subjects ( 59.15 4.12 vs. 6.30 1.30 ; p < 0.001 ) .
diabetic subjects also had 43.4% slower gsh fsr ( 79.21 5.75 vs. 44.86 2.87%/day ; p < 0.001 ) and 85.5% slower asr ( 5.26 0.61 vs. 0.74 0.10 mol / g hb / day ; p < 0.001 ) ( figs .
compared with control subjects , diabetic subjects also had significantly lower rbc concentrations of glycine ( 514.7.7 33.1 vs. 403.2 18.2
mol / l ; p < 0.01 ) and cysteine ( 25.2 1.5 vs. 17.8 1.5 , mol / l ; p < 0.01 ) but not glutamate ( 530.1 88.3 vs. 451.5 120.7
control subjects versus diabetes pretreatment , p < 0.001 ; diabetes pretreatment versus diabetes posttreatment , p < 0.001 ) .
diabetic subjects received treatment with cysteine and glycine supplementation for 14 days , and this led to 85.1% increase in erythrocyte gsh fsr ( 44.86 2.87 vs. 83.03 3.66%/day ; p < 0.001 ) , resulting in a 64.4% increase in erythrocyte gsh concentrations ( 1.65 0.16 vs. 2.72 0.15 mol / g hb ;
p < 0.001 ) and a 193.8% increase in gsh asr ( 0.74 0.10 vs. 2.17 0.17 mol gsh / g hb / day ; p < 0.001 ) .
precursor supplementation increased gsh fsr to the level of nondiabetic control subjects and led to significant increases in gsh concentrations and gsh asr .
however , when gsh concentrations and asr were compared between diabetic subjects and control subjects diabetic after supplementation , they remained at 59.7% ( 2.72 0.15 vs. 6.75 0.47 mol gsh / g hb ;
p < 0.001 ) and 58.7% ( 0.74 0.10 vs. 5.26 0.61 mol gsh / g hb / day ; p < 0.001 ) lower , respectively , in the diabetic subjects postsupplementation ( figs .
c ) . compared with presupplementation values , the post supplementation values of erythrocyte concentrations of gssg ( 0.33 0.07 vs. 0.28 0.07 mmol / g hb ;
p = ns ) and the ratio of gsh to gssg ( 6.30 1.30 vs. 12.63 3.15 ; p = ns ) did not change significantly .
the slower rates of gsh synthesis in the diabetic subjects at baseline were associated with significantly higher concentrations of markers of oxidative damage ( plasma droms and lipid peroxides ) ( table 1 ) than in control subjects .
after 14 days of cysteine and glycine supplementation , there was a significant fall in these parameters in the diabetic subjects , although not to the levels observed in the nondiabetic control subjects .
the results of this study demonstrate that intracellular concentrations of gsh , as well as of its precursor amino acids cysteine and glycine , are decreased in adult patients with poorly controlled type 2 diabetes compared with nondiabetic subjects . whereas previous studies also have found that diabetic patients have deficient cellular levels of gsh ( 35 ) , the present data go further to demonstrate that the gsh deficiency seems to be attributed to a markedly lower synthetic rate of gsh and
fourteen days of oral dietary supplementation with cysteine and glycine in diabetic subjects restored the fractional synthesis rates of gsh to those observed in nondiabetic control subjects . this was accompanied by significant declines in both oxidative stress and plasma markers of oxidant damage .
suboptimal restoration of the absolute synthesis rate of gsh after cysteine and glycine supplementation , despite full normalization of its fractional synthesis , suggests that there is also persistent , accelerated consumption of gsh in diabetic patients with uncontrolled hyperglycemia .
furthermore , although the levels of the oxidative stress markers were significantly diminished after 2 weeks of precursor supplementation , they did not attain the low levels observed in the nondiabetic control subjects
. a longer duration of intervention may be required to normalize synthesis and intracellular concentrations of gsh .
gsh is a tripeptide of glutamate , cysteine , and glycine , and measurement of these amino acids within erythrocytes showed low levels of cysteine and glycine but not of glutamate .
deficiency of cysteine and glycine in diabetic humans also has been reported previously in the literature ( 14 ) . because catabolic processes of virtually all amino acids cycle through glutamate production , it is not surprising that glutamate levels were not different from those of nondiabetic subjects .
the deficiency in cysteine and glycine is intriguing because both these amino acids traditionally are considered to be
nonessential , meaning that they can be synthesized endogenously . why are patients with uncontrolled type 2 diabetes unable to synthesize cysteine and glycine adequately ?
the plasma flux of a nonessential amino acid results from the sum of its rate of release from protein breakdown , de novo synthesis , and dietary absorption .
studies evaluating protein turnover in diabetic patients have reported abnormal overall protein balance ( 15 ) , and disruption of metabolic pathways resulting from hyperglycemia could impose higher dietary protein requirements ( 15 ) .
hence , a combination of impaired protein turnover and dietary deficiency could underlie inadequate availability of cysteine and glycine for gsh synthesis in type 2 diabetes .
additional studies are needed to evaluate the mechanisms underlying decreased availability of cysteine and glycine in type 2 diabetes .
although the exact mechanisms underlying cysteine and glycine deficiency in type 2 diabetes are not clear , the net result of this deficiency could have a domino effect leading to oxidative stress and tissue damage .
first , gsh synthesis would be blunted , and this would result in a critical imbalance between gsh - driven antioxidant protection and the harmful effects of unopposed elevated oxidative stress in uncontrolled diabetes .
deficiency of sulfur amino acids ( 16 ) or protein content ( 17 ) in the diets of healthy humans has been previously shown to result in suppression of gsh turnover in vivo .
further , animals fed diets specifically lacking gsh precursor amino acids , especially cysteine , develop gsh deficiency ( 1821 ) .
together with the present findings , these data indicate that an important underlying cause for intracellular gsh deficiency in diabetes is decreased in vivo gsh synthesis because of a reduced availability of the precursor amino acids cysteine and glycine .
could the lower concentrations of gsh be a result of impaired cycling between its oxidized and reduced isoforms , with a greater proportion of glutathione trapped as the oxidized form ? to answer this question , we also measured concentrations of total gsh by converting oxidized glutathione to its reduced isoform with a reducing agent , and found that subjects with diabetes still had significantly lower concentrations of total glutathione .
this suggests that in poorly controlled type 2 diabetes , there is a true deficiency of glutathione .
sustained hyperglycemia is linked to increased oxidative stress , and with an increased risk of diabetic microvascular and macrovascular complications .
mechanisms implicated in hyperglycemia - driven tissue damage in diabetes include abnormal signaling through protein kinase c , elevated advanced glycation end products , and the aldose reductase pathway ( 1 ) .
ros is known to stimulate these pathways by activation of aldose reductase , protein kinase c isoforms , and nuclear factor-b and induction of diacylglycerol and advanced glycation end - product formation ( 22 ) .
lowering levels of mitochondrial ros ( and thereby oxidative stress ) successfully prevents activation and induction of these mechanisms ( 23 ) .
because ros production is increased by hyperglycemia , optimizing glycemic control in diabetic subjects should decrease ros , but , in clinical practice , normalizing glycemia remains a major challenge in diabetes management .
do not attain the american diabetes association 's recommended glycemic goals , and 67% do not attain the more stringent glycemic targets of the american association of clinical endocrinologists .
therefore , interventions directly aimed at lowering ros - mediated oxidative stress are needed to prevent diabetic tissue damage even in the presence of hyperglycemia .
the present data suggest that increasing gsh levels with oral precursor supplementation is a viable intervention to target diabetic oxidative stress directly and could constitute a novel , safe , and inexpensive form of nutritional treatment .
when used as an adjunct to standard glycemic management , this approach could significantly attenuate tissue damage due to oxidative stress in patients with diabetes . in conclusion , these data show that an important reason underlying elevated oxidative stress in type 2 diabetes is deficiency of glutathione , which occurs because of the decreased synthesis caused by limited availability of the precursor amino acids cysteine and glycine .
dietary supplementation of these amino acid precursors restores fractional synthesis of gsh and significantly reduces oxidative stress and markers of oxidant damage .
providing supplemental cysteine and glycine in the diet could be a safe , inexpensive , and innovative approach to increase gsh synthesis and concentrations and thus combat oxidative stress and prevent chronic complications in patients with diabetes .
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### Summary:
: objectivesustained hyperglycemia is associated with low cellular levels of the antioxidant glutathione ( gsh ) , which leads to tissue damage attributed to oxidative stress .
we tested the hypothesis that diminished gsh in adult patients with uncontrolled type 2 diabetes is attributed to decreased synthesis and measured the effect of dietary supplementation with its precursors cysteine and glycine on gsh synthesis rate and oxidative stress.research design and methodswe infused 12 diabetic patients and 12 nondiabetic control subjects with [ 2h2]-glycine to measure gsh synthesis .
we also measured intracellular gsh concentrations , reactive oxygen metabolites , and lipid peroxides .
diabetic patients were restudied after 2 weeks of dietary supplementation with the gsh precursors cysteine and glycine.resultscompared with control subjects , diabetic subjects had significantly higher fasting glucose ( 5.0 0.1 vs. 10.7 0.5 mmol / l ; p < 0.001 ) , lower erythrocyte concentrations of glycine ( 514.7 33.1 vs. 403.2 18.2
mol / l ; p < 0.01 ) , and cysteine ( 25.2 1.5 vs. 17.8 1.5 mol / l ; p < 0.01 ) ; lower concentrations of gsh ( 6.75 0.47 vs. 1.65 0.16 mol / g hb ;
p < 0.001 ) ; diminished fractional ( 79.21 5.75 vs. 44.86 2.87%/day ; p < 0.001 ) and absolute ( 5.26 0.61 vs. 0.74 0.10 mol / g hb / day ; p < 0.001 ) gsh synthesis rates ; and higher reactive oxygen metabolites ( 286 10 vs. 403 11 carratelli units [ ucarr ] ; p < 0.001 ) and lipid peroxides ( 2.6 0.4 vs. 10.8 1.2 pg / ml ; p < 0.001 ) .
following dietary supplementation in diabetic subjects , gsh synthesis and concentrations increased significantly and plasma oxidative stress and lipid peroxides decreased significantly.conclusionspatients with uncontrolled type 2 diabetes have severely deficient synthesis of glutathione attributed to limited precursor availability .
dietary supplementation with gsh precursor amino acids can restore gsh synthesis and lower oxidative stress and oxidant damage in the face of persistent hyperglycemia .
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: although magnus was the first to describe the opercular syndrome in 1837 , the syndrome is also known as foix - chavany - marie syndrome named after the french authors who described the syndrome in 1926 .
the classical opercular syndrome presents with loss of voluntary facial , pharyngeal , lingual , and mastication movements .
reflexive and automatic movements with the exception of the gag reflex , are being preserved .
usually the gag reflex is decreased or absent [ 1 , 13 , 22 ] .
automato - voluntary dissociation of movements with the muscles of the larynx , pharynx , tongue , lips , and cheeks has been described in oral apraxia as well [ 1 , 8 ] .
bilateral abnormality of the opercular cortex forms the neuroanatomical basis of the opercular syndrome in the classical cases .
multiple strokes form the major etiology of this syndrome [ 13 , 23 ] . the voluntary phase of the swallowing act is severely affected in the majority of these patients while reflex swallowing is preserved [ 1 , 13 , 22 ] .
very often , patients with opercular syndrome receive percutaneous endoscopic gastrostomy ( peg ) tube feeding . in this case study , a new treatment for dysphagia consisting of neuromuscular electrical stimulation applied on a patient diagnosed with opercular syndrome ,
three years ago , a 76-year - old male was referred to the department of neurology because of the sudden onset of difficulty to speak and weakness of the right arm .
six months later he experienced a second stroke with inability to speak or swallow and a paralysis of the left arm . during neurologic examination no voluntary movements of the jaw , lips or tongue were present . a bilateral dysfunction of the 5th
, 7th , 9th , 10th , and 12th cranial nerves was found with the exception of the automatic movements of the same muscles .
although the presence of the swallowing reflex was clinically observed , the patient totally depended on nasogastric tube feeding because of massive aspiration , including his own saliva .
besides the earlier left - sided cortical infarction , the mri - scan showed diffuse atrophy of the brain .
an infarction was diagnosed in the right pre- and post - central convolutions . also , right - sided subcortical lacunar foci were seen ( fig . 1 ) .
the scan shows diffuse atrophy of the brain , an old left - sided cortical infarction , a new infarction in the right pre- and post - central convolutions , and right - sided subcortical lacunar foci mri scan performed after the second stroke .
the scan shows diffuse atrophy of the brain , an old left - sided cortical infarction , a new infarction in the right pre- and post - central convolutions , and right - sided subcortical lacunar foci despite initial logopedic dysphagia treatment during the first year after the second stroke , the dysphagia did not improve and the patient fully depended on peg tube feeding .
he was referred to the dysphagia clinic and offered neuromuscular electrical stimulation of the muscles involved in the swallowing act simultaneous with logopedic dysphagia treatment . during 5 months , the patient received treatment sessions of 1 h each , on five consecutive days per week . the major treatment goals are to improve the hyolaryngeal elevation and to stimulate the sensory input that may facilitate volitional triggering of swallowing in dysphagia [ 16 , 17 ] .
two dual channel modified hand - held battery - powered electrical stimulators ( vitalstim therapy ; frequency 80 hz , pulse width 700 s , chattanooga group , chattanooga , tn , usa ) were used by an experienced speech therapist .
the initial intensity of the electrical current was 6.5 ma in position a
2a ) using two sets of snap skin electrodes , located on each side of the midline , above and beneath the lesser horns of the hyoid bone , on the mylohyoid muscles , and on the thyrohyoid muscles . position b ( fig .
2b ) using one set of electrodes , located on each side of the mouth , on the orbicularis oris muscle and the masseter muscles . the highest electrical current level the patient could tolerate , resulting in maximum muscle contraction without spasm ,
was applied as maximum motor level in position a and b .
during the following sessions , the position b and the combination of position a with b were alternatively applied with increasing intensity of the electrical current up to 17.5 ma for position b and 10.0 ma for position a. logopedic dysphagia treatment was given simultaneously with electrical stimulation .
initial small amounts ( 2 till 5 ml ) of thickened liquids were offered to the patient progressively followed by the intake of various food consistencies , using swallowing manoeuvres [ 6 , 15 ] .
fig .
a on each side of the midline , above and beneath the lesser horns of the hyoid bone , on the mylohyoid muscles , and on the thyrohyoid muscles .
b on each side of the mouth , on the orbicularis oris muscle and the masseter muscles the position of the skin electrodes . a on each side of the midline , above and beneath the lesser horns of the hyoid bone , on the mylohyoid muscles , and on the thyrohyoid muscles .
b on each side of the mouth , on the orbicularis oris muscle and the masseter muscles before and after treatment , a clinical assessment ( table 1 ) was performed by the speech therapist using an oral motor function test ( 5-point scale ) and a functional oral intake scale for dysphagia according to crary .
no considerable difference of voluntary control of swallowing was present at the end of therapy as was confirmed by the patient s inability to perform six out of seven voluntary exercises of the oral motor function test .
only minor movements of the lips were observed while the speech therapist was presenting oral movements as imitative tasks . during therapy
the functional oral intake scale showed changes from peg tube feeding to oral diet with multiple consistencies requiring special preparation or compensations .
however , the patient s extreme weak condition and inability to swallow without great risk of massive aspiration , did not allow a pretreatment videofluoroscopic examination ( vfs ) , neither a fiberoptic endoscopic evaluation of swallowing ( fees ) . after therapy , both assessment techniques were performed successfully .
the fees and videofluoroscopy were judged independently by the speech therapist and laryngologist using the penetration - aspiration scale according to rosenbek ( table 1 ) .
table 1pre- and post - treatment measurements [ 5 , 14 , 21]measurementpretreatmentposttreatmentoral motor function test ( seven exercises scored on a five - point scale ; 0 = normal ; 4 = total disability)28 pointsunable to perform voluntary oral motor exercises26 pointsunable to perform six out of seven voluntary oral motor
exercisesfunctional oral intake scale for dysphagia level 1 : nothing by mouthlevel 5 : total oral diet with multiple consistencies , requiring special preparation or compensationsfees ( 3 5 ml thin and 3 5 ml thickened liquid boluses ) 1 .
penetration - aspiration scale ( 1 = normal , 6 = material enters the airway , passes below the vocal folds and is ejected into the larynx or out of the airway)2 . pharyngeal delay time3 .
. mild symmetrical pooling in the pyriform cavities after swallowing thin- and thick - ened liquidsvideofluoroscopy ( 3 10 ml high - density barium boluses ) penetration - aspiration scalenot feasible because of massive aspirationscore of six during first swallowing attempt.score of one during second and third swallowing attemptfunctional oral intake scale for dysphagia ( crary et al . ) level 1 : nothing by mouth ; level 2 : tube dependent with minimal attempts of food or liquid ; level 3 : tube dependent with consistent oral intake of food or liquid ; level 4 : total oral diet of a single consistency ; level 5 : total oral diet with multiple consistencies , but requiring special preparation or compensations ; level 6 : total oral diet with multiple consistencies without special preparation , but with specific food limitation ; level 7 : total oral diet with no restrictions.oral motor function test1 .
blow up the cheeks while the mouth is closed . then press a finger against the left cheek and the right cheek a couple of times , while keeping the mouth closed .
open the mouth and move the tongue as far as possible to the left.6 . while the tip of the tongue pushes into the left cheek , press a finger against the tongue .
( if there is normal tongue strength it should be possible to resist mild finger pressure.)7 . while the tip of the tongue pushes into the right cheek , press a finger against the tongue .
( if there is normal tongue strength it should be possible to resist mild finger pressure.)the test should be evaluated according to the scale below.scale0 normal1 mild dysfunction2 moderate dysfunction3 severe dysfunction4 impossible to perform pre- and post - treatment measurements [ 5 , 14 , 21 ] functional oral intake scale for dysphagia ( crary et al . )
level 1 : nothing by mouth ; level 2 : tube dependent with minimal attempts of food or liquid ; level 3 : tube dependent with consistent oral intake of food or liquid ; level 4 : total oral diet of a single consistency ; level 5 : total oral diet with multiple consistencies , but requiring special preparation or compensations ; level 6 : total oral diet with multiple consistencies without special preparation , but with specific food limitation ; level 7 : total oral diet with no restrictions .
2 . blow up the cheeks while the mouth is closed . then press a finger against the left cheek and the right cheek a couple of times , while keeping the mouth closed .
4 . open the mouth and move the tongue as far as possible to the right 5 .
6 . while the tip of the tongue pushes into the left cheek , press a finger against the tongue .
( if there is normal tongue strength it should be possible to resist mild finger pressure . )
7 . while the tip of the tongue pushes into the right cheek , press a finger against the tongue .
( if there is normal tongue strength it should be possible to resist mild finger pressure . )
the test should be evaluated according to the scale below . 2 moderate dysfunction 4 impossible to perform during the posttreatment fees , the patient identified sensory testing correctly .
the oral transit was severely insufficient so that the bolus had to be positioned at the base of the tongue by means of a tablespoon to initiate the swallowing reflex .
the pharyngeal delay time was measured from the moment the bolus was positioned at the base of the tongue until the swallowing reflex was triggered while the endoscopic image was in the home position .
the pharyngeal delay time was less then 0.40 s for both thin and thickened liquid boluses of 5 ml . after swallowing , mild symmetrical pooling in the pyriform cavities
was observed without laryngeal penetration nor aspiration , resulting in a score of one on the penetration - aspiration scale . during the first attempt of the posttreatment vfs ( 3 10 ml high - density barium boluses ) , minor aspiration during swallowing was observed .
the response of the patient to aspiration was six on the penetration - aspiration scale ( table 1 ) . during the two other swallowing attempts ,
neither penetration nor aspiration was observed . in conclusion , posttreatment , dysphagia with minor diet restrictions , consisting of multiple consistencies requiring special preparation , was observed .
one year after therapy , the patient s clinical condition has not changed ; he is still on oral diet without pneumonia .
the primary neural pathway for voluntary swallowing is blocked in the opercular syndrome [ 1 , 13 , 22 ] .
the voluntary control of the oral musculature is absent , resulting in disuse of the swallowing musculature , with preservation of the reflexes like the swallowing reflex . in general , disuse of striated muscles
electrical stimulation is a well - documented clinical method of augmenting muscle performance in both normal and paralyzed muscles [ 7 , 11 , 20 ] .
some studies report an increase in contractile qualities and muscle force after electrical stimulation . according to hainaut et al .
nmes as a training modality is not a substitute for , but a complement of voluntary exercise of disused and healthy muscles . in this patient ,
it can also initiate muscle re - education [ 10 , 16 ] and may create a relearning process of the brain in controlling the muscles responsible for the swallowing act .
found that surface electrical stimulation of the thyrohyoid muscles helps to improve the swallow function by optimized hyolaryngeal elevation .
observed that paired intramuscular stimulation of the mylohyoid and/or thyrohyoid muscles produced about 50% of the laryngeal elevation with about 80% of the velocity that normally occurs during a swallow .
hyolaryngeal elevation plays an important role in the cricopharyngeal opening [ 4 , 16 ] . according to ludlow et al .
sensory levels of surface electrical stimulation may facilitate triggering of swallowing in dysphagia . in this patient
, the muscles involved in swallowing were presumed to be atrophied because of disuse due to complete loss of voluntary control and peg tube feeding .
it is hypothesized , that in this patient after surface electrical stimulation combined with logopedic dysphagia treatment , an improvement of the reflexive and automatic movements during the swallowing act appeared , based on an increase of contractile qualities and muscle force . despite the fact that a pretreatment fees and a videofluoroscopic examination could not be performed in this patient , posttreatment improved muscle force resulting in improvement of amplitude of the hyolaryngeal elevation , and improvement of the cricopharyngeal opening during the reflexive phase of the swallowing act , are presumed . despite some movements of the lips , the voluntary control of
a second hypothesis is based on nmes serving as a cue to break through the apraxia . in literature , some patients with opercular syndrome have been described as suffering from buccofacial and/or verbal apraxia , especially those with lesions extending to broca`s area .
non - verbal oral movements , being less complex than articulatory movements , may recover in some cases of oral apraxia . during the treatment consisting of logopedic dysphagia training combined with nmes ,
this phenomenon could explain some voluntary oral movements in this patient during the application of nmes without imitative tasks at the end of therapy .
no universal accepted protocol for surface electrical stimulation for dysphagia , including intensity of the current , frequency and length of the treatment , does exist at the moment .
neuromuscular electrical stimulation as a treatment for dysphagia has been documented in the literature rarely .
this case report describes the possibility of neuromuscular electrical stimulation to treat dysphagia in the opercular syndrome .
neuromuscular electrical stimulation as a treatment for dysphagia is a promising paramedical technology that has to be studied further to specify the treatment protocol as well as the medical indications .
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### Summary:
: a 76-year - old man with opercular syndrome characterized by complete bilateral loss of voluntary control of facial , lingual , pharyngeal and masticatory muscles is presented with focus on the severe dysphagia .
three years earlier the patient had experienced two strokes resulting in opercular syndrome with severe dysphagia . despite initial logopedic dysphagia treatment ,
swallowing did not improve .
a new treatment for dysphagia , consisting of neuromuscular electrical stimulation was applied on the patient .
he returned to oral feeding .
clinical and treatment observations are reported .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the focus of policy , media and many academic discourses on drugs in sport has been upon cheating and negative health outcomes ( gleaves , 2010 ; simon , 2004 ) .
these are the two main underlying reasons for the funding and implementation of anti - doping testing , and the subsequent legal and quasi - legal process aimed at punishing the cheats .
the development of organised international anti - doping policy has been based on these central tenets since the 1960s ( beamish & ritchie , 2004 ; dimeo , 2007 ; hunt , dimeo , & jedlicka , 2012 ) .
more recently , the world anti - doping agency ( wada ) included a third guideline known as the spirit of sport .
for a substance or technique to be banned , it would have to contravene two of these three : fair play , health of the athlete and the spirit of sport ( wada , 2009 ) .
previous research on doping in cycling has focused on the professional level ( mignon , 2003 ; ohl , fincoeur , lentillon - kaestner , defrance , & brissonneau , 2013 ; sefiha , 2012 ; waddington , 2000 ) , while largely neglecting the lower amateur levels of sport and masters competitors in higher age categories . in this study , we focus on the cases of all american cyclists , amateur and professional , who were caught doping and sanctioned during the period 2001 and summer 2014 .
the range of cases includes athletes whose intentions to cheat others are not obvious , as athletes may have used recreational drugs like cannabis , used medicines that contained banned drugs without realising it , or bought and used nutritional supplements contaminated with banned substances .
taking a broader view of us cycling that includes amateurs exposes patterns of doping behaviour beyond the narrow perspective of a small number of professionals whose motivations clearly lies with a desire for financial gain and celebrity status ( backhouse , mckenna , robinson , & atkin , 2007 ; laure & reinsberger , 1995 ) .
lentillon - kaestner and carstairs ( 2010 ) noted doping may occur at any level of competition , asking what happens before cyclists become professional ?
we add an exploration of what happens when cyclists are unlikely to ever become professional or when cyclists compete as older adults .
in addition to elite cases , we describe and explain the doping culture that emerged in domestic us cycling among amateurs , those who compete at the lower categories of cycling , and semi - professionals , those who may win large races and prize purses but who do not have contracts with the largest professional teams .
the critical approach adopted here aims to analyse and discuss the nature of policy in practice .
we demonstrate the variety of doping situations and critically assess the outcomes of anti - doping against wada 's stated purpose and the general ideology underpinning anti - doping .
the patterns that emerged starkly contrasted with the policy and media - led demonisation of doping athletes and with common assumptions of extrinsically motivated cheating .
these cases point to possible trends in doping and raise new questions about the fairness of current anti - doping policies .
the united states anti - doping agency ( usada ) was formed in 2000 as the trend globally was to move away from anti - doping being embedded within organisations with a vested interest in maintaining the integrity of their image , towards independent organisations that would be judged by their ability to protect
thus , in parallel to the leadership shifting from the international olympic commission ( ioc ) to wada , the american re - organisation took responsibility away from the us olympic commission and established usada . similarly , the situation within professional cycling had dramatically altered after the 1998 festina scandal , an event that brought forward proposals for an independent global body .
wada increased the pressure on the union cycliste internationale ( uci ) , not least because cycling at the top level had a reputation for allowing doping to occur and not punishing cyclists who did get caught with sufficient bans to act as a deterrent ( hoberman , 2003 ; mller , 2006 ; waddington , 2000 ) .
there had been some precedence of doping behaviours in us cycling , such as the use of blood doping among the olympic team for the 1984 los angeles games ( gleaves , llewellyn , & lehrbach , 2014 ) .
establishing the nature of the doping culture within us cycling in the 1990s is challenging .
even in the extensive evidence presented against lance armstrong the point of origin for his doping decision is not entirely clear , but some evidence would suggest it was in 1995 with motorola ( hamilton & coyle , 2012 ) .
however , matt dicanio and tyler hamilton both explained that their encounters with doping occurred only once they were established within the professional european scene . for hamilton ,
it was in 1997 he made the decision to dope , and he argues that for most professionals of that time period , the realisation that doping was a necessity would come in their second year and their own decision would have to be made in their third year ( hamilton & coyle , 2012 , p. 66 ) .
we would propose , therefore , that the extent of doping within the domestic context was relatively low in the late 1990s on the basis that american professionals learned from european doctors , and as we detail below , evidence of a doping culture really emerges around the time that lance armstrong was winning his seven consecutive tour de france titles .
it should be noted here that it is almost impossible to say with any certainty what the patterns of drug use were .
evidence from testing and the eventual confessions of a small number of professional dopers can offer some indications .
even when higher numbers of cyclists were caught , it may have been the result of the development or refinement of tests for specific drugs , rather than any specific pattern .
many recent scholarly approaches to the study of doping in sport aim to support anti - doping through improving understanding of the contexts of athletes ' lives and training , psychological make - up and the processes through which they are educated ( backhouse & mckenna , 2012 ; morente - snchez & zabala , 2013 ; ntoumanis , ng , barkoukis , & backhouse , 2014 ) .
there have recently been a significant number of approaches to modelling the doping decision , and statistically testing the relevant variables ( bilard , ninot , & hauw , 2011 ; ntoumanis , ng , barkoukis , & backhouse , 2013 ; sas - nowosielski & swiatkowska , 2008 ; tsorbatzoudis , rodafinos , spiliopoulou , barkoukis , & lazuras , 2009 ) .
some of these studies have been funded by wada with the explicit remit to help the fight against drug misuse in sports .
while these studies can be credited for improving the evidence base , there appears to be several unchallenged assumptions : that the decision to dope firstly is a rational , intentional and conscious decision to cheat ( hoff , 2012 ; overbye , knudsen , & pfister , 2013 ) that emerges from inherent psychological traits ( bilard et al .
, 2011 ; petrczi & aidman , 2009 ) combined with environmental pressures ( smith et al . , 2010 ) , secondly is perceived as deviant by athletes and their entourage ( christiansen , 2005 ; pitsch , emrich , & klein , 2007 ) , and lastly that anti - doping is a legitimate and fair policy that functions to catch dopers and deter potential dopers ( martin , baron , & gold , 2006 ; mazanov , huybers , & connor , 2011 ) .
however , it could be more critically argued among this wealth of recent empirical knowledge there has not yet been a study that shows the variety of doping situations and describes patterns of doping behaviour according to this variety , despite the availability of information on every sanctioned athlete ( yonamine , garcia , & de moraes moreau , 2004 ) .
dopers are not homogenous and there is a significant conceptual and real difference between someone who systematically dopes over a period of time , and many innocuous doping situations ( see ramachandra et al . , 2012 ; strelan & boeckmann , 2006 ) .
the social groupings affected by anti - doping are much more diverse than previous studies have considered where the focus has been on the extrinsically motivated elite and aspiring elite , male athletes and their use or potential use of peds ( bloodworth & mcnamee , 2010 ; christiansen , 2010 ; outram & stewart , 2015 ) .
this narrow focus has left gaps in the existing research , overlooking patterns of behaviours , motivations and situations occurring outside the upper reaches of the sport . beyond the level of the individual and their immediate circumstances ,
some recent historical , sociological and policy analyses of anti - doping have driven towards a more critical deconstruction of ideological principles , common sense claims , self - governance of international agencies and the equity of policy decisions ( denham , 2011 ; hanstad & waddington , 2009 ; kayser & broers , 2012 ; stewart & smith , 2008 ; straubel , 2008 ; wiesing , 2011 ) . mller ( 2014 ) has used the term corrupt idealism to frame his criticism of anti - doping leaders who are willing to accept or indeed promote unethical behaviour in order to support the
there are cases of athletes who likely did not intend to violate anti - doping regulations , such as those who unintentionally ingested a banned substance ( cox , 2014 ; pluim , 2008 )
. there may be others who failed to acquire a therapeutic use exemption ( tue ) but were following orders from their personal physician , risking a positive test and a sanction ( fitch , 2013 ; overbye & wagner , 2013 ) .
however , under wada 's strict liability principle all athletes are held to account for the presence of any detected banned substance , regardless of their intent ( cox , 2014 ) .
there are numerous examples from a range of sports where athletes have been punished for inadvertently breaking the rules .
thus , it may be that the war on drugs in sport has been so heavily skewed towards the claimed outcomes of catching cheats that relatively innocent athletes who did not intend to enhance performance ( pluim , 2008 ) are swept up , in a sense becoming collateral damage
the critical approach adopted here therefore aims to analyse and discuss the nature of policy in practice .
we use a case study to demonstrate the variety of doping situations and critically assess the outcomes of anti - doping against wada 's stated purpose and the general ideology underpinning anti - doping .
the social groupings affected by anti - doping are much more diverse than previous studies have considered where the focus has been on elite , male athletes .
first , we utilised the on - line records of the national governing body , usa cycling , and the usada , the organisation that caught the us postal riders .
we recorded details of all 88 sub - cases that resulted in a sanction . in our collection
, we included the type of test ( in or out of competition ) , where the test was administered , the type and name of the substance the athlete tested positive for , and the length of the competition ban imposed .
second , we used information available through usa cycling 's website regarding cyclists ' race results and competitive history , categories for racing and cycling discipline ( i.e. track , road ) . though we do not present this data here , it was the basis for identifying the range of case types we identify below . in some instances , the athlete challenged the outcome through the arbitration process .
where this is so , the full details and decision are available through the usada website and were included in the analysis .
third , we also recorded details from news reports of cases that attracted mainstream media attention .
rather than ignore those sub - cases often left out of mass media coverage for lacking a newsworthy aspect , we sought to include these hidden in plain sight accounts in our analysis . to this end , we gathered information from online news sources , some of which were connected to print media and some that are exclusively web based . in most cases , these reports were found in american cycling magazines such as velopress and on websites reporting cycling news .
we used google to search for each cyclists name . in the cases where the name search returned multiple or unrelated results , we entered a second search for the cyclists name with the word doping
in each case this returned at least one relevant result other than the relevant usada press release .
some cyclists had wikipedia pages , though information from these pages was used only where the information source was cited and the source could be confirmed . in cases outside of the widely covered elite doping scandals
however , we agree with laurendeau and moroz ( 2012 ) that we might infer from the relatively small number of articles that the ideas that they produce and reproduce are so commonsense as to generate little controversy and , hence , little ( public ) discussion ( p. 387 ) yet are useful for analysis . many of these lesser - known cases contained details about cyclists motivations and circumstances that contradict those most commonly discussed in the literature on doping .
as such , our findings provide correction to the myopic view of doping within us cycling .
the news reports on each sub - case were collected and analysed for details of any response to the test result by the athlete , such as an admission or denial of intent , or for any alternative explanation for the positive result .
often , the news reports functioned to provide background and context for several cases involving lesser or unknown amateur and master cyclists .
there are factual elements of each sub - case such as the length of a sanction , drug type , location where the test was conducted , age of the cyclist , etc . , as well as descriptive and/or subjective elements , including statements by cyclists to sports journalists .
we have analysed and presented the former type of data , then used the latter type to contextualise and highlight aspects of the patterns that emerged from the official records .
we approached these more descriptive data with a sense of critical detachment , though inevitably used our judgment to select key quotes and interpretations to build an overarching argument .
there are , of course , limitations to this form of data collection , not least the reliance on reporters and others to produce reliable accounts . especially with regard to the issue of drugs in sport , sportspersons create particular forms of self - presentation .
dopers who have not been caught claim to be clean , those under suspicion divert blame elsewhere to distract attention , those who are caught usually only admit to the specific offence that has been proven , and even
full confessions can not be trusted ( lamont - mills & christensen , 2008 ) .
similarly , journalists and academic researchers who do access relevant sources are trying to create a version of events that fits dominant ideological and policy paradigms and expectations of readers ( denham , 2011 ; vetteniemi , 2010 ) .
therefore , rather than accepting any one account as the singular truth of a case we cross - referenced journalistic reports with all available information from usa cycling , usada , and the cas and took note of any inconsistencies or contradictions in the journalistic accounts . additionally , we included only professional journalist accounts , and excluded blogs , forums , and other user - generated material , as well as opinion pieces pertaining to the sub - cases from the analysis .
usada 's first tranche of tests in 2000 produced only three adverse analytical findings all of these for ephedrine and the length of bans were zero , one and three months .
however , it would not be long before tests began to catch more serious cheats . through the years from 2002 to 2014 , there was a gradual increase in the number of cyclists who were caught trying to enhance their performance using testosterone , steroids , erythropoietin ( epo ) , growth hormone and blood doping .
these cyclists may have been caught through blood or urine testing , but they may also have received sanctions resulting from a violation such as refusal to submit to a test or through their own admission .
the total number of sanctions in a single year peaked at 15 in 2012 , the result of a long - term usada investigation into the us postal team .
as the us postal team became more successful the doping prevalent in european cycling seeped into the american context , laying the foundation for a culture of doping to emerge ( brewer , 2002 ; lentillon - kaestner & carstairs , 2010 ; lentillon - kaestner , hagger , & hardcastle , 2012 ; usada , 2012 ) .
it seems clear that elite american cycling had , in a broad sense , accepted the necessity of doping in order to compete in major races against european teams .
this acceptance is evidenced by the extensive doping system detailed in usada 's reasoned decision against lance armstrong ( usada , 2012 ) .
lance armstrong had won several of the world 's top races , including the tour de france ( 19992005 ) .
usada have shown that he was using performance - enhancing drugs for all of those victories , and this is supported by the testimony of many other top american cyclists who also doped for part or all of this time ( usada , 2012 ) . yet
of the 88 total sanctions from 2000 to 2014 , in all types of cycling , the majority of positive tests was for anabolic agents ( 42% ) .
other forms of deliberate cheating were using peptide hormones such as epo ( 26% ) and blood doping ( 5% ) .
the more ambivalent categories are stimulants ( 22% ) that may or may not have been for enhancing performance , and missing / refusing tests ( 11% ) .
a number were sanctioned for non - analytical reasons , including the members of us postal who were subpoenaed by the federal investigators so had to confess .
kayle leogrande 's case is more subtle : he told his team 's soigneur he was worried about being caught and she reported him to usada , suggesting that even the small number of known doping cases were not always the result of good anti - doping control mechanisms .
the endurance - boosting drug epo had been popularised through the 1990s , due to the perceived performance benefit and lack of a test to detect usage ( lundby , achman - andersen , thomsen , norgaard , & robach , 2008 , for development and critique of test ) .
once such a test was developed in 2004 , we could see that domestic cyclists were familiar with the drug : the first positive tests being adham sbeih ( 2004 ) , adam bergman ( 2005 ) , alvaro tardaguila ( 2006 ) and neal schubel ( 2006 ) .
sbeih was a national level competitor ( usa cycling , 2004 ) , bergman was a member of the elite domestic team jelly belly ( knapp , 2004 ) , tardaguila was an amateur rider ( usa cycling , 2006 ) and schubel was a low achiever at masters level ( stokes , 2010 ) .
the canadian woman who raced to a successful level in the usa , genevive jeanson , came to admit using epo for a period of 8 years , beginning when she was 16 years old , from 1997 to 2005 ( cbs sports , 2007 ) .
since there was not a reliable test for epo use until 2004 , it is quite possible that other cyclists were using it before this time , and the lack of systematic testing makes it likely that these cases were the unfortunate ones who were caught rather than the only guilty parties .
moreover , the total number of tests conducted relative to the increased number of competitive cyclists combined with evidence from those who used epo and other drugs without being caught , suggest the prevalence was significantly higher than the handful of positive cases .
the emergence of doping behaviours the taking or using of prohibited substances or methods of performance enhancement depends upon suppliers , and in turn entrepreneurial business - like suppliers were responding to demand ( martin et al . , 2006 ;
stewart & smith , 2008 ) . when joe papp first became part of this history , he was a 32-year - old moderately successful rider who tested positive for 6a - oh - androstenedione and was banned for 2 years .
he was then given a lifetime ban in 2011 for distributing banned drugs ( ford , 2011 ) .
investigators discovered that papp had a client list of 187 individuals , though not all of these were cyclists .
the consequences of further investigations into papp 's customers led to a number of confessions and sanctions , and also provided some indication of wider doping among amateur and semi - professional teams . in 2007 , for example , chuck coyle was given a two - year ban when usada found a record of purchases for epo and insulin growth factor made on his credit card from papp 's website .
however , coyle responded by claiming that some of his younger teammates had borrowed his credit card and laptop computer , which was a common practice in general , to buy the drugs ( rogers , 2010 ) .
other cases seem to indicate a developing pattern of ped use among aspiring , non - elite cyclists . in 2001 ,
semi - professional rider duane dickey tested positive for three banned drugs : phentermine , boldenone and nandrolone ( usa cycling , 2010 ) .
in 2002 , a former member of us postal , kirk o'bee , tested positive for elevated testosterone ( rogers , 2012 ) .
female track cyclist , tammy thomas was given a lifetime ban for a second offence after testing positive for norbolethone in 2002 ( macur , 2004 ) .
these and other similar cases demonstrate that drug use was indeed going on within the ranks of non - professional cycling .
these cases are not directly linked to the 2012 us postal case but are a domestic sub - set of the doping culture that was disseminated from the elite context through the lower levels of the sport .
kayle leogrande 's experience around the same time period helps to illustrate how strongly a doping culture had taken hold in american cycling , including among those cyclists who were not quite at the uppermost echelons of the sport . during the period 20042006 , other professionals
he bought epo from joe papp in 2006 , and had to self - experiment with dosages .
he joined the rock racing team in 2007 where he was introduced to former teammates of lance armstrong 's [ and ] began to dope more regularly
there is no direct connection between leogrande and us postal , except that his eventual admission assisted the federal investigation led by jeff novitzky .
later , travis tygart , chief executive of usada , would say that leogrande 's evidence played a significant role in piecing together the evidence against us postal , perhaps because leogrande speculated that doping would be necessary to compete successfully in the top european races ( ibid . ) . moreover , the former professional floyd landis gave evidence that the owner of the domestic team , rock racing , was involved in doping
thus , we can see the emergence of doping as well as the failings of anti - doping to stop this culture from developing . within a few years of the first epo cases , doping had spread to amateur and masters levels such that organisers of mass participation events felt the requirement to fund and organise testing . in the new york gran fondo in 2012
, two masters - level riders tested positive for epo ( dreier , 2012 ) . yet
, the authorities focused upon the top - level riders , in particular lance armstrong , and have not created an adequate system that would include regular , random in- and out - of - competition testing for the recreational and master levels of cycling .
riders are disadvantaged and most seriously competitive riders would feel under pressure to take part in doping .
level playing field is incongruous here , not least because a wide range of factors influence performance and that doping is an unknown contributing factor to race results .
anti - doping policy did not serve to protect the fairness of sport or indeed the spirit of sport . as evidenced by the official doping cases ,
a sub - culture developed where amateur and semi - professional cyclists came to mimic the behaviours of their professional counterparts and indulged in doping .
while it is hard to be certain about this , it may have been the case that a serious amateur competitor felt the need to participate in doping for reasons of identity , status and belonging within a social environment that respected and emulated those in the higher echelons of the sport .
while such cases pointed to a sub - culture of deliberate , conscious cheating using the most serious of drugs , other cases showed the dilemmatic nature of policy : that not all dopers are created equally .
anti - doping efforts aimed at detecting those who seek to cheat may result in bans for athletes who never intended such .
for example , the three ephedrine cases in 2000 were given shorter bans , suggesting that the authorities did not deem them to be worthy of a full sanction due to the relatively innocuous nature of the substance and the likelihood that it was not intentionally consumed .
these are indicative of a wider pattern wherein the intention to cheat is unsubstantiated yet competition bans still apply .
the chuck coyle episode highlights this , and he was informed that the cost of appealing the decision was around $ 20,000 , so he had no choice but to accept it .
thus , the legal process disadvantages amateur cyclists or lower paid semi - professionals . mller ( 2014 ) has recently argued that the creation of a doping - specific legal process is problematic , and does not give those charged with an offence the same legal protection or opportunities to defend their case in comparison to normal civic prosecutions .
the use of the strict liability principle is designed to counter any athletes ' appeals and puts the onus fully of them to explain any substance found in their sample .
american cases such as coyle and armstrong show how agencies can successfully pursue a charge on the basis of non - scientific evidence , such as coyle 's credit card purchases .
it is questionable whether a similar case would be upheld under civic law when the defence has more scope to challenge the nature of the prosecution 's evidence .
nonetheless , we can say that coyle 's unfortunate position of being unable to mount an appeal shows how discriminatory the legal process can be .
however , as in the 2003 cases of mountain bikers kathi krause and gary houseman , the use of narcotics and cannabis during competition is explicitly banned by the anti - doping agencies . both were caught using cannabis and both were banned for a year .
houseman was also stripped of his first place title in the uci world cup event ( albert , 2003 ) .
krause was aged 41 and had only finished 15th in the national championships ( usada , 2003 ) .
it is a different conceptual argument to propose that the use of drugs that are likely to inhibit rather than enhance performance is not a form of cheating or allow one competitor an advantage over another ( henne , koh , & mcdermott , 2013 ) .
the social and moral value of this regulation has been debated among sports philosophers and sociologists , but wada insists that recreational drugs contravene the principle of the spirit of sport despite the problematic nature of that idea .
bans for non - performance enhancing drugs do seem particularly harsh in the context of us cycling when an unknown quantity of riders doped to enhance performance without being caught , and when the majority of the us postal team was given reduced bans of six months because they provided additional information to assist the investigations .
that is an unlikely option for cyclists unable to offer such information , which is likely to be the case for many at the amateur level . in total
as mentioned above , they are generally accepted to be non - performance enhancing and the regulations an unnecessary intrusion into athletes ' private lives ( kayser , mauron , & miah , 2007 ) .
perhaps more importantly , the science behind banning these drugs shows that cannabinoids can be present in urine long after it has been consumed ( varying depending upon consumption habits and amount used ) .
wada changed the threshold from 150 to 15 ng in 2013 because it was recognised that this was a significant issue ( wada , 2013 ) .
the rules state that consumption out - of - competition is allowable but not in - competition . under the pre-2013 rules ,
the presence of metabolites in urine during an event period might indicate usage occurring up to three weeks prior to the test ( huestis , mazzoni , & rabin , 2011 ) .
thus , not only is the wider social context of banning recreational drug problematic , but also within wada 's very own rules .
even the organisation 's first president richard pound said that an athlete who used marijuana a month before competition was likely to be detected , as was someone exposed to second - hand marijuana smoke two weeks before an event ( miceli , 2013 ) .
as such , there clearly are inconsistencies and inequalities where innocent parties can end up sanctioned .
there have also been several cases where the substance ingested appears to have come from a source unwittingly consumed by the athlete . a case in point here
is that of 23-year - old amber neben who was found to have 19-norandrosterone in her sample in 2003 .
she had the resources to take her appeal to the north american court of arbitration for sport ( nacas ) , and identified the source of the banned substance to be from a contaminated supplement .
the panel agreed her positive test to be unintentional but still ruled that she be sanctioned with a 6-month ban .
indeed , the transcription of neben 's arbitration decision shows the dilemmas faced when confronted with an inadvertent case of doping ( nacas , 2003 ) .
the experts agreed that supplements were normal , such as electrolyte drinks and glucose gels .
they even suggested not using supplements contravened the stated purpose of the fight against doping , to protect the health of athletes
( nacas , 2003 , p. 6 ) since these were needed to maintain health , avoid fatigue and mental lapses during races .
ironically , they cite the example of lance armstrong to show that road racing is gruelling and all too often dangerous the demands placed on the body are greater than most world - class athletes in other sports .
the source of neben 's banned substance was not fully explicated but it was proposed that it possibly came from a supplement bought from hammer nutrition by usa cycling coaches and distributed to the team .
what neben 's appeal showed was potential negligence on the part of those who had responsibility to protect her from the risk of a positive test , and that all athletes are at risk of inadvertently taking contaminated supplements , which independent analyses have shown can contain banned substances ( cohen , 2009 ; cohen , travis , & venhuis , 2013 ) .
though usa cycling was in the spotlight for this mistake and stood accused of not providing any real education to athletes about the dangers of supplement contamination
( nacas , 2003 , p. 10 ) , it remains the athlete who bears the brunt of the legal process including potentially career and reputation damaging sanctions ( amos , 2007 ) .
taken together , these examples suggest that anti - doping regulations can have consequences for individuals whose offence is relatively innocuous , perhaps even completely unintentional , or even the result of negligence by their coaches or national governing bodies .
yet there seems to be an acceptance among anti - doping policy decision - makers that there will be a degree of collateral damage in the pursuit of the real cheats .
it seems ironic that lance armstrong negotiated his way around the anti - doping system for a period of 810 years , that his guilty team - mates received a light sanction and were allowed to return to the sport , yet others have faced consequences for behaviours that are completely different to the classic sense of doping as intentional cheating .
perhaps it is not surprising when highly competitive riders wish to retain some level of their youthful competitive success .
this appears to be the explanation for such cases as that of kenneth williams who was aged 42 when he tested positive for dhea ( weislo , 2009 ) .
he was a well - known and popular racer who wished to maintain his performance levels .
forty - nine - year - old todd robertson tested positive in 2011 in an out of competition test for oxygen - enhancing peptide hormone ( epo ) , and admitted using it for 2 years previously .
, he was found to have the stimulant modafinil in his sample and thus was banned for 8 years at age 51 for this second offence ( usa cycling , 2014 ) .
the second offence appears to have been accidental , since he learned from his first to be vigiliant , he said : i still do not know how or why a banned stimulant was found in my system ( usa cycling , 2014 ) .
interestingly , robertson also admitted using supplements , which shows how even those over 50 years old seek performance - enhancing substances , whether legal or otherwise , to maintain their levels of competitiveness across their life - cycle .
the new york gran fondo 2012 cases of david anthony ( aged 45 ) and gabriele guarini ( aged 49 ) brought this issue some national attention when they were reported in the new york times ( dreier , 2012 ) .
however , anthony 's case presents a different scenario from life long competitors looking to maintain competitiveness .
he was a relative latecomer to cycling but became by his own admission obsessed with improving his ability and performances .
he had won the new york gran fondo for his age group , so had a degree of success , but was never going to become a professional or reap extrinsic rewards .
however , he spoke of seeking relevance within his local cycling community ( ibid . ) .
this raises questions about identity among non - elite and older sports men and women . rather than the rewards being related to prize - money , high salaries or sponsorship deals , their desire is for localised recognition and to belong to a specific sub - culture .
thus , the increasing popularity of cycling in the usa , and the widening of race participation opportunities , has helped to create
tribes of serious recreational riders who buy expensive equipment , learn about the science of training and preparation , and perhaps have a personal coach . within this culture doping
is transmitted from older or more experienced cyclists to less experienced riders ( lentillon - kaestner & carstairs , 2010 ) , normalising doping as a rational part of higher level competition ( sefiha , 2012 ) .
anthony , and no doubt others , took the next step towards the pseudo - professionalisation of their hobby by using doping drugs ( brewer , 2002 ) .
though doping may have seeped into domestic semi - professional teams through connections and influences from elite riders , a further effect was to prompt amateurs to dope .
the theme of older riders has another important dimension related to the notion of collateral damage : the overlap of anti - doping regulations and anti - ageing therapeutic drugs .
an example here is that of 62-year - old david leduc who was caught and banned for 2 years in 2013 for using epo , testosterone and amphetamines .
he did not manage to explain the epo , but the other drugs were prescribed by a doctor for age - related compensation and for attention deficit disorder .
similarly , sloan teeple , aged 42 , was banned for 2 years for using testosterone prescribed by a doctor for therapeutic reasons , but he had not received a tue .
other evidence points to the challenges associated with the overlap between anti - ageing therapies and older cyclists . a more publicly discussed case ( but not one that led to a sanction ) was that of jeff hammond ( beaudin , 2013 ) who was a low - level amateur category 4 cyclist , aged 58 . in order to treat hypogonadism and low bone density
when he contacted usada to request a tue he was denied , in effect being told to either stop racing or stop medicating .
a letter from usada informed him that his tue was denied because his use was to treat a functional disorder without demonstrating the specific root cause of his hypogonadism :
justification for the use of testosterone must meet the standard of demonstrating an organic cause of androgen deficiency / male hypogonadism .
a diagnosis based simply on a functional disorder does not meet this standard rather functional diagnoses often focus solely on low testosterone and generalized symptoms ( cited in beaudin , 2013 ) .
though hammond 's testosterone therapy has successfully restored his energy levels to where he feels normal , the lack of a tue prevents him from racing .
hammond 's analysis cut to the core of the anti - doping policy challenge here : they 're treating us like 20-year old olympians . something that 's considered a performance - enhancing drug for an 18-year - old may be a necessary life - saving medication for a senior athlete .
it was reported at this time that usada had ( in 2012 ) received 409 requests for tues , of which 52 were for anabolic agents such as testosterone . the science director for usada ,
we 're seeing more athletes that are at masters level realising that they were perhaps taking a prohibited substance
there is a certain irony to the risk of running afoul of a policy designed to protect health by using a substance that a doctor agrees is for health protection .
another source of information on this subject is andrew tilin 's ( 2011 ) self - experiment that formed the basis of his 2011 book the doper next door : my strange and scandalous year on performance enhancing drugs .
tilin had interviewed papp for velonews and subsequently sought other sources of doping products . as a male over 40
treatment even when he admitted to the advisors that he intended to use these to improve his cycling .
he showed that the anti - ageing industry had grown to significant proportions valued in the billions of dollars annually , its leading proponents had become millionaires .
it seems that the confluence of cycling 's popularity with anti - aging opportunities , and the pressures to promote
clean sport , has created a perfect storm of older riders who wish to maintain youthful vigour finding themselves punished and marginalised ( hoberman , 2005 ; lopez , 2011 ) .
of course , many other cyclists may take the view that they are unlikely to be podium finishers in events that have testing procedures so therefore may simply continue with their medical prescription regimes . to avoid such cases becoming further examples of collateral damage of anti - doping efforts , addressing doping requires a different approach to those presented in studies of high level professional sports . the motivation to take a banned substance may be purely medical , or part of strategy to reduce the effects of the ageing process .
the deterrents may also be fewer as there is little risk of getting caught , and a two - year sanction for a cyclist over the age of 40 may not seem like a particularly onerous punishment , especially for those for whom cycling is merely a hobby . rather than the extrinsic motivations often provided as the main rationale for doping , the cases of amateur cyclists demonstrate that the reasons for using banned substances are varied and may be unrelated to any perceived sports reward . nonetheless , if doping behaviours are on the increase among a wider population with variable access to medical expertise , then a potentially significant public health issue may be emerging ( sjqvist , garle , & rane , 2008 ) .
the prevalence of doping with amateur ranks and competitions may be an unknown quantity but there has been sufficient anecdotal evidence to prompt grassroots organisations to develop their own anti - doping programmes ( burns , 2014 ) .
partly , the basis for this is the failure of usada to provide sufficient levels of testing to deter doping .
however , usa cycling has committed funding of $ 270,000 to cover professional and amateur events .
the latter is on the condition that local cycling associations can match fund the costs involved , for which the full costs are $ 3500 for a single day event and $ 7000 for two days . by january 2014 , 16 local organisations , comprising 70% of usa
cycling 's membership had joined the programme ( burns , 2014 ) . by so doing ,
the responsibility for initiating , planning and raising funds lies with amateur cyclists whose desire is to protect their specific local sports environment from doping . working in collaboration with usa cycling to apply the wada rules creates this perhaps unique situation in which non - experts are collectively imposing the rules designed for professionals upon themselves and their compatriots .
this represents an interesting innovation , that builds upon notions of discipline and ( self ) surveillance that are integral to anti - doping ( henning , 2013 ) , but where the power to decide who is observed and disciplined lies with a small group of well - organised cyclists who aim to promulgate the ideologies and practices of systematic anti - doping policy .
these developments may be unique , we do not know of other similar initiatives , and may be a precursor of other forms of grassroots anti - doping .
it raises questions about decision - making , transparency and trust , when those leading the anti - doping groups are potentially open to bias in the course of targeting specific races and riders .
moreover , given some of the problematic cases outlined above , how would local organisational anti - doping movements be sustainable if they were largely catching inadvertent dopers , older riders using prescription anti - ageing drugs , and recreational drug users ?
the commonly accepted assumption about and reasons for doping by professionals do not necessarily hold true at the lower levels of cycling . at these lower levels questions of intent , knowledge , accident and lifestyle
, these cases call into question the basic tenets of health promotion , fair play and spirit of sport underpinning anti - doping . a broader and in - depth investigation into doping cases in cycling reveals that current anti - doping policies can have severe implications for non - professional cyclists . though the patterns of actual use are unclear , there are indications that banned substances function as different practices at different levels of the sport .
current anti - doping test and ban efforts have had some success detecting a number of cyclists using banned substances for performance enhancement , as evidenced by the 2012 decision and sanctions against members of the us postal service team .
however , the relatively few anti - doping victories have done little to prevent a doping culture from taking root in us cycling .
professional cyclists competing on the european circuit likely had to choose between acquiescing to new performance demands by taking banned substances or to race at a disadvantage against their doping counterparts . during the same period anti - doping efforts were unable to stymie the spread of doping at the elite level and doping culture spread to lower levels of the sport .
this culture of risk around doping ( bette , 2004 ) was normalised in this environment as a way to be competitive . instead of being viewed as a deviant practice doping
might be viewed as a way to fit into cycling culture and demonstrate one 's competitive status .
thus , by the early 2000s testing results and discoveries of distribution networks like the papp list reveal that doping was occurring at all levels of cycling , though the focus remained on the elite cases where intentional doping was likely .
this analysis has shown that while some aspirational non - professionals did use peds with the intention of cheating , many infractions by non - professional cyclists are likely the result of recreational drug use not intended to aid performance , supplements containing banned substances , or doctor prescribed medications or anti - ageing products .
anti - doping regulations have not made allowances for these substances despite the trends of decriminalisation and even legalisation of cannabis , expanding markets for supplement and anti - ageing products , and the increasing social acceptability of each within wider society .
the strict liability principle leaves little room for explaining innocuous or incidental use of banned substances , as presence immediately equals guilt regardless of intent .
however , the time and financial costs of appealing a ruling may act as a disincentive to challenging a positive test for many amateurs .
the low number of appeals by non - professionals has resulted in a situation where professional riders engaged in intentional , systematic doping serve lighter bans than their amateur counterparts . as such , the unintentional or recreational use of a banned substance can result in a relatively innocent cyclist becoming an incidental casualty in the war on doping , a situation that seemingly runs afoul of the notions of fairness and spirit of sport that anti - doping policies are meant to foster .
these problems are further compounded by the problematic tue system under which athletes may be denied a waiver to use a medically prescribed banned substance while actively competing . in glaring contradiction to the principle of health promotion
, some athletes seeking to comply with anti - doping regulations are effectively told to decide between taking a substance that may be medically necessary or stop competing .
it is perhaps unsurprising that riders may forgo the process altogether , taking their chances at being asked to submit for a test .
one innovative outcome has been the emergence of localised anti - doping , which aims to focus on reducing cheating through use of performance - enhancing drugs . however , if the established expertise of ( inter)national anti - doping agencies can not address the extent of doping but creates innocent victims in pursuit of that failed ambition , what hope is there for community groups forced to follow wada guidelines ? there is perhaps an opportunity for implementing standards different from those aimed at professionals and that take local lifestyles and the variety of drug use into account . if such a model for volunteer anti - doping could be established , almost like a 2nd tier doping control , then groups in other sports and other countries may help forge a closer link between anti - doping idealism and athlete behaviour .
rather than relying on the national - level usada and nacas to decide exemptions and hear appeals , localised anti - doping groups could take governance in their own hands .
local groups could set up low or no - cost arbitration programs to allow athletes to appeal or explain specific situations , such as amber neben 's tainted supplement case or jeff hammond 's therapeutic testosterone use .
carrying out these functions themselves , in tandem with localised testing , these grassroots anti - doping groups may allow them to correct some of the injustices that result from the current centralised anti - doping system .
thus behind the headlines of us postal and lance armstrong may lie a form of anti - doping with the potential for changing policy and engaging all athletes in a realistic approach to clean sport .
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### Summary:
: abstractthe focus of researchers , media and policy on doping in cycling is often limited to the professional level of the sport .
however , anti - doping test results since 2001 demonstrate that banned substances are also used by us cyclists at lower levels of the sport , necessitating a broader view of the patterns and motivations of substance use within the sport . in this article , we describe and explain the doping culture that has emerged in domestic us cycling among amateur and semi - professionals . through analysis of records from sports governing bodies and journalistic reports , we assess the range of violation types and discuss the detection and punishing of riders who were not proven to have intended to cheat but became collateral damage in the war on doping .
we argue that the phenomenon of doping is more complex than what has been shown to occur in elite sport , as it includes a wider variety of behaviours , situations and motivations .
we develop fresh insights by examining cases where doping has been accidental , intrinsically motivated , non - performance enhancing or the result of prescribed medical treatments banned by anti - doping authorities .
such trends call into question the fairness of anti - doping measures , and we discuss the possibility of developing localised solutions to testing and sanctioning amateur athletes .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: stabilin-2 ( stab2 ) and hare ( half - length stab2 ) function as primary scavenger receptors for the systemic clearance from lymph and blood of hyaluronan ( ha ) , heparin ( hep ) , and 12 other functionally and structurally distinct ligands [ 26 ] .
ha turnover and catabolism by hare have been studied extensively for decades [ 1 , 7 , 8 ] and the responsible receptor was molecularly identified > 15 years ago after it was purified and cloned [ 5 , 6 , 9 , 10 ] .
hare endocytosis of ha occurs over a broad range of sizes from ~2.5 kda to > mda .
hep is cleared from the body by two different mechanisms : larger hep is rapidly cleared from blood in a high - affinity saturable binding mechanism by hare / stab2 in liver sinusoidal endothelial cells [ 12 , 13 ] , whereas low mass hep is primarily cleared by kidney in a nonsaturable renal excretion mechanism .
ha and hep have distinct binding sites within the hare ectodomain and neither ligand competes for the binding and endocytosis of the other . several articles in this special issue summarize the many functions of ha . as with ha , the biological and clinical activities of hep have been studied for decades , and hep is the most highly prescribed drug in the usa ( e.g. , for preventing or treating thromboembolic diseases and postsurgery clotting ) .
ha is synthesized by many cell types and is the longest ( up to 5 10 sugars ) and only unsulfated glycosaminoglycan . in contrast , hep is synthesized by mast cells as a serglycin proteoglycan with much shorter polysaccharide chains , < 50 sugars [ 17 , 18 ] .
hep is the most anionic glycosaminoglycan , due to extensively sulfated disaccharide isomers and binds to many different matrix , soluble , and cell surface proteins , including growth factors .
many receptors require bound ligand in order to interact with adapter proteins and then be targeted to coated pits .
in contrast , hare and other constitutively recycling clearance receptors ( e.g. , asialoglycoprotein and ldl receptors ) are continuously targeted to coated pits , internalized , and recycled back to the cell surface whether bound to ligand or not .
endocytic receptors often contain a tyrosine - based motif ( e.g. , yxx or npxy , where x is any amino acid and is a hydrophobic residue ) or a dileucine motif ( d / exxxll / i ) involved in clathrin - mediated endocytosis [ 2326 ] .
yxx and dileucine motifs interact with ap-2 adaptor complexes , whereas npxy motifs interact with ap-2 and other adaptor proteins such as dab2 and arh .
the adaptor protein gulp is required for stab2-mediated phagocytosis of aged ( apoptotic ) red blood cells , by recognition of a phospho - tyr in the hare cd .
l in full - length stab2 ) contains at least four endocytic motifs , an unusually high number : ysyfri ( m1 ) , fqhf ( m2 ) , nply ( m3 ) , and dpf ( m4 ) .
surprisingly , three of these four motifs ( m1 , m2 , and m3 ) mediate endocytosis of ha , with m3 being the most active motif .
all three motifs participate in total coated pit targeting of hare - ha complexes , and no single motif is required for uptake if the other functional motifs are present .
the hare cd motif network responsible for targeting the receptor to coated pits reflect either a very high level of redundancy or the presence of multiple distinct endocytic and signaling pathways .
our objective here was to identify the endocytic motifs responsible for hare - hep endocytosis .
the results indicate that m1 , m3 , and m4 are utilized for hep endocytosis , which is a different subset of three motifs compared to that used for ha , and that in the absence of other motifs , only m3 is able to mediate the endocytosis of both ha and hep ; hare containing m2 or m4 alone did not mediate ha or hep endocytosis .
flp - in 293 cells , fbs , dmem , hygromycin b , zeocin , lipofectamine 2000 , glutamate , plasmid expression vectors , and super - competent top10 escherichia coli were from in - vitrogen ( carlsbad , ca ) .
stable cells expressing hare and hare - mutants were generated as described previously [ 26 , 28 ] .
hep was from celsus ( cincinnati , oh ) or sigma - aldrich ( st . louis , mo ) .
sodium i - iodide ( 100 mci / ml ; specific activity of > 0.6 tbq / mg ) in naoh and pd-10 columns were from ge / amersham biosciences ( piscataway , nj ) .
preparation and quantification of biotinylated and iodinated ligands and the compositions of other buffers were described previously [ 13 , 29 , 30 ] .
other materials , reagents , and kits were obtained as described or were from sigma - aldrich .
hare cdna constructs and vectors for creation of stably transfected flp - in 293 cell lines expressing wildtype ( wt ) hare or hare mutants with single or multiple endocytic motif deletions or site - specific substitutions were described previously [ 26 , 28 ] .
the results among different hare - expressing cell lines were normalized for hare expression based on western blot quantification of equal lysate protein samples .
binding or endocytosis result values are expressed as the mean se fmol/10 cells / hare .
cells expressing wt hare , hare - mutants , or ev were grown in dmem with 8% fbs and 100 g / ml hygromycin b ( complete medium ) in 12-well tissue culture plates for at least 2 days prior to experiments .
radiolabeled i - sab - hep or i - sab - ha complexes were prepared using a 2 : 1 molar ratio of b - gag : i - sa and were incubated in 0.5 ml of endocytosis medium for 1 h on a rotary mixer at 22c just prior to the experiment . for nonspecific binding controls ,
cells were washed with hanks ' balanced salts solution and incubated at 37c for 1 h with endocytosis medium ( no serum ) to allow hare - mediated internalization of any bound serum glycosaminoglycans .
the medium was aspirated and replaced with endocytosis medium containing 50 nm preformed complexes of i - sa with b - hep or b - ha with or without a 50-fold excess of unlabeled ligand as competitor .
the cells were then incubated either at 37c for 1 , 2 , or 4 h to assess the rate of endocytosis or at 4c for 2 h with or without 0.055% digitonin to assess total cellular or surface binding , respectively .
nonspecific binding of i - sa was also assessed in parallel samples by incubating cells with i - sabiotin complexes .
the medium was removed by aspiration , and cells were washed three times ( 2 ml each ) with cold hanks ' balanced salts solution to remove unbound ligand and solubilized in 1 ml 0.3 n naoh .
radioactivity was measured using a packard cobra ii gamma counter and lysate protein content was determined by the method of bradford using bovine serum albumin as standard .
for each cell line , including ev , the binding of i - sabiotin was subtracted from the binding of i - sab - ligand to correct for nonspecific binding of sa .
wt , hare mutants , or ev cells were preincubated in endocytosis medium as noted above and then incubated at 37c for 30 min with dmso alone or 300 m dynasore , as indicated .
i - complexes in endocytosis medium were then added to a final concentration of 50 nm and the cells were incubated at 37c for 4 h. for hyperosmolar treatment , preincubated cells were further incubated in endocytosis medium with or without 0.45 m sucrose at 37c for 30 min . after 30 min
, medium was removed , and endocytosis medium with or without 0.45 m sucrose containing 50
nm i - ligand was added and the cells were incubated at 37c for 4 h. the medium was aspirated and cells were washed three times ( 2 ml each ) with cold hanks ' balanced salts solution to remove unbound i - ligand and processed as noted above .
at least 24 independent experiments were performed in triplicate ( n = 612 ) and combined data are presented as the mean se .
all regression lines had correlation coefficients 0.97 and experimental and control results were compared by unpaired student 's t - tests using sigmaplot v10 ( systat software , inc . ,
point richmond , ca ) . values of p < 0.05 were considered statistically significant .
hare and stab2 are scavenger receptors that bind and clear 14 different ligands , including seven glycosaminoglycans , from lymph and blood . we designate the full - length 315 kda protein as stab2 and hare as the 190 kda isoform generated by an unknown proteolytic mechanism .
both hare / stab2 are the main systemic clearance receptors for ha and presumably hep , in all mammals studied [ 3437 ] .
hare is the predominant stab2-related protein expressed in sinusoidal endothelial cells of lymph node and liver , the main systemic clearance tissues [ 10 , 38 ] . although both ha and hep are anionic glycosaminoglycans , they bind to discrete and nonoverlapping sites in the hare ectodomain .
ha binding requires the link domain , which it likely binds to directly , whereas hep binds to an uncharacterized site and binding is unaffected by deletion of the link domain .
since , ha and hep bind to different sites , we wanted to determine if hare utilizes the same subset of three redundantly functional endocytic motifs for hep endocytosis as found previously for ha endocytosis .
most of the cd mutants used here had been characterized previously for their hare - mediated ha binding and uptake ability .
two additional single - motif containing cd mutants were created for the present study ( + m2 and + m4 ) to obtain a set of hare cd variants expressing only one of the four motifs ( e.g. , m1m2m4 = + m3 ) ; the panel of cd mutants used is shown schematically in figure 1 .
we were not successful in creating cell lines expressing only motif m1 . to understand further the importance of human hare having the ability to internalize both ha and hep , we wanted to determine which of the four cd endocytic motifs were functional for each ligand .
we previously found that hare expression levels , as well as ha binding to surface and intracellular hare , were similar to wt in a panel of stable flp - in 293 cell lines expressing various cd - mutants .
here we used a set of variant cell lines , expressing hare mutants that were either single - motif deletions or containing a single - motif ( i.e. , three motifs deleted ) . to determine whether the cellular hare distribution of hep binding was affected in any of the variants ,
we compared i - sab - hep binding at 4c to cell surface or total cellular hare ( cell surface and intracellular receptors ) in the various hare cd - mutant cells .
total and surface binding were monitored in the presence or absence of digitonin , respectively , under conditions that selectively permeabilize endocytic , but not nuclear , mitochondrial or lysosomal compartments [ 31 , 39 ] . since hep nonspecifically binds to many cell surface and intracellular proteins , the binding of hep by ev cells is higher relative to wt cells than the nonspecific binding of ha [ 13 , 26 ] .
only small amounts of i - sabiotin ( e.g. , < 1% of i - sab - hep values ) bound to cells and this did not increase with time .
in contrast , i - sab - hep uptake was time - dependent and linear over 4 h , as in figure 3 . cell surface ( figures 2(a ) , 2(c ) , and 2(e ) ) and total ( figures 2(b ) , 2(d ) , and 2(f ) ) i - sab - hep binding to wt or hare cd - mutant cells were 2 - 3 times greater than to ev cells.as expected , the distribution of i - sab - hep binding sites between surface and internal was similar to that for ha binding in wt and the hare cd mutants .
hare is a constitutively active receptor involved in continuous and repeated cycles of ligand internalization and the hare recycling time of 79 min [ 28 , 40 ] is similar to that of other constitutively active recycling receptors [ 13 , 41 , 42 ] .
the majority of recycling receptors , including hare [ 28 , 33 ] , are localized in intracellular endocytic and recycling compartments .
thus , hep total binding ( surface and internal ) by wt or cd - mutant cells was much greater than surface binding , as expected . among the group of nine cd - mutants examined , there were no significant differences in hep surface binding ( figure 2 top panels ) , confirming that deletion of one or more endocytic motifs did not alter the dynamic ongoing movement of hare to and from the cell surface ; the steady - state surface receptor pool was similar among a set of hare variants .
total hep binding was identical to wt among the set of nine hare mutants except for m1 and m3 ( figure 2(b ) ) , which were significantly higher ( p < 0.05 ) . to assess the contributions of the various endocytic motifs to the kinetics of hep endocytosis
, cells expressing wt , hare - mutants , or ev were incubated at 37c with i - sab - hep for different times ( figure 3 ) .
partial impairment of i - sab - hep endocytosis relative to wt cells occurred in m1 or m4 cells ; hare - specific uptake ( wt uptake minus ev uptake ) was 65% and 68% of wt rates , respectively , for m1 or m4 cells ( figure 3(a ) ) .
cells expressing the m3 mutant showed even greater impairment of hare - specific hep endocytosis ( 35% of wt ) , indicating that m3 is responsible for more targeting to coated pits than m1 or m4 .
surprisingly , m2 cells did not show a defect in hare - specific hep endocytosis , but rather a 35% increase in hare - specific uptake compared to wt as though m2 itself had an inhibitory effect on hep uptake .
thus as found for ha endocytosis , three of the four motifs are involved in hep uptake and no particular motif is absolutely required for hep endocytosis , if the other three motifs are present .
however , the subset of active motifs for hep uptake ( m1 , m2 , and m3 ) was not the same as that for hare - ha complexes ( m1 , m3 , and m4 ) .
although m1 and m3 are used similarly for both ha uptake and hep uptake , a different third motif is utilized by hare for hep ( m4 ) versus ha ( m2 ) endocytosis .
since it is well known that phosphorylated tyr residues in npxy motifs are important in signaling pathways [ 43 , 44 ] , we wanted to identify further the importance of y in nply for targeting hare - ligand complexes to coated pits .
we used two cd - mutant hare cell lines , one with only a y - to - a substitution , wt ( y2519a ) , and the other with the same substitution in the m1m2m4 background , + m3 ( y2519a ) .
wt ( y2519a ) cells showed no significant defect in i - sab - hep endocytosis ( 95% of specific wt uptake ) , whereas + m3 ( y2519a ) cells were identical to ev cells , showing complete impairment of hep endocytosis ( figure 3(b ) ) .
the results show that tyr in the hare nply motif is critical for targeting to coated pits by + m3 cells , but it is not required if hare has functional m2 and m4 motifs ; these motifs compensate for a potential defect in m3 .
the data are consistent with either the ability of npla to retain targeting function in the presence of , but not the absence of , the two other hephare targeting motifs or the ability of m1 and m4 to compensate for npla and perform the targeting function . to address how multiple motifs function together to facilitate hep endocytosis , we examined i - saligand uptake in cells expressing different triple - motif deletions so that only single motifs remained ( figure 4 ) .
interestingly , i - sab - hep endocytosis by + m2 or + m4 cells was severely impaired by 95% .
in contrast + m3 cells retained 65% of the hare - specific endocytic capability of wt cells , an effect similar to the single - motif deletions m1 or m4 .
based on studies with the single - motif deletion variants , especially m3 cells , we expected that all three hare cd variants containing only m2 , m3 , or m4 would be able to target hare - hep complexes to coated pits and mediate effective uptake . since m2
does not participate in hep uptake ( figure 3(a ) ) , we expected + m2 cells to be defective in hep endocytosis .
however , the inability of + m4 cells to take up hep was unexpected , since this motif is functional in wt cells .
the unexpected functional differences among the single - motif containing hare variants are not ligand specific , as the same pattern was observed when ha endocytosis was examined ( figure 4(b ) ) .
again , + m2 cells ( expected to be active ; figure 4(a ) ) or + m4 cells ( expected to be inactive ) were identical to ev cells ; they were both unable to internalize ha , indicating the lack of coated pit targeting and uptake .
in contrast + m3 cells showed ~60% of the endocytic capability of wt cells , a very similar result to that for hep uptake ( figure 4(a ) ) .
thus , although both ha ( data not shown ) and hep ( figures 2(c ) and 2(d ) ) bind equally well to hare variants with only a single m2 , m3 or m4 motif and these variants show similar surface - internal distributions ( figure 2 ) , only m3 by itself is able to target hare - ligand complexes to coated pits and mediate efficient uptake .
the quantitative and relative rates of i - sab - hep endocytosis of the various hare cd mutants are summarized and compared to the values for ha uptake in table 1 .
the unexpected behavior of hare single - motif containing variants prompted us to verify that the various hare cd variants mediate endocytosis using a clathrin coated pit pathway , as shown previously for native and recombinant wt hare [ 28 , 40 , 45 ] .
hyperosmolar conditions inhibit clathrin assembly into coated pits and , thus , clathrin - dependent internalization of many plasma membrane receptors [ 4648 ] . to verify further that ligand uptake by the various hare cd - mutant cells is clathrin - dependent , we assessed the effects of hyperosmolarity on endocytosis using medium containing 0.45 m sucrose .
hyperosmolar sucrose treatment blocked internalization of ha by ~77% in wt cells compared to control ( untreated ) cells and by 4070% in the single - motif deletion hare cd mutants ( figure 5(a ) ) .
similar results were obtained for the effects of hyperosmolarity on hep uptake ( figure 5(b ) ) .
overall , the results confirm that hep and ha internalization by the various hare cd mutants occurs via clathrin - coated pit pathways .
many endocytic pathways in mammalian cells , including those involving clathrin - coated pits , phagocytosis , and caveolae , require the molecular motor protein dynamin for vesicle formation .
dynasore is a small cell - permeable chemical that specifically inhibits the gtpase activity of dynamin and interferes with dynamin - dependent endocytic pathways .
although not absolutely specific for clathrin - mediated uptake , dynasore should inhibit hare - mediated uptake that occurs via coated pits .
dynasore treatment significantly inhibited ha uptake by hare cd variants with alterations in the motif subset involved in ha uptake , compared to dmso - alone controls ( figure 6(a ) ) .
similarly , dynasore inhibited hep endocytosis by ~7085% in several hare cd mutants of the motif subset involved in hep uptake ( figure 6(b ) ) .
as expected , the above dynasore and hyperosmolar sensitivity results indicate that the various hare cd mutants mediate hare - hep and hare - ha endocytosis by dynamin - dependent clathrin - coated pit pathways .
full - length stab2 and 190 kda hare ( the c - terminal half of stab2 ) are the primary scavenger receptors for systemic clearance of multiple structurally distinct ligands ( most of which are derived from tissue biomatrix degradation or cell debris ) including ha , hep , chondroitin sulfates ( types a , c , d , and e ) , dermatan sulfate , advanced glycation end products , acetylated or oxidized ldl , collagen n - terminal propeptides , and m2 and 55 integrins [ 2 , 4 , 13 , 28 , 45 , 5154 ] . in addition , apoptotic cells and debris are rapidly cleared from blood and lymph by macrophages and sinusoidal endothelial cells via hare - mediated binding to phosphatidylserine and then phagocytosis [ 3 , 55 ] . both functional receptor isoforms are expressed in sinusoidal endothelial cells of liver , lymph node , spleen , and bone marrow with the 190 kda hare being the predominant species .
both are also expressed in some specialized tissues , such as corneal and lens epithelium , heart valve mesenchymal cells , epithelial cells in renal papillae , and oviduct .
hare - mediated endocytosis of ha or hep activates intracellular signaling leading to activation of erk1/2 and nf-b stimulation of gene expression .
uptake of the hare ligands dermatan sulfate and acetylated ldl and phosphatidylserine also activated nf-b mediated gene expression , whereas chondroitin sulfates types a , c , d , and e did not .
although all 9 of these ligands are effectively endocytosed , erk1/2 and nf-b signaling pathways are activated by only about half of them .
we proposed that stab2 and hare have two important physiological functions : ( i ) to clear and degrade multiple ligands reflecting the status of tissue biomatrices , as first reported for ha , and ( ii ) to serve as a tissue stress sensor system that responds to the amounts and ratios of multiple biomatrix ligands via a signal transduction network that leads to the secretion of tgf- and other , yet to be identified , factors such as pro- or anti - inflammatory cytokines .
the physiological importance of hare / stab2 for ha homeostasis was verified in stab2 knockout mice , which have impaired systemic clearance of ha resulting in abnormally high circulating ha levels .
hare may also act as a homing receptor for human prostate tumor cells , allowing metastasis to lymph nodes and likely other hare - expressing tissues , such as liver and bone marrow .
metastasis was > 95% blocked by treating mice with a specific anti - hare ha - blocking antibody .
it is well established that hare - ha uptake is clathrin coated pit - mediated [ 40 , 45 ] , and this was confirmed for hep uptake in various hare cd mutants based on the inhibition of ligand uptake in cells treated with either the dynamin inhibitor dynasore or sucrose , under hyperosmolar conditions ( figures 5 and 6 ) .
many endocytic receptors utilize a single cd motif for endocytosis , such as yxx ( e.g. , transferrin and asialoglycoprotein receptors [ 62 , 63 ] ) or npxy ( e.g. , ldl , insulin , and egf receptors [ 64 , 65 ] ) . to our knowledge
few other , if any , receptors contain multiple different endocytic motifs that are cooperatively utilized for endocytosis .
for example , ldl receptor - related protein contains five possible endocytic motifs ( 1 , yxx ; 2 , npxy ; and 2 , ll ) , but only yxx is utilized as the dominant endocytic signal .
hare is unusual and possibly unique in having four different functional endocytic motifs and in utilizing subsets of three motifs for the uptake of ha and hep .
an unexpected finding in this study was that hare utilizes a different subset of three motifs for the endocytosis of hep compared to ha ( figure 7 ) .
three of the four endocytic motifs in the hare cd ( m1 ( ysyfri ) , m3 ( nply ) , and m4 ( dpf ) ) are utilized for hep internalization .
in contrast , a different subset of three motifs ( m1 , m2 ( fqhf ) , and m3 ) is utilized for ha endocytosis .
this result and the previous finding that hep and ha bind to independent nonoverlapping sites in the hare ectodomain indicate that the binding of ha or hep may create distinct conformational states within the intracellular cd that promoted differential recognition of endocytic motifs m2 and m4 by the relevant adaptor proteins .
different conformational or multimeric states of the intracellular cd could favor efficient binding of particular adaptor proteins to specific motifs .
the cd conformation of hare - ha complexes may allow m2 recognition by an appropriate adaptor protein , but not m4 recognition , whereas the cd conformation of hare - hep complexes may allow m4 recognition by an appropriate adaptor protein , but not m2 recognition .
consistent with the idea that binding in the ectodomain may influence intracellular signaling , hep does not bind within the ha - binding hare link domain , whereas both ha and hep bind to the link domain of tsg6 .
the consequences of this differential mechanism of hep versus ha endocytosis are unknown but might include different downstream signaling events or trafficking outcomes for a portion of the internalized pool of hep or ha .
the impairment of ha or hep endocytosis due to a single - motif deletion was not compensated by the other two functional motifs , indicating that each motif mediates targeting and endocytosis by a distinct independent and saturable pathway , perhaps through a subset of coated pits .
if true , this has significant implications for possible independent concurrent signaling pathways mediated by different hare - ligand complexes .
the signaling stimulated by hep uptake is that ha signaling is very size - dependent .
only ha sizes between 40 kda and 400 kda are able to activate hare - mediated erk1/2 and nf-b signaling pathways ; smaller or larger ha is endocytosed but does not activate signaling .
perhaps the use of different motif subsets for ha and hep uptake is related to the mechanism by which ha size dependence is achieved during internalization of hare - ha complexes .
the results indicate that each subset of three motifs participates in the total uptake of ha or hep , but that the nature of their cooperation is unequal and complicated . although the loss of only m3 ( in m3 cells ) impaired hep or ha endocytosis by ~40% , indicating that m3 shares one - third of the hep uptake burden , the loss of the other two hep uptake motifs m1 and m4 ( in + m3 cells ) only decreased endocytosis by the same amount , 35% .
this was a surprising functional difference among the three motifs , since they appear to function together when all are present , but only one can function if alone .
hep and ha endocytosis were completely eliminated in + m3 ( y2519a ) cells , showing that tyr is important for the endocytic process mediated by m3 alone . in wt ( y2519a ) cells there was essentially no effect on uptake of either ligand .
however , ongoing studies show that wt ( y2519a ) cells are completely unable to activate nf-b during uptake of ha , hep , dermatan sulfate , or acetylated ldl .
thus , tyr is critical for signaling to downstream effectors , when the receptor is endocytosing loaded cargo , but it is not needed for just cargo endocytosis alone .
further studies are required to define the adaptor proteins ( e.g. , gulp or ap-2 ) that interact with the four endocytic motifs in the hare cd and to understand the biological relevance of the complex coated pit targeting network and how it is coupled to signal transduction for a subset of internalized ligands .
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### Summary:
: the hyaluronan ( ha ) receptor for endocytosis ( hare ) is a multifunctional recycling clearance
receptor for 14 different ligands , including ha and heparin ( hep ) , which bind to discrete nonoverlapping
sites .
four different functional endocytic motifs ( m ) in the cytoplasmic domain
( cd ) target coated pit mediated uptake : ( ysyfri2485 ( m1 ) , fqhf2495 ( m2 ) , nply2519 ( m3 ) , and
dpf2534 ( m4 ) ) .
we previously found ( pandey et al .
j. biol .
chem .
283 , 21453 , 2008 ) that m1 ,
m2 , and m3 mediate endocytosis of ha .
here we assessed the ability of hare variants with a
single - motif deletion or containing only a single motif to endocytose ha or hep .
single - motif
deletion variants lacking m1 , m3 , or m4 ( a different subset than involved in ha uptake ) showed decreased hep
endocytosis , although m3 was the most active ; the remaining redundant motifs did not
compensate for loss of other motifs . surprisingly , a hare cd variant with only m3 internalized
both ha and hep , whereas variants with either m2 or m4 alone did not endocytose either ligand .
internalization of ha
and hep by hare cd mutants was dynamin - dependent and was inhibited by
hyperosmolarity , confirming clathrin - mediated endocytosis .
the results indicate a complicated
relationship among multiple cd motifs that target coated pit uptake and a more fundamental role
for motif m3 .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: a 57-year - old female patient who was admitted for decompensated cirrhosis of liver developed sudden onset of ocular pain associated with loss of vision .
ocular examination revealed peribulbar hemorrhage , lid edema , conjunctival congestion with chemosis , and mild ( 2 mm ) proptosis .
fresh vitreous hemorrhage with no view of fundus was noted , and the intraocular pressure was 44 mmhg . left eye examination was normal .
patient denied history of trauma of any nature and had no past history of any ocular ailment .
the patient was started on timolol 0.5% eye drops and oral acetazolamide 250 mg 6 hourly .
after 24 hours , on review , the patient was found to have perforation at the inferior limbus with prolapse of iris tissue and total hyphema [ fig . 1 ] .
pressure patch was applied , and the patch was found soaked with blood within 30 minutes . an emergency evisceration was planned , but surgery could not be done because of bleeding diathesis .
in test vs. 14 sec . in control with international normalized ratio ( inr ) of 2.15 , for
but , by 24 hours , there was spontaneous expulsion of intra - ocular contents with the crystalline lens found expelled out [ fig . 2 ] .
the hemorrhage arrested spontaneously , and the eyeball became phthisical [ fig . 3 ] .
computerized tomography scan of the orbit showed a collapsed and deformed globe with absence of crystalline lens [ fig .
4 ] . collapsed globe with inferior limbal perforation with iris prolapse and hyphema expulsive hemorrhage with crystalline lens extruded out phthisical eye with large sub - conjunctival hemorrhage computerized tomography scan showing collapsed globe
the 3 possible mechanisms of supra choroidal hemorrhage are sudden decompression causing rupture of posterior ciliary arteries , acute inflammatory necrosis of the choroidal vessel wall , and a third mechanism of hemorrhages from posterior ciliary artery as the primary event .
necrosis or rupture of posterior ciliary arteries can be induced by hypertension , arteriosclerosis , or glaucoma .
most of the reported cases of sesch had glaucoma with corneal ulceration predisposing to the supra choroidal hemorrhage.[24 ] but , sudhir et al . reported a 54-years - old diabetic patient with spontaneous expulsive choroidal hemorrhage who had a normal cornea , except for blood staining documented on the day before the patient developed sesch .
they postulated that an elevated intra - ocular pressure with possible weakening of cornea caused by blood staining would have caused the globe rupture .
similarly , our patient also had an intact cornea on the day before she developed sesch though she had a 2 mm hyphema .
have suggested that difference in elasticity of the cornea at the limbus makes it vulnerable to perforation at this site . in their case report , a central corneal ulcer was complicated by an annular rupture at the limbus due to sech .
yang et al . reported the management and outcome of 5 cases of spontaneous choroidal hemorrhage without expulsion .
the possible sequence of events in this case could be the bleeding diathesis secondary to the liver disease resulted in a massive intra - ocular and peri - ocular hemorrhage with sudden elevated intra - ocular pressure .
the inferior limbal perforation was possibly caused by dellen due to chemosis or exposure keratopathy due to proptosis .
amarapurkar et al . have suggested that global evaluation of coagulation like thrombin generation time , thromboelastography , sonorheometry , and national normalized ratio calibrated for cirrhosis ( inrliver ) are more relevant to study coagulopathy in liver disease since there is reduction in both anti and procoagulant factors . in the case
being reported , we carried out only the routine pt ( the facility for which was available in our hospital ) as per the management protocol devised by the treating physician . decompensated liver disease was the only predisposing factor we could identify in the present case as cause of sesch .
we are reporting this case for its unique presentation in that the patient had no corneal pathology or pre - existing glaucoma prior to the expulsion while other reports suggest some form of corneal pathology and glaucoma .
also , it is the first case of sesch caused by bleeding diathesis secondary to decompensated liver disease to be reported in literature .
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### Summary:
: expulsive suprachoroidal hemorrhage can be surgical or spontaneous . spontaneous expulsive suprachoroidal hemorrhage ( sesch )
is a rare entity .
most of the reported cases of sesch were caused by a combination of corneal pathology and glaucoma .
we are reporting a rare presentation of sesch with no pre - existing glaucoma or corneal pathology and caused by massive intra- and peri - ocular hemorrhage due to decompensated liver disease .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: students ( n=91 ) in four psychology and neuroscience courses ( sizes ranging from 11 to 31 ) over four different semesters participated in the class demonstration .
the activity had three main components : part 1 : monocular dark - adaptation , 1825 minutes .
this period always took place in the regular classroom and consisted in one eye being dark - adapted behind an eyepatch while class proceeded under normal ( photopic ) light conditions so that the other eye stayed light - adapted .
, both eyes were exposed to the dark so that the effects of asymmetric dark adaptation could be observed .
this second part was conducted in a darkened , windowless room , which in some cases was the regular classroom itself and in others a lab room located across the hallway from the regular classroom .
part 3 : gathering of results and discussion as a whole class , 1020 minutes .
while the present paper focuses on the demonstration of the cross - modal illusion , the monocular dark adaptation induced in part 1 also lends itself to a demonstration of the effects of dark adaptation on luminance threshold and on spectral sensitivity ( purkinje shift ) during part 2 , should this content be appropriate for a given course .
while the exact description of these methods goes beyond the purpose of this paper , interested readers will find links to materials and information below , as well as a brief description of the procedure and the results from one class of 31 students .
cross - modality : for part 1 , each student was given an eyepatch ( black , with elastic headband ) and 23 facial tissues .
they were asked to fold up the tissues to a square of about 2x2 inches that would cover the entire orbit of the eye and that was slightly larger than the eyepatch itself .
they were then asked to cover one eye with the tissue square , to put the eyepatch on top of it , and to secure the patch around the head with the elastic strap .
the tissues were used to create a better seal to the face than what the patch alone would provide so that the light block would be more complete .
students were asked to close the other eye and to adjust the tissues and patch so as to minimize the light they could see with the patched eye .
( students wearing glasses were asked to put the tissues and patch behind the glasses on one eye . )
they were then asked to keep the patch undisturbed for the next 1825 minutes so that the eye behind the patch would dark - adapt during this time , while class proceeded in normal light conditions that were in the photopic range .
( the illuminance was between approximately 700 lux and 2000 lux , depending on the lighting fixtures and on whether or not the classroom had windows . for an approximation of illuminance values under different conditions ,
depending on the focus of the class , this period of time was used to discuss the phenomenon of cross - modal interaction ( however , without mentioning the specific illusion to be demonstrated ) , and/or the mechanisms of dark - adaptation and different spectral sensitivity in photopic and scotopic vision .
part 2 : after 1825 minutes , student were asked to put one hand over the eyepatch and cover it tightly and to look right into the overhead light for about 30 seconds , so as to strongly light - adapt the unpatched eye and to thus maximize the difference between the two eyes states of adaptation . following this ,
all room lights were turned off but light was allowed to enter from a door that was left ajar by about one inch .
students were asked to remove the eyepatch and tissues and to keep both eyes open .
they were asked to make a mental note of any sensations they felt in the eyelids and the skin surrounding each eye .
they were then asked to cover the light - adapted eye by hand and to make a mental note of whether the sensation surrounding the eye changed when the eye was thus covered .
luminance thresholds and purkinje shift : an in - depth outline of the purkinje shift and its demonstration can be found at http://www.yorku.ca/eye/toc-sub.htm ( under purkinje shift ) . during part 1 ( i.e. , under photopic conditions ) , students were given a sheet of paper ( 8x3.5 inches ) displaying an approximately equiluminant red and blue square ( see http://www.yorku.ca/eye/purkink1.htm ) and asked to mark the square that looked lighter to them under these photopic conditions .
they were also given a paper ( 8x2 inches ; see supplementary materials ) with a grayscale composed of 20 rectangles ( ranging in luminance from black to white ) displayed on a black background that would be used to estimate their luminance threshold in the dark - adapted and light - adapted eye when in the dark .
then , during part 2 , students were asked to take their luminance threshold with each eye separately while closing the other eye by marking the darkest rectangle they could distinguish against the black background .
( alternatively , students can simply use any sheet of paper with text on it , and they can try to read the text with their dark - adapted and their light - adapted eye .
students will generally find that it is impossible to read anything with their light - adapted eye but that they can make out some text with the dark - adapted one ) . to illustrate the purkinje shift ,
students were asked to look at the sheet with the red and blue square using the dark - adapted eye , and to mark the square that looked lighter to them when in the dark .
students were asked to indicate their answers to a number of questions with a show of hands and to give open - ended comments on the open - ended questions .
1 . when in the dark , did it feel as though the eyelid of the light - adapted ( blind ) eye was sagging or drooping?2 .
when in the dark , did it feel as though the eyelid of the light - adapted ( blind ) eye was sagging or drooping ? 2 .
students were then asked what they thought causes the illusion of eyelid sag under the conditions that were induced by asymmetric dark adaptation . for an exploration of luminance threshold and purkinje shift ,
which eye could detect darker areas on the grayscale , the light- or dark - adapted eye?5 . which square looked brighter to you in the light , the red or the blue?6 . which square looked brighter in the dark ( to the dark - adapted eye ) ?
which eye could detect darker areas on the grayscale , the light- or dark - adapted eye ?
5 . which square looked brighter to you in the light , the red or the blue ? 6 . which square looked brighter in the dark ( to the dark - adapted eye )
cross - modality : for part 1 , each student was given an eyepatch ( black , with elastic headband ) and 23 facial tissues .
they were asked to fold up the tissues to a square of about 2x2 inches that would cover the entire orbit of the eye and that was slightly larger than the eyepatch itself .
they were then asked to cover one eye with the tissue square , to put the eyepatch on top of it , and to secure the patch around the head with the elastic strap .
the tissues were used to create a better seal to the face than what the patch alone would provide so that the light block would be more complete .
students were asked to close the other eye and to adjust the tissues and patch so as to minimize the light they could see with the patched eye .
( students wearing glasses were asked to put the tissues and patch behind the glasses on one eye . )
they were then asked to keep the patch undisturbed for the next 1825 minutes so that the eye behind the patch would dark - adapt during this time , while class proceeded in normal light conditions that were in the photopic range .
( the illuminance was between approximately 700 lux and 2000 lux , depending on the lighting fixtures and on whether or not the classroom had windows . for an approximation of illuminance values under different conditions ,
, this period of time was used to discuss the phenomenon of cross - modal interaction ( however , without mentioning the specific illusion to be demonstrated ) , and/or the mechanisms of dark - adaptation and different spectral sensitivity in photopic and scotopic vision .
part 2 : after 1825 minutes , student were asked to put one hand over the eyepatch and cover it tightly and to look right into the overhead light for about 30 seconds , so as to strongly light - adapt the unpatched eye and to thus maximize the difference between the two eyes states of adaptation .
following this , all room lights were turned off but light was allowed to enter from a door that was left ajar by about one inch .
students were asked to remove the eyepatch and tissues and to keep both eyes open .
they were asked to make a mental note of any sensations they felt in the eyelids and the skin surrounding each eye .
they were then asked to cover the light - adapted eye by hand and to make a mental note of whether the sensation surrounding the eye changed when the eye was thus covered .
luminance thresholds and purkinje shift : an in - depth outline of the purkinje shift and its demonstration can be found at http://www.yorku.ca/eye/toc-sub.htm ( under purkinje shift ) . during part 1 ( i.e. , under photopic conditions ) , students were given a sheet of paper ( 8x3.5 inches ) displaying an approximately equiluminant red and blue square ( see http://www.yorku.ca/eye/purkink1.htm ) and asked to mark the square that looked lighter to them under these photopic conditions .
they were also given a paper ( 8x2 inches ; see supplementary materials ) with a grayscale composed of 20 rectangles ( ranging in luminance from black to white ) displayed on a black background that would be used to estimate their luminance threshold in the dark - adapted and light - adapted eye when in the dark .
then , during part 2 , students were asked to take their luminance threshold with each eye separately while closing the other eye by marking the darkest rectangle they could distinguish against the black background .
( alternatively , students can simply use any sheet of paper with text on it , and they can try to read the text with their dark - adapted and their light - adapted eye .
students will generally find that it is impossible to read anything with their light - adapted eye but that they can make out some text with the dark - adapted one ) . to illustrate the purkinje shift ,
students were asked to look at the sheet with the red and blue square using the dark - adapted eye , and to mark the square that looked lighter to them when in the dark .
students were asked to indicate their answers to a number of questions with a show of hands and to give open - ended comments on the open - ended questions .
1 . when in the dark , did it feel as though the eyelid of the light - adapted ( blind ) eye was sagging or drooping?2 .
when in the dark , did it feel as though the eyelid of the light - adapted ( blind ) eye was sagging or drooping ?
students were then asked what they thought causes the illusion of eyelid sag under the conditions that were induced by asymmetric dark adaptation . for an exploration of luminance threshold and purkinje shift ,
which eye could detect darker areas on the grayscale , the light- or dark - adapted eye?5 . which square looked brighter to you in the light , the red or the blue?6 . which square looked brighter in the dark ( to the dark - adapted eye ) ?
which eye could detect darker areas on the grayscale , the light- or dark - adapted eye ?
5 . which square looked brighter to you in the light , the red or the blue ? 6 . which square looked brighter in the dark ( to the dark - adapted eye ) ?
as illustrated in figure 1 , 86 of the 91 students ( 95% ) reported the cross - modal illusion of eyelid sagging in response to question 1 .
some students offered other descriptions of the sensation in response to question 2 , such as : blind , numb , tingly , swollen , puffy , like someone punched me , like having had novocaine , eyelid is paralyzed , eye is closed , can not tell if the eye is open or closed . in response to question 3 , all 86 students experiencing the illusion reported that the sensations decreased or disappeared when the eye was covered by hand . to make some informal observations about students response to the effect : students react with great surprise to their experience of the illusion .
many shout out in surprise , laugh , or express how strange a sensation it is .
similar reactions occur when the sensation magically disappears ( or at least decreases ) when the eye is covered by hand . several students commented informally or on course evaluations that this demonstration was one of their favorites in the course .
a few students even commented that they went on to tell their friends about it and tried it out again at home .
given the compelling nature of the demonstration , it is thus not surprising that students were easily led into speculations and discussions of the causes of the illusion , including a discussion of its possible neural substrate .
such discussion can simply be sparked by asking students what they believe could be the reason for this effect .
where appropriate for the level and content of the class , the conversation can then lead to advanced topics such as probabilistic perceptual processing and brain areas with multimodal neurons .
readers interested in integrating a time - efficient demonstration of dark - adaptation and spectral sensitivity into this class activity on cross - modality might find it helpful to know that in the class for which this was tested , all 31 students ( 100% ) reported the expected effect of dark - adaptation on luminance thresholds as measured on the grayscale , in that the dark - adapted eye could detect far darker rectangles than the light - adapted eye .
twenty - nine students ( 94% ) reported the purkinje shift in that the red square looked brighter in the light and the blue square looked brighter in the dark
. one student thought that the two squares looked equally bright under both conditions , and one student thought the red square looked brighter under both conditions .
as the numerical data and the informal observations above illustrate , the eyelid droop illusion is an effective teaching tool .
it is experienced by nearly all students and is a dramatic demonstration of cross - modal integration and the probabilistic nature of neural and perceptual processing .
it can be reversed by a simple manipulation so that it can be made to disappear and reappear at will .
it requires few resources , is feasible for a large audience , can be adjusted to take anywhere between about 30 and 60 minutes ( including discussion ) , and can be combined with a demonstration of other important neuroscience or perceptual principles such as the duplex nature of the retina , dark - adaptation , threshold measurements , and spectral sensitivity
. some limitations of the demonstration , or issues arising in its discussion , might include : using informal
raise your hand questioning might influence students to answer in conformity with others and might thus have distorted the numbers presented in the results . while this is a possibility ,
the proportion of students reporting the illusion ( 95% ) here is identical to the percentage of observers reporting it in carefully controlled experiments where participants recorded their responses privately and were asked several control questions ( wolfe et al . , 2007 ; 20 out of 21 participants ) making it unlikely that the present results were due to normative influences .
if class time allows , and where appropriate for the level of the course , one can either use the carefully controlled questioning used by wolfe and colleagues ( 2007 ) for the demonstration or introduce a class discussion of good experimental design in this context .
some students actually have a hard time believing that the eyelid droop is illusory because the effect is so strong .
it is thus important to emphasize that the effect is indeed an illusion and that the eye is actually open , as was confirmed in the original study of the illusion .
the suggestion that the eye is actually closed could also be a starting point for discussion of why the eye would return to normal when covered by hand .
this reversibility of the illusion will not only convince students that this is an illusion , not a real lid droop , it can also provide a good example of the probabilistic nature of perception , or of the phenomenon of perceptual explaining away discussed in the introduction . because asymmetric dark - adaptation was accomplished with prolonged wearing of a patch that exerts slight pressure to the area of the eye , some students wondered if the strange sensation in the eyelid and skin around the eye might have been caused by the prolonged asymmetry in tactile input to the two sides of the face rather than the asymmetry in dark adaptation .
again , this could lead into a discussion of why the illusion would disappear when the eye is covered by hand .
tactile asymmetry would not provide a parsimonious explanation of this change in the illusion , especially since the original study ( wolfe et al . , 2007
) demonstrated that the illusion disappears / decreases when either eye is covered or actively closed .
similarly , in the original study asymmetric dark - adaptation was induced while all but eliminating any tactile asymmetry : first , both eyes were dark - adapted and then one eye was briefly light - adapted ( < 1 min ) while the other eye was held closed and covered by hand .
finally , in more recent studies ( wolfe and carpinella , 2008 ) , we induced the illusory lid droop by inserting an occluder contact lens into one eye thus inducing visual asymmetry in the absence of any tactile asymmetry . while the demonstration is clearly effective in terms of the number of students experiencing the illusion and of generating interest in the phenomenon , there is no evidence yet that the activity leads to better learning of the concepts involved .
it is tempting to speculate that first - hand experience of the illusion would lead to better understanding and retention of concepts such as cross - modality , dark adaptation , and probabilistic nature of perception , but it is impossible to make this assertion without first gathering data on indicators of student long - term and short - term learning . despite these possible limitations , the demonstration outlined here can serve as a valuable and accessible teaching tool .
it can be used in the context of teaching several different and important perceptual and neuroscience concepts , and it may help integrate the concept of cross - modality into the standard content of undergraduate neuroscience and perception courses .
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### Summary:
: cross - modality , or the interaction between the different senses , has emerged as a fundamental concept in perceptual neuroscience and psychology .
the traditional idea of five separate senses with independent neural substrates has been invalidated by both psychophysical findings of sensory integration and neurophysiological discoveries of multi - modal neurons in many areas of the brain .
even areas previously thought to be unimodal have been shown to be influenced by other senses , thus establishing multisensory integration as a key principle of perceptual neuroscience.there are several obstacles to students understanding of the concept .
first , everyday subjective experience is modal : one sees , hears , smells the world and is rarely aware that these seemingly separate impressions are in reality fully integrated with each other .
second , standard content in undergraduate classes and textbooks still emphasizes the modal model of the senses and their corresponding brain areas and rarely mentions cross - modal phenomena .
third , feasible classroom demonstrations of cross - modality are few , making it difficult to provide students with first - hand experience that would aid their understanding of the principle.this article describes an accessible and effective classroom demonstration of cross - modality between low - level vision , touch and proprioception .
it consists in the illusion of eyelid droop in one eye when the other eye has been dark - adapted and when both eyes are exposed to the dark .
the perceptual effect is dramatic and reliable .
it illustrates cross - modality at a fundamental level of perception and might provide a means to help integrate the teaching of the concept into the standard content of undergraduate classes .
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: the ad2 e1a short constructs ( e1acr1(27 - 105 ) , e1an - cr1(1 - 105 ) and e1acr2(106 - 139 ) ) were obtained via thrombin digestion of the longer e1a constructs ( e1acr1-cr2(27 - 139 ) or e1an - cr1-cr2(1 - 139 ) ) .
all e1a cys mutants used for ensemble fluorescence or single - molecule frster / fluorescence resonance energy transfer ( smfret ) experiments have the additional mutations c6s and c124s , which replace two natural cys residues that are respectively located in cbp taz2 and prb binding regions .
although c124 is in a conserved prb lxcxe binding motif , it has been shown that a cys to ser mutation in the site exhibits marginal effects on e1a binding .
alexa fluor 488 and 594 ( molecular probes , carlsbad , ca ) fluorescent dyes were attached at sites that are unlikely to cause structural perturbations or affect e1a binding to cbp taz2 or prb ( residue positions 3 , 36 , 88 , 111 and 137 , where residue 1 - 139 comprise the e1a sequence and positions 4 to 1 are the residues gshm ) . for direct e1a titrations against cbp taz2 and/or prb monitored by ensemble fluorescence anisotropy , e1a constructs with single cys ( s36c for e1an(1 - 36 ) ; e137c for e1acr2(106 - 139 ) ; otherwise , s88c ) were used to attach alexa fluor 594 probes . for ensemble competition experiments , the competing e1a ligands ( e1an - cr1-cr2(1 - 139 ) , e1acr1-cr2(27 - 139 ) , e1an(1 - 36 ) , and e1acr2(106 - 139 ) )
have the wild - type e1a sequence except for the g139 residue that was mutated to trp for more accurate protein concentration determination by uv spectroscopy . for e1acr2(106 - 139 ) , protein with the wild - type sequence was used in direct titration measurements , with the e1a protein n - terminally labeled with dylight594 ( thermo scientific , rockford , il ) nhs ester probe . to investigate the role of the e1a n - terminus in the protein s binding properties , four sets of pair - labeled e1a constructs were used for smfret studies : e1acr1(27 - 105 ) and e1an - cr1(1 - 105 ) , 36c88c ; and , e1acr1-cr2(27 - 139 ) and e1an - cr1-cr2(1 - 139 ) , 36c88c , ( 3)c111c , 36c137c .
all e1a single cys mutants were labeled in 50 mm tris , 6 m guanidine hcl , ph 7.2 using ~3 - 5 fold molar excess of maleimide dye . for e1a double cys mutants , approximately 5 nmol of e1a
were incubated with 1:3 concentration ratio of alexa fluor 488 : alexa fluor 594 dye .
all dye - labeled e1a samples were purified using an analytical c18 reverse - phase hplc column , and were checked for correct mass and for incorporation of the alexa dyes by maldi - tof mass spectrometry .
isothermal titrations in 20 mm tris , 50 mm nacl , 1 mm dtt , ph 7.0 at 21c were performed by monitoring ensemble fluorescence anisotropy .
two titration methods were employed : direct protein - ligand titration and competition binding measurements .
direct titrations were carried out by detecting fluorescence anisotropy changes in solutions containing 25 nm of dye - labeled e1a macromolecule ( m ) as a function of ligand ( l ) concentration ( cbp taz2 or prb ) .
northampton , ma ) by nonlinear least - squares ( nls ) fitting of the data to a one - site binding model ( see eq . 2 below ) . to determine the goodness of fit and test the validity of the simplified model
, simulations were performed using the fitted parameters and compared to the data on the basis of a more complete binding model that considers the macromolecule concentration ( see the model defined below and described by eq .
application of the more exact model is not feasible for the analysis of the ensemble fluorescence anisotropy data due to the number of fitting parameters . for cases of low - affinity binding ,
where kd>>m ( such as with the titration of e1acr1(27 - 105 ) and e1acr2(106 - 139 ) against prb ) , the assumptions of the simplified one - site binding model become valid , as can be shown by simulations using the derived parameters as applied to the second model . for cases of high - affinity binding ,
where kd<<m , the estimates for kd using the first binding model are not accurate .
in such cases , an upper bound for the kd was used ( supplementary table 1 ) . for the competition method ,
25 nm labeled e1a were initially bound with 500 - 1000 nm prb or 350 - 500 nm cbp taz2 , and competed with the unlabeled e1a counterpart to see the effect of the probes ( e.g. , e1an - cr1(1 - 105 ) , 88c - alexa fluor594 , competed against wild - type sequence e1an - cr1(1 - 105 ) ) .
an estimate of the kd from the direct titration was necessary to fit the kd of the competing ligand .
single - molecule frster / fluorescence resonance energy transfer ( smfret ) experiments were carried out as described previously using a home - built laser confocal microscope system that employs an axiovert 200 microscope ( zeiss , thornwood , ny ) . excitation was achieved by focusing the 488 nm - line of a 543-ap - a01 tunable argon - ion laser ( melles griot , carlsbad , ca ) into the sample solution , 30 m above a glass cover - slip surface , using a water immersion objective ( 1.2 na , 63x ; zeiss ) .
the fluorescence emission was collected using the same objective , separated from the excitation light using a dichroic mirror ( q495lp ; chroma tech .
, rockingham , vt ) , spatially filtered using a 100 m - pinhole then split into donor and acceptor components using a second dichroic mirror ( 560 dcxr ; chroma ) .
the donor and acceptor signals were further filtered using an hq 525/50 m band - pass filter ( donor ; chroma ) and a 590 lpv2 long - pass filter ( acceptor ; chroma ) , then detected using spcm - aqr-14 avalanche photodiode ( apd ) photon counting modules ( perkin - elmer optoelectronics , fremont , ca ) .
photon counts were recorded using a photon counting card ( pci 6602 ; national instruments , austin , tx ) interfaced with a computer .
fret efficiency ( efret ) histograms were generated by using a two - channel data collection mode to simultaneously record donor and acceptor signals as a function of time , with a binning time of 500 s .
the donor - acceptor solutions used were ~100 pm in fluorophore concentration ( i.e. , ~100 pm fret - labeled e1a ) , ensuring that virtually all of the detected signals were from single molecules .
the background counts , the leakage of donor emission into the acceptor channel ( ~8% ) and the acceptor emission due to direct excitation ( ~5% ) were determined in separate experiments , and used to correct the signals before fret analysis .
a threshold of 50 counts ( the sum of signals from the two channels ) was used to separate background noise from fluorescence signals , and efret values were calculated for each accepted event using eq . 1 and plotted in the form of histograms .
i d and ia are the corrected donor and acceptor fluorescence intensities , respectively , and is a correction factor that is dependent on the donor and acceptor fluorescence quantum yields , and donor channel and acceptor channel detection efficiencies . using the same experimental setup and fret dye - pair , we previously measured to be approximately equal to unity .
although the accuracy of the determined value is critical for measurement of inter - dye distances , does not play a part in the calculation of population distributions .
binding of unlabeled cbp taz2 and/or prb to different constructs of e1a labeled with alexa fluor 488 ( donor ) and 594 ( acceptor ) [ see sample preparation section above and fig .
the same solution conditions were used as for the ensemble fluorescence measurements ( 20 mm tris , 50 mm nacl , 1 mm dtt , ph 7.0 ) .
an average of ~5000 single - molecule events was collected for each smfret histogram measurement . in total , the complete set of smfret titration data reported here comprise in excess of 700,000 events .
efret histograms were fitted to gaussian functions by using originpro 8.0 with the peak positions , areas and widths at half height used as fitting parameters . for experimental conditions where e1a predominantly adopts a single binding state ( i.e. , free , cbp taz2-bound , prb - bound , or in ternary complex with cbp taz2 and prb ) , smfret histograms showed two peaks one corresponding to the protein signal , and another to the
zero peak , which is present in all histograms due to molecules with photo - bleached , missing , or non - fluorescent acceptor probe .
these histograms of single populations or pure states were used as references in determining ( via independent nls gaussian fits ) the characteristic efret signatures of the different e1a binding states ( see supplementary table 3 ) .
these precisely determined efret values were then used as fixed parameter inputs in the analyses of smfret histograms exhibiting resolved multiple protein peaks that correspond to different e1a conformations ( e.g. , unbound and cbp taz2-bound states ) .
the areas under each protein peak determined by nls gaussian fitting were then used to calculate fractional populations ( e.g. , fraction unbound and fraction cbp taz2-bound ) , which were analyzed further as a function of ligand concentration ( e.g. , [ cbp taz2 ] ) to determine binding constants ( see fig . 1a , supplementary table 2 , and kd determination method discussion below ) .
3a - f , 4a - f , 5a - c and 6 a - d were all analyzed independently via nls gaussian fitting . in some cases , smfret histograms acquired under different solution conditions
this global analysis was especially useful in cases where protein peaks were not resolved well or when efret values can not be satisfactorily determined independently using just the histograms of pure states .
fractional populations were calculated using the area parameters derived from global fitting and analyzed further for kd determination ( see below ) .
detection of macromolecular interactions in solution at single - molecule resolution holds a number of important advantages over ensemble methods , including the direct measurement of population distributions , the ability to experimentally handle aggregation - prone systems , and improved resolution in the study of high - affinity interactions . applying smfret to derive kd values for the binding of a ligand l to a macromolecule m , assuming that the bound and unbound populations of the fret - labeled macromolecule exhibit distinct fret efficiencies , is straightforward and can be performed empirically , without the need for model fitting .
kd , or the ligand concentration at which the bound ( ml ) and unbound ( m ) macromolecule populations are equal , can be determined simply by titrating m with increasing concentration of l until the measured smfret histogram shows approximately equal areas for the peaks associated with the two binding states .
alternatively , population distributions can be similarly measured , then used as an experimental variable that depends on [ l ] and analyzed using a binding model .
2 ( see below ) assumes that the total ligand concentration [ lt ] is approximately equal to the concentration of free ligand , i.e. , [ m ] < < kd , a requirement that is easily achieved using smfret , in which measurements are usually performed using 100 pm labeled molecules ( or less ) .
1a ) were determined as a function of ligand concentration ( i.e. , [ cbp taz2 ] or [ prb ] ) using the fractional populations ( i.e. , fraction bound and unbound ) directly derived from the analyses of smfret histogram data ( described above ) .
fraction populations plotted against total ligand concentration ( expressed in terms of log[ligand]total or plt ) were analyzed graphically using the general binding model : ml m + l , and fitted with originpro 8.0 using eq . 2 m represents a macromolecule binding to a ligand l , y is the experimental observable ( i.e. , fraction bound or unbound ) , ym and yml are the binding transition baselines ( i.e. , the constants 0 and 1 , respectively , if using fraction bound as y ; otherwise , 1 and 0 ) , = 10^(plt pkd ) , [ ligand]total represents both bound and unbound forms of l , pkd = log[kd ] , and kd is the dissociation constant .
the model assumes that the concentration of unbound ligand is approximately equal to [ ligand]total , i.e. , the total concentration of the macromolecule e1a ( ~100 pm ) is significantly less than the kd values being measured , which in the case here are in the 1 - 50 nm range ( see supplementary table 2 ) .
in addition , y can be any observable / signal that is able to distinguish the different binding states , e.g. , efret ( see supplementary fig .
a more general expression describing the same model ( i.e. , ml m + l ) is given by ( chek ) eq .
3
y=([ml][mt])(ymlym)+ym
mt is the total m concentration independent of ligation state , y is the observable , ym and yml are the binding transition baselines , and [ ml ] = ( b(b-4ac))/2a , with a=1 , b=kd[mt][lt ] , and c=[mt][lt ] . presented in supplementary fig
. 7 are simulations for ligand binding at different mt , highlighting the advantage of single - molecule detection in resolving binding constants of high - affinity interactions .
using the binding constants derived from ensemble and single - molecule measurements ( see above and supplementary tables 1 - 2 ) , phase diagrams were generated to visualize the ligand concentration dependence of e1a interaction with its binding partners cbp taz2 and prb ( figs .
detailed descriptions of the general properties of protein phase diagrams , and their construction and interpretation are provided elsewhere . here
1a to describe the coupled folding and binding of e1a with cbp taz2 and prb . k1 and k1 , and k2 and k2 are equilibrium constants for e1a binding to cbp taz2 in the absence and presence of prb , and to prb in the absence and presence of cbp taz2 .
because the reaction scheme constitutes a complete thermodynamic cycle , it can be shown that k1/k1 = k2/k2. 50% phase separation lines were constructed as previously described , using partition functions ( qi ) that describe each of the four binding states ( i.e. , unfolded and unbound ( u ) , folded and cbp taz2-bound ( fl1 ) , folded and prb - bound ( fl2 ) and ternary ( fl1l2 ) states ) . for example , 50% phase separation lines between the u state and the three other binding states are calculated by equating qu with the sum of the remaining partition functions qfl1 , qfl2 and qfl1l2 .
the ad2 e1a short constructs ( e1acr1(27 - 105 ) , e1an - cr1(1 - 105 ) and e1acr2(106 - 139 ) ) were obtained via thrombin digestion of the longer e1a constructs ( e1acr1-cr2(27 - 139 ) or e1an - cr1-cr2(1 - 139 ) ) .
all e1a cys mutants used for ensemble fluorescence or single - molecule frster / fluorescence resonance energy transfer ( smfret ) experiments have the additional mutations c6s and c124s , which replace two natural cys residues that are respectively located in cbp taz2 and prb binding regions .
although c124 is in a conserved prb lxcxe binding motif , it has been shown that a cys to ser mutation in the site exhibits marginal effects on e1a binding .
alexa fluor 488 and 594 ( molecular probes , carlsbad , ca ) fluorescent dyes were attached at sites that are unlikely to cause structural perturbations or affect e1a binding to cbp taz2 or prb ( residue positions 3 , 36 , 88 , 111 and 137 , where residue 1 - 139 comprise the e1a sequence and positions 4 to 1 are the residues gshm ) . for direct e1a titrations against cbp taz2 and/or prb monitored by ensemble fluorescence anisotropy , e1a constructs with single cys ( s36c for e1an(1 - 36 ) ; e137c for e1acr2(106 - 139 ) ; otherwise , s88c ) were used to attach alexa fluor 594 probes . for ensemble competition experiments , the competing e1a ligands ( e1an - cr1-cr2(1 - 139 ) , e1acr1-cr2(27 - 139 ) , e1an(1 - 36 ) , and e1acr2(106 - 139 ) )
have the wild - type e1a sequence except for the g139 residue that was mutated to trp for more accurate protein concentration determination by uv spectroscopy . for e1acr2(106 - 139 ) , protein with the wild - type sequence was used in direct titration measurements , with the e1a protein n - terminally labeled with dylight594 ( thermo scientific , rockford , il ) nhs ester probe . to investigate the role of the e1a n - terminus in the protein s binding properties , four sets of pair - labeled e1a constructs were used for smfret studies : e1acr1(27 - 105 ) and e1an - cr1(1 - 105 ) , 36c88c ; and , e1acr1-cr2(27 - 139 ) and e1an - cr1-cr2(1 - 139 ) , 36c88c , ( 3)c111c , 36c137c .
all e1a single cys mutants were labeled in 50 mm tris , 6 m guanidine hcl , ph 7.2 using ~3 - 5 fold molar excess of maleimide dye . for e1a double cys mutants , approximately 5 nmol of e1a
were incubated with 1:3 concentration ratio of alexa fluor 488 : alexa fluor 594 dye .
all dye - labeled e1a samples were purified using an analytical c18 reverse - phase hplc column , and were checked for correct mass and for incorporation of the alexa dyes by maldi - tof mass spectrometry .
isothermal titrations in 20 mm tris , 50 mm nacl , 1 mm dtt , ph 7.0 at 21c were performed by monitoring ensemble fluorescence anisotropy .
two titration methods were employed : direct protein - ligand titration and competition binding measurements .
direct titrations were carried out by detecting fluorescence anisotropy changes in solutions containing 25 nm of dye - labeled e1a macromolecule ( m ) as a function of ligand ( l ) concentration ( cbp taz2 or prb ) .
dissociation constants ( kd ) were determined using originpro 8.0 ( originlab corp . , northampton , ma ) by nonlinear least - squares ( nls ) fitting of the data to a one - site binding model ( see eq .
2 below ) . to determine the goodness of fit and test the validity of the simplified model
, simulations were performed using the fitted parameters and compared to the data on the basis of a more complete binding model that considers the macromolecule concentration ( see the model defined below and described by eq . 3 ) .
application of the more exact model is not feasible for the analysis of the ensemble fluorescence anisotropy data due to the number of fitting parameters . for cases of low - affinity binding ,
where kd>>m ( such as with the titration of e1acr1(27 - 105 ) and e1acr2(106 - 139 ) against prb ) , the assumptions of the simplified one - site binding model become valid , as can be shown by simulations using the derived parameters as applied to the second model . for cases of high - affinity binding , where kd<<m ,
in such cases , an upper bound for the kd was used ( supplementary table 1 ) . for the competition method ,
25 nm labeled e1a were initially bound with 500 - 1000 nm prb or 350 - 500 nm cbp taz2 , and competed with the unlabeled e1a counterpart to see the effect of the probes ( e.g. , e1an - cr1(1 - 105 ) , 88c - alexa fluor594 , competed against wild - type sequence e1an - cr1(1 - 105 ) ) .
an estimate of the kd from the direct titration was necessary to fit the kd of the competing ligand .
single - molecule frster / fluorescence resonance energy transfer ( smfret ) experiments were carried out as described previously using a home - built laser confocal microscope system that employs an axiovert 200 microscope ( zeiss , thornwood , ny ) . excitation was achieved by focusing the 488 nm - line of a 543-ap - a01 tunable argon - ion laser ( melles griot , carlsbad , ca ) into the sample solution , 30 m above a glass cover - slip surface , using a water immersion objective ( 1.2 na , 63x ; zeiss ) .
the fluorescence emission was collected using the same objective , separated from the excitation light using a dichroic mirror ( q495lp ; chroma tech .
rockingham , vt ) , spatially filtered using a 100 m - pinhole then split into donor and acceptor components using a second dichroic mirror ( 560 dcxr ; chroma ) .
the donor and acceptor signals were further filtered using an hq 525/50 m band - pass filter ( donor ; chroma ) and a 590 lpv2 long - pass filter ( acceptor ; chroma ) , then detected using spcm - aqr-14 avalanche photodiode ( apd ) photon counting modules ( perkin - elmer optoelectronics , fremont , ca ) .
photon counts were recorded using a photon counting card ( pci 6602 ; national instruments , austin , tx ) interfaced with a computer .
fret efficiency ( efret ) histograms were generated by using a two - channel data collection mode to simultaneously record donor and acceptor signals as a function of time , with a binning time of 500 s .
the donor - acceptor solutions used were ~100 pm in fluorophore concentration ( i.e. , ~100 pm fret - labeled e1a ) , ensuring that virtually all of the detected signals were from single molecules .
the background counts , the leakage of donor emission into the acceptor channel ( ~8% ) and the acceptor emission due to direct excitation ( ~5% ) were determined in separate experiments , and used to correct the signals before fret analysis .
a threshold of 50 counts ( the sum of signals from the two channels ) was used to separate background noise from fluorescence signals , and efret values were calculated for each accepted event using eq . 1 and plotted in the form of histograms .
i d and ia are the corrected donor and acceptor fluorescence intensities , respectively , and is a correction factor that is dependent on the donor and acceptor fluorescence quantum yields , and donor channel and acceptor channel detection efficiencies . using the same experimental setup and fret dye - pair , we previously measured to be approximately equal to unity .
although the accuracy of the determined value is critical for measurement of inter - dye distances , does not play a part in the calculation of population distributions .
binding of unlabeled cbp taz2 and/or prb to different constructs of e1a labeled with alexa fluor 488 ( donor ) and 594 ( acceptor ) [ see sample preparation section above and fig .
the same solution conditions were used as for the ensemble fluorescence measurements ( 20 mm tris , 50 mm nacl , 1 mm dtt , ph 7.0 ) .
an average of ~5000 single - molecule events was collected for each smfret histogram measurement . in total , the complete set of smfret titration data reported here comprise in excess of 700,000 events .
efret histograms were fitted to gaussian functions by using originpro 8.0 with the peak positions , areas and widths at half height used as fitting parameters . for experimental conditions where e1a predominantly adopts a single binding state ( i.e. , free , cbp taz2-bound , prb - bound , or in ternary complex with cbp taz2 and prb ) , smfret histograms showed two peaks one corresponding to the protein signal , and another to the
zero peak , which is present in all histograms due to molecules with photo - bleached , missing , or non - fluorescent acceptor probe .
these histograms of single populations or pure states were used as references in determining ( via independent nls gaussian fits ) the characteristic efret signatures of the different e1a binding states ( see supplementary table 3 ) .
these precisely determined efret values were then used as fixed parameter inputs in the analyses of smfret histograms exhibiting resolved multiple protein peaks that correspond to different e1a conformations ( e.g. , unbound and cbp taz2-bound states ) .
the areas under each protein peak determined by nls gaussian fitting were then used to calculate fractional populations ( e.g. , fraction unbound and fraction cbp taz2-bound ) , which were analyzed further as a function of ligand concentration ( e.g. , [ cbp taz2 ] ) to determine binding constants ( see fig . 1a , supplementary table 2 , and kd determination method discussion below ) .
3a - f , 4a - f , 5a - c and 6 a - d were all analyzed independently via nls gaussian fitting . in some cases , smfret histograms acquired under different solution conditions
this global analysis was especially useful in cases where protein peaks were not resolved well or when efret values can not be satisfactorily determined independently using just the histograms of pure states .
fractional populations were calculated using the area parameters derived from global fitting and analyzed further for kd determination ( see below ) .
detection of macromolecular interactions in solution at single - molecule resolution holds a number of important advantages over ensemble methods , including the direct measurement of population distributions , the ability to experimentally handle aggregation - prone systems , and improved resolution in the study of high - affinity interactions . applying smfret to derive kd values for the binding of a ligand l to a macromolecule m , assuming that the bound and unbound populations of the fret - labeled macromolecule exhibit distinct fret efficiencies , is straightforward and can be performed empirically , without the need for model fitting .
kd , or the ligand concentration at which the bound ( ml ) and unbound ( m ) macromolecule populations are equal , can be determined simply by titrating m with increasing concentration of l until the measured smfret histogram shows approximately equal areas for the peaks associated with the two binding states .
alternatively , population distributions can be similarly measured , then used as an experimental variable that depends on [ l ] and analyzed using a binding model .
2 ( see below ) assumes that the total ligand concentration [ lt ] is approximately equal to the concentration of free ligand , i.e. , [ m ] < < kd , a requirement that is easily achieved using smfret , in which measurements are usually performed using 100 pm labeled molecules ( or less ) .
1a ) were determined as a function of ligand concentration ( i.e. , [ cbp taz2 ] or [ prb ] ) using the fractional populations ( i.e. , fraction bound and unbound ) directly derived from the analyses of smfret histogram data ( described above ) .
ml m + l , and fitted with originpro 8.0 using eq . 2 m represents a macromolecule binding to a ligand l , y is the experimental observable ( i.e. , fraction bound or unbound ) , ym and yml are the binding transition baselines ( i.e. , the constants 0 and 1 , respectively , if using fraction bound as y ; otherwise , 1 and 0 ) , = 10^(plt pkd ) , [ ligand]total represents both bound and unbound forms of l , pkd = log[kd ] , and kd is the dissociation constant .
the model assumes that the concentration of unbound ligand is approximately equal to [ ligand]total , i.e. , the total concentration of the macromolecule e1a ( ~100 pm ) is significantly less than the kd values being measured , which in the case here are in the 1 - 50 nm range ( see supplementary table 2 ) . in addition , y can be any observable / signal that is able to distinguish the different binding states , e.g. , efret ( see supplementary fig .
3
y=([ml][mt])(ymlym)+ym
mt is the total m concentration independent of ligation state , y is the observable , ym and yml are the binding transition baselines , and [ ml ] = ( b(b-4ac))/2a , with a=1 , b=kd[mt][lt ] , and c=[mt][lt ] . presented in supplementary fig .
7 are simulations for ligand binding at different mt , highlighting the advantage of single - molecule detection in resolving binding constants of high - affinity interactions .
using the binding constants derived from ensemble and single - molecule measurements ( see above and supplementary tables 1 - 2 ) , phase diagrams were generated to visualize the ligand concentration dependence of e1a interaction with its binding partners cbp taz2 and prb ( figs .
detailed descriptions of the general properties of protein phase diagrams , and their construction and interpretation are provided elsewhere . here
1a to describe the coupled folding and binding of e1a with cbp taz2 and prb . k1 and k1 , and k2 and k2 are equilibrium constants for e1a binding to cbp taz2 in the absence and presence of prb , and to prb in the absence and presence of cbp taz2 .
because the reaction scheme constitutes a complete thermodynamic cycle , it can be shown that k1/k1 = k2/k2. 50% phase separation lines were constructed as previously described , using partition functions ( qi ) that describe each of the four binding states ( i.e. , unfolded and unbound ( u ) , folded and cbp taz2-bound ( fl1 ) , folded and prb - bound ( fl2 ) and ternary ( fl1l2 ) states ) . for example , 50% phase separation lines between the u state and the three other binding states are calculated by equating qu with the sum of the remaining partition functions qfl1 , qfl2 and qfl1l2 .
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### Summary:
: allostery is an intrinsic property of many globular proteins and enzymes that is indispensable for cellular regulatory and feedback mechanisms .
recent theoretical1 and empirical2 observations indicate that allostery is also manifest in intrinsically disordered proteins ( idps ) , which account for a significant proportion of the proteome3,4 .
many idps are promiscuous binders that interact with multiple partners and frequently function as molecular hubs in protein interaction networks .
the adenovirus early region 1a ( e1a ) oncoprotein is a prime example of a molecular hub idp5 .
e1a can induce drastic epigenetic reprogramming of the cell within hours after infection , through interactions with a diverse set of partners that include key host regulators like the general transcriptional coactivator creb binding protein ( cbp ) , its paralog p300 , and the retinoblastoma protein ( prb)6,7 .
little is known about the allosteric effects at play in e1a - cbp - prb interactions , or more generally in hub idp interaction networks . here
, we utilized single - molecule frster / fluorescence resonance energy transfer ( smfret ) to study coupled binding and folding processes in the ternary e1a system .
the low concentrations used in these high - sensitivity experiments proved essential for these studies , which are challenging due to a combination of e1a aggregation propensity and high - affinity binding interactions .
our data revealed that e1a - cbp - prb interactions display either positive or negative cooperativity , depending on the available e1a interaction sites .
this striking cooperativity switch enables fine - tuning of the thermodynamic accessibility of the ternary vs. binary e1a complexes , and may permit a context - specific tuning of associated downstream signaling outputs .
such a modulation of allosteric interactions is likely a common mechanism in molecular hub idp function .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: although the term lupus erythematosus was introduced by the 19 century researchers to describe the cutaneous manifestations of the disease , it took almost a century to realize that the disease is systemic and spares no organ , and that it is caused by an aberrant immune response against self - antigens .
the prevalence ranges from 20 to 150 cases per 100,000 , with the highest prevalence reported in south america , and appears to be increasing steadily as the disease is recognized more readily and the survival is increasing . in the usa , people of hispanic , african or asian ancestry , as compared with those of other ethnic or racial groups , tend to have an increased prevalence of systemic lupus erythematosus ( sle ) and greater involvement of the key organs .
the clinicopathological studies from around the world , although showing variable incidence and prevalence rates among different populations , agree that the majority of patients with sle are women of childbearing age ; the female : male ratio ranges between 6 and 14:1 .
immune system aberrations , as well as hormonal , environmental and hereditary factors , contribute to the expression of the organ damage .
immune complexes , auto - reactive lymphocytes , auto - antibodies , dendritic cells and local factors are all involved in the manifestation of sle .
multiple mechanisms lead to a loss of self - tolerance and the emergence of auto - reactive clones and the production of auto - antibodies . as the immune response to self - antigens widens , the auto - antibody repertoire is enriched .
the nervous system is also frequently involved in sle , and the manifestations of nervous system involvement are protean .
we herein report a case of an adolescent girl with known sle who presented with eye signs and symptoms and was found to have raised intracranial pressure ( icp ) .
a 14-year - old female presented with complaints of diplopia , squint and severe generalized headache .
the patient was diagnosed with sle 3 months ago when she presented with acute renal failure and was found to have class iv lupus nephritis ( ln ) on renal biopsy and had anemia , butterfly rash and positive antinuclear antibody ( ana ) and anti - double stranded dna ( anti - dsdna ) .
she received methyl prednisolone 1 g for 3 days followed by two cycles of monthly cyclophosphamide along with oral steroids , with complete recovery of renal functions .
her course was complicated by bone marrow suppression and she was then treated with broad - spectrum antibiotics and antifungal agents .
she also developed a large grade 4 decubitus ulcer on her sacral area that required debridement .
she was discharged home on maintenance treatment of mycophenolate mofetil ( mmf ) on an outpatient basis .
her current admission 3 months later was for acute - onset diplopia and squint [ figure 1 ] .
she also complained of headache and subtle cognitive impairment , but no motor deficits were observed .
regarding extraocular movement , there was evidence of right abducens nerve involvement with restricted lateral movement in the right eye [ figure 2 ] . on eye examination ,
cornea , lens , vitreous humour and macula were all clear and normal in both eyes .
light brightness and red perception were sharper in the left eye compared with the right eye .
magnetic resonance arteriography / venography / imaging ( mra / mrv / mri ) showed abnormal signal intensity areas in the bilateral periventricular region , which provided evidence of vascular compromise and ischemic infarction .
the patient was given three more doses of methyl prednisolone suspecting lupus cerebritis , but her papilledema and squint did not improve .
it was raised significantly to 420 mmh2o ( normal : 50180 mmh2o ) , raising the suspicion of papilledema being secondary to raised icp .
azathioprine was stopped and the patient was discharged home on mmf and prednisolone and advised regular follow - up . at 2 months of follow - up , her squint and diplopia improved [ figure 4 ] , headache disappeared and visual functions normalized .
typically , the disease course in most patients is characterized by periods of flare and remission .
the duration and frequency of these flares , their severity and precise clinical picture differ significantly among patients .
this makes sle a challenging disease to diagnose and treat . in the most severe forms of sle ,
the kidney and the central nervous system are affected . according to the criteria set up by the american college of rheumatology ( acr ) in 1999 , neuropsychiatric sle ( npsle )
can be attributed to the disease ( primary npsle ) or be a complication of the disease or its treatment ( secondary npsle ) or be completely unrelated to sle representing an accidentally co - occurring disorder .
current knowledge holds the ischemia as the main cause of central nervous system ( cns ) manifestations in sle .
the mechanisms leading to ischemia are diverse and involve abnormalities of coagulation ; the development of focal atherosclerotic plaques in large arteries , thickening of the vessel walls due to different causes and , in some cases , inflammatory processes . in a few patients ,
cns syndromes are due to intracranial and intraspinal hemorrhages , but the factors that lead to the rupture of vessel walls have not yet been explored sufficiently .
lesions in the cerebral white matter are in general ischemic in origin and , in a few cases , they are due to reversible edema .
the white matter changes in the optic nerves and spinal cord are poorly understood . to the best of our knowledge ,
we have thoroughly worked up for all the possible causes of raised icp and abducens nerve palsy .
the raised icp leading to isolated abducens nerve palsy is a possible explanation ; however , there is no direct evidence supporting this postulated pathogenesis . in our case , even treatment with immunosuppression
the dramatic improvement on drainage of the csf might suggest that raised icp was responsible for the symptoms of this patient . to conclude , we have reported a case of an adolescent girl with sle who developed raised icp and abducens nerve palsy .
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### Summary:
: systemic lupus erythematosus ( sle ) is an auto - immune systemic disorder with protean manifestations .
it can involve any of the organs and systems of the body .
involvement of the nervous system and eye is not uncommon and is multifactorial .
we herein present a case of an adolescent girl with sle whose first presentation was with acute renal failure . her renal functions improved and she made full recovery .
three months later , she presented with eye symptoms and was found to have right abducens nerve palsy and bilateral papilledema .
her intracranial pressure was raised .
drainage of cerebrospinal fluid during lumber tap improved her eye signs and symptoms .
nervous system involvement and its pathogenesis are discussed with reference to this case and the published literature .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: in the current study , a self - administered questionnaire previously used by eldarrat ( 14 ) was utilized to assess the main aims of the study .
the questionnaire questions were related to participants nationality , age and sex , type and duration of diabetes , and their awareness for systemic and oral diseases as complications associated with diabetes . also , the questionnaire included questions to assess participant 's attitudes toward maintaining good oral health .
i do not know, encircling disease name , they were aware of as a complication of diabetes , or filling blank spaces .
a pilot study was carried out on 20 diabetic volunteers to assess the response of participants to the questionnaire before conducting the study .
two hundred questionnaires and consent forms were distributed to the diabetic patients attending the outpatient diabetic clinic in rashid hospital , one of the largest governmental hospitals in dubai , united arab emirates .
an information sheet explaining the need for the study and the procedure for responding to the questionnaire was enclosed as a cover sheet .
eligible participants were confirmed diabetes mellitus patients who can read and write and were free from any mental disabilities .
however , questionnaires with uncompleted answers were excluded and a total of 100 completed questionnaires were entered on an excel spreadsheet and imported into statistical package for social sciences ( spss ) version 13 ( spss inc . , chicago , il , usa ) for data statistical analysis .
the diabetic patients participating in the current survey were 10% united arab emirates ( uae ) nationals and 90% non - uae nationals , of whom 50% were male and 50% were female .
1 . as shown in the figure of the participants , 58% had type 2 diabetes , 26% had type 1 , and 16% did not know what type of diabetes they had .
regarding diabetic patients knowledge and awareness of systemic and oral complications associated with diabetes , in this survey the percentage of participants who were aware of their increased risk for eye disease ( 85% ) , heart disease ( 75% ) , kidney diseases ( 90% ) , periodontal disease ( 60% ) , dental caries ( 54% ) , and oral fungal infections ( 42% ) .
of these , 60% were unaware of the serious consequences of dry mouth on their oral health .
2 , the majority of the participants ( 70% ) were aware that bleeding during brushing is a sign of gingival disease , while 63% were aware that swollen red - colored gingiva is a sign of gum disease , and 19% were aware that soreness of the gingiva is a sign of periodontal disease .
figure 3 shows the diabetic patients attitude toward using a toothbrush for oral self - care . as the graph indicates , 19% of the respondents did not use a brush on a daily basis , 31% brushed twice a day , and a significantly higher number of respondents ( 50% ) brushed once a day .
figure 4 is a breakdown of the respondents attitude toward using dental floss as part of their oral self - care .
a significant proportion ( 66% ) never used dental floss , 11% reported using dental floss once a day , and 23% did not use on a daily basis .
the questionnaire also revealed that there is a relatively low percentage ( 40% ) of yearly visits to a dental clinic .
only 14% reported they visited for a regular dental check - up . in response to the question about whether they would wish to save a mobile tooth ,
24% of participants said they would prefer extraction and 16% would consent to extraction of an anterior tooth .
the decision made by a dentist in considering whether to extract a loose front tooth was favored by 70% of respondents . in decisions whether to have extraction of the mobile tooth
time and cost factors were less likely to influence the consent for extraction of either anterior or posterior tooth ( 4.2 and 7.1% , respectively ) .
as for the sources of participants knowledge and awareness of their increased risk for oral diseases , 37% of the participants had received this information from dentists , 4% from dental hygienists , and 45% from other sources such as television programs , the internet , magazines , and friends .
the recent rise in diabetes is not a genetic shift only but also an environmental shift as a result of lifestyle habits .
it was declared by who that 366 million people are expected to suffer from diabetes mellitus by 2030 . in the current study ,
more than half of the participants ( 58% ) had type 2 diabetes , 26% suffered from type 1 and , unexpectedly , 16% of participants did not know what type of diabetes they had .
the data presented in this study reveals an important finding : it clearly demonstrates that diabetics have more knowledge about their increased risk for systemic complications associated with diabetes than they do for oral and dental complications .
the percentage of participants who were aware of their increased risk for eye disease was 85% , heart disease 75% , kidney diseases 90% , periodontal disease 60% , dental caries 54% , and oral fungal infections 42% .
similar findings were reported by several researchers , who assessed the knowledge diabetic patients had of their risk for periodontal disease , their attitude toward oral health and their oral health - related quality of life .
researchers found that 98% of the participants were aware of their increased risk for eye disease , 84% for heart disease , 94% for kidney disease , and 33% for periodontal disease ( 13 ) .
another important finding of the present study is that the knowledge of diabetic patients of their increased risk for oral diseases such as periodontal disease , tooth caries , and fungal infections as result of mouth dryness was very inadequate .
more than 70% of the participants were suffering from dry mouth and were unaware of the harmful effect of xerostomia on their oral health .
it is well known that a significant reduction of salivary flow leading to xerostomia is the most common oral manifestation of diabetes .
it is of paramount importance to inform and make diabetics aware of the beneficial properties of saliva .
saliva 's function of washing and cleansing the oral cavity is known to prevent the accumulation of plaque and debris , which could be a contributing factor in diabetics increased risk for periodontal disease and dental caries ( 8 , 9 ) .
in addition , saliva has antimicrobial actions , which when impaired and the blood and saliva glucose concentrations are high , allows for the growth of candida organisms ( 16 ) .
moreover , diabetics should be informed and educated about the importance for keeping the oral cavity moist by stimulating salivary flow and frequent sips of water .
this study also revealed the additional important finding that diabetic patients have limited knowledge of the associations between oral health and overall health . in the current study
moreover , the majority of the participants were without dentures and ate selected soft foods that were easy to chew and swallow .
this has negative consequences on their glycemic control , general health , and health - related quality of life .
a recent study showed a significant association between dentate status of diabetics and their metabolic control scores , as a higher proportion of patients in the dentate group were found to have lower metabolic control scores ( 13 ) . in terms of their oral self - care , maintaining good oral hygiene was also poor among the participants .
half of the participants brushed their teeth once daily , 31% of the participants brushed their teeth twice daily , and 19% did not brush on a daily basis .
in addition , more than half of the participants never used dental floss to clean between their teeth .
similar results were reported by several investigators who found that of 299 participants , only 29% brushed their teeth on a twice - daily basis ( 17 ) .
the data of the present study showed that about 40% of the participants had not visited a dental clinic within the last year .
the main reason to visit a dental clinic within the last year was to receive treatment for pain and/ or discomfort .
this showed that participants attitude toward their oral health was poor in comparison with the findings of other surveys .
only 14% of participants in this survey visited regularly for dental check - ups compared with 37 , 47 , and 59% in a survey done in the uk ( 13 , 17 , 18 ) .
the results of this survey showed that the information regarding participants increased risk for oral diseases associated with diabetes came from dentists ( 37% ) , dental hygienists ( 4% ) , and 45% from other sources such as television programs , the internet , magazines , and friends .
it is of paramount importance for dental professionals to raise the awareness of diabetic patients of their increased risk for oral diseases and the impact of oral health on their general health .
research projects to determine awareness for diabetic patients of their increased risk for oral and dental diseases and their attitude to maintaining good oral health will significantly and positively impact their oral health - related quality of life .
early detection and treatment of tooth caries , periodontal disease , and other oral diseases would be of enormous benefit to protect diabetic patients from the harmful oral complications associated with diabetes .
in fact , one of the us national health objectives to be achieved by 2010 was to increase to 71% the proportion of people with diabetes who have an annual dental checkup ( 19 ) .
furthermore , it is necessary for dental professionals and related government agencies to promote awareness of the relationship between diabetes and oral heath in order to prevent harmful dental complications and expensive treatment .
within the limitations of the current study , the data presented in this study clearly demonstrated that diabetics have more knowledge about their increased risk for systemic complications associated with diabetes than they do for oral and dental complications . in order to promote proper oral health and to reduce the risk of oral diseases , health professionals in both the dental and medical fields need to take the responsibility to develop programs to educate the public about the oral manifestations of diabetes and its complications on oral health
the author has not received any funding or benefits from industry or elsewhere to conduct this study .
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### Summary:
: objectivesthe objectives of the study were to : ( 1 ) assess the knowledge and awareness of diabetic patients of their risk for systemic and oral diseases as complications associated with diabetes , ( 2 ) to assess their attitudes toward sustaining good oral health through proper oral hygiene and regular dental check - ups , and ( 3 ) to the extent that they are aware , to determine how they became aware.methodstwo hundred self - administered questionnaires were distributed to assess the main objectives of the study .
only completed questionnaires were used in the current study data analysis.resultsa majority of the participants had type 2 diabetes ( 58% ) .
the awareness of diabetic patients of their increased risk for oral diseases is low compared to their awareness of systemic diseases .
their attitude toward maintaining good oral health was also not to desired standard .
of the participants , 50% brushed their teeth once daily and 66% never used dental floss .
regarding participants sources of awareness , 37% learned from dentists and 45% through other media sources.conclusionsdiabetic patients are found to have little knowledge of their increased risk for oral diseases . in order to promote proper oral health and to reduce the risk of oral diseases , health professionals in both the dental and medical fields need to take the responsibility to develop programs to educate the public about the oral manifestations of diabetes and its complications on oral health .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: predicting an antidepressant s outcome early is important in the treatment of depression , as it helps clinicians decide on the next - best option for pharmacotherapy as soon as possible , shortening therapeutic time , and decreasing morbidity .
there is a growing body of literature suggesting that an early reduction in depressive symptoms by 24 weeks of treatment predicts the later response to the antidepressants.15 duloxetine , a serotonin
noradrenalin reuptake inhibitor , has been widely used and is the first choice among the options available for the treatment of depression , as with selective serotonin reuptake inhibitors.6 to date , there has been only one report investigating the relationship between early improvement in depressive symptoms and eventual outcomes in the treatment with duloxetine ; the study adopted a post hoc analysis and used the hamilton rating scale for depression ( ham - d ) for assessing the clinical status of the patients.7 we here examined whether early reduction in depressive symptoms could predict later remission to duloxetine during treatment of depression in a prospective manner , using the montgomery asberg depression rating scale ( madrs ) , which is designed to be more sensitive to treatment changes in the symptomatology of depression than the ham - d , as the primary outcome measure.8,9 based on our previous studies,10,11 the ten items of the madrs were classified into three factors : 1 ) dysphoria factor ( pessimistic thoughts , suicidal thoughts , reported sadness ) , 2 ) retardation factor ( lassitude , inability to feel , apparent sadness , concentration difficulties ) , and 3 ) vegetative factor ( reduced sleep , reduced appetite , inner tension ) .
we assessed whether early improvement in any of these factors is associated with eventual remission during the treatment of depression with duloxetine .
the inclusion criteria were as follows : 1 ) major depressive disorder according to the diagnostic and statistical manual of mental disorders , fourth edition , with a total score of 20 on the madrs ; 2 ) no other axis i or ii disorder ; 3 ) no treatment for the present episode ; 4 ) 18 years of age ; 5 ) absence of psychotic , catatonic , or atypical features ; 6 ) absence of postpartum onset or seasonal pattern ; and 7 ) absence of clinically meaningful physical disease or abnormal findings on physical examination or laboratory testing .
all patients who met the inclusion criteria and gave written informed consent were enrolled in this study .
duloxetine was administered at a dose of 20 mg / day , and then the dose was adjusted in the range of 2060 mg / day , based on the clinical status of the patients .
the starting dose of 20 mg / day was the recommended one for the treatment of duloxetine in japan .
clinical status was assessed using the madrs at weeks 0 , 4 , 8 , 12 , and 16 .
blood samples were obtained at least 2 weeks after the final dose adjustment of duloxetine had been made .
duloxetine plasma concentrations were detected by high - performance liquid chromatography . to analyze the data ,
the intent - to - treat last - observation - carried - forward method was used .
remission was defined as an madrs total score of 10 at the end point . to identify predictors of remission ,
binary logistic models of remission classification were generated , using the change in the madrs score from baseline to that at 4 weeks as the main predictor of interest , and age , sex , body mass index , madrs score at baseline , blood concentration of duloxetine , and duloxetine dose as secondary predictors .
as the madrs score consists of three components that are added for the total score , the dysphoria , retardation , and vegetative scores were analyzed as well .
the inclusion criteria were as follows : 1 ) major depressive disorder according to the diagnostic and statistical manual of mental disorders , fourth edition , with a total score of 20 on the madrs ; 2 ) no other axis i or ii disorder ; 3 ) no treatment for the present episode ; 4 ) 18 years of age ; 5 ) absence of psychotic , catatonic , or atypical features ; 6 ) absence of postpartum onset or seasonal pattern ; and 7 ) absence of clinically meaningful physical disease or abnormal findings on physical examination or laboratory testing .
all patients who met the inclusion criteria and gave written informed consent were enrolled in this study .
duloxetine was administered at a dose of 20 mg / day , and then the dose was adjusted in the range of 2060 mg / day , based on the clinical status of the patients .
the starting dose of 20 mg / day was the recommended one for the treatment of duloxetine in japan .
clinical status was assessed using the madrs at weeks 0 , 4 , 8 , 12 , and 16 .
blood samples were obtained at least 2 weeks after the final dose adjustment of duloxetine had been made .
to analyze the data , the intent - to - treat last - observation - carried - forward method was used .
remission was defined as an madrs total score of 10 at the end point . to identify predictors of remission ,
binary logistic models of remission classification were generated , using the change in the madrs score from baseline to that at 4 weeks as the main predictor of interest , and age , sex , body mass index , madrs score at baseline , blood concentration of duloxetine , and duloxetine dose as secondary predictors .
as the madrs score consists of three components that are added for the total score , the dysphoria , retardation , and vegetative scores were analyzed as well .
among the total of 106 patients enrolled , 67 were included in the statistical analysis , and the other 39 patients were excluded from it for the following reasons : no visit to our hospital after enrollment in the study ( 20 patients ) , stopped taking duloxetine due to side effects a few days after commencement of the study ( 12 patients ) , refusing to continue the study before first assessment ( three patients ) , and assumption of poor adherence to the treatment because blood concentration of duloxetine was ~0 ng / ml ( four patients ) . table 1 shows the patients characteristics , and the odds ratio estimated from our univariate logistic regression analysis of remission , with each factor cited in the table as a predictor .
table 2 shows the association between improvement at week 4 for each of the madrs scores and subsequent remission . from the univariate logistic regression analysis of remission , with each madrs score as a predictor
, we found that improvements in both the madrs total score and the dysphoria score at week 4 had a significant interaction with subsequent remission .
however , in the multivariate model using change in the madrs total , dysphoria , retardation , and vegetative scores from baseline to week 4 , in which age and sex were included as covariates , only sex retained significance except for improvement in dysphoria score ( table 3 ) .
figures 1 and 2 show the mean madrs total and subscale scores by visit , respectively .
from our univariate logistic regression analysis of remission based on the change in the madrs score from baseline to week 4 as predictor , we found that improvements in both the madrs total score and the dysphoria score at week 4 had a significant interaction with subsequent remission . furthermore , age and sex were significant predictors of remission , with an increase of nearly 4% in the odds of remission for each unit increase in age , and with females having 0.318 times that of the males odds of remission ( remission rate for men was 73.1% [ 19/26 ] and for women
however , in the multivariate model , using the change in the madrs score from baseline to week 4 , with age and sex included as covariates , only sex retained a significant effect , except for an improvement in the dysphoria score .
the mean madrs baseline score for males and females was 30.67.7 and 30.55.7 , respectively , with no significant difference between them ( t=0.063 , p=0.95 ) .
in seven clinical trials of duloxetine ( 40120 mg / day ) up to 9-week duration , kornstein et al suggested that the magnitude of improvement in depressive symptoms did not differ significantly between male and female patients.12 although this finding is inconsistent to ours , some previous reports assist our results in terms of sex difference .
tricyclic antidepressants , which affect both noradrenaline and serotonin reuptake inhibition , had a preferential effect in males,13,14 whereas females responded more poorly to tricyclic antidepressants than males1315 and appeared to respond better to selective serotonin reuptake inhibitors.14 morishita and arita have also reported that there was a tendency for a higher rate of improvement among males than among females in the treatment of depression with milnacipran , a serotonin
noradrenalin reuptake inhibitor , when improvement was defined by a 50% reduction from the baseline total ham - d score.16 the findings of these studies , as well as our own , may indicate that stimulating noradrenergic function is important for the treatment of depression in males .
katz et al investigated the association between early symptom reductions of 20% in the 17-item ham - d score during the first 2 weeks and the subsequent remission of depression over 8 months , which was defined by a ham - d score of 7 , in the treatment of depression with duloxetine .
they suggested that a 20% improvement in the ham - d total scores after 2 weeks of treatment with duloxetine , as well as some factor subscales , such as the core depression factor , including depressed mood , the anxiety factor , and the retardation factor , but not the sleep factor
, was predictive of sustained remission.7 although there are numerous differences in study design between our study and that of katz et al , including the definition of early response and the duration of the study period , our study also showed a change in the dysphoria factor score , including the subscale of depressed mood , after 4 weeks of treatment .
this was highly significant as a predictor of remission in the univariate model ( p=0.023 ) , but only borderline significant ( p=0.067 ) in the multivariate model . in the univariate models ,
a change from baseline to week 4 was borderline significant for the retardation factor ( p=0.06 ) , but was quite nonsignificant for the vegetative factor ( p=0.222 ) , including the sleep disturbance subscale , of the madrs .
this may suggest that early improvements in specific factors of depressive symptoms associated with depressed mood and retardation , as well as overall symptom reduction , tend to be useful values for predicting the later remission upon treatment with duloxetine .
madrs-6 is widely recognized as one that focuses on the core symptoms of depression ( as assessed by the madrs items : apparent sadness , reported sadness , inner tension , lassitude , inability to feel , and pessimistic thoughts ) .
an additional analysis in the univariate model showed that the change in madrs-6 score from baseline to week 4 was a significant predictor of remission ( p=0.043 ) .
however , in the multivariate model with age and sex included as covariates , early reduction in madrs-6 score had a no significant effect ( p=0.079 ) .
first , the uncontrolled nature of the study design is a major limitation , which substantially limits the conclusion that can be drawn .
inclusion of a placebo control arm would have helped significantly with the interpretation of the data .
second , we did not use the % improvement , which has often been used in similar types of reports,5,7 but adopted the change in score of the madrs from baseline to week 4 as the definition of early response , which makes it difficult to compare our results with those of others .
similarly , rather than using the % improvement , sakurai et al also adopted the score change in the quick inventory of depressive symptomatology from baseline to week 2 as a predictor of early response , and investigated its association with later remission during citalopram treatment in the star*d trial.3 third , the present study allowed clinicians to use some adjunctive anxiolytics and hypnotics , which could have contributed to a change in the clinical status of our patients .
fourth , the sample size was small , and the dropout rate was large , which may have affected the validity of our results .
there are some previous reports focusing on the same field as ours , in which the number of patients included is ~100.17,18 although we decided sample size of this study according to those reports described , more appropriate approach for sample size determination should have been adopted .
to date , this is the first study investigating whether early symptom changes could predict later remission among patients with depression receiving duloxetine treatment , adopting the madrs for clinical assessment .
no significant interaction was found between early madrs score reduction during the first 4 weeks and eventual remission at 16 weeks with the treatment with duloxetine .
when separating the madrs score into its three components , viz the dysphoria , retardation , and vegetative factors , we also did not find any significant association between early improvement in any of these factors and the final treatment outcomes . on the other hand ,
sex difference was found to be a predictor of subsequent remission in patients with depression who were treated with duloxetine , with males more likely to undergo remission than females .
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### Summary:
: purposein this prospective study , we examined whether early reduction in depressive symptoms predicts later remission to duloxetine in the treatment of depression , as monitored using the montgomery
asberg depression rating scale ( madrs).patients and methodsamong the 106 patients who were enrolled in this study , 67 were included in the statistical analysis .
a clinical evaluation using the madrs was performed at weeks 0 , 4 , 8 , 12 , and 16 after commencing treatment . for each time point
, the madrs total score was separated into three components : dysphoria , retardation , and vegetative scores.resultsremission was defined as an madrs total score of 10 at end point . from our univariate logistic regression analysis
, we found that improvements in both the madrs total score and the dysphoria score at week 4 had a significant interaction with subsequent remission . furthermore , age and sex were significant predictors of remission .
there was an increase of approximately 4% in the odds of remission for each unit increase in age , and female sex had an odds of remission of 0.318 times that of male sex ( remission rate for men was 73.1% [ 19/26 ] and for women
46.3% [ 19/41 ] ) .
however , in the multivariate model using the change from baseline in the total madrs , dysphoria , retardation , and vegetative scores at week 4 , in which age and sex were included as covariates , only sex retained significance , except for an improvement in the dysphoria score.conclusionno significant interaction was found between early response to duloxetine and eventual remission in this study .
sex difference was found to be a predictor of subsequent remission in patients with depression who were treated with duloxetine , with the male sex having greater odds of remission .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: when learning a new motor skill , the output of the motor system is adjusted following movement errors . a paradigmatic approach to examine
adaptation to a visuomotor rotation is seemingly automatic and gradual . nonetheless , when the errors are large , participants are aware that the stimulus - response mapping has been perturbed , and this may lead them to explore a compensatory strategy .
indeed , when participants are made aware of task manipulations , strategies can facilitate performance [ 35 ] , leading to the idea that strategic and adaptation processes may work in concert .
studies of visuomotor adaptation have generally not controlled or manipulated strategic processes : the generation and use of a strategy has been left up to the prerogative of the participant and probed in post - experimental interviews .
participants find it hard to verbalize use of a strategy and their descriptions tend to be highly idiosyncratic .
taking a more direct approach , mazzoni and krakauer provided an explicit strategy to facilitate learning of a visuomotor rotation .
participants were instructed that they could minimize the perturbing effects of the rotation by aiming at a landmark that was shifted in the opposite direction ( and angular size ) as the rotation .
this counterintuitive behavior was attributed to an implicit adaptation process that utilizes a movement error signal resulting from the mismatch between the strategic aiming location and visual feedback of the hand .
the persistent adaptation of the motor system to reduce this error resulted in learning that was counterproductive to good task performance . this profile one in which performance actually becomes worse with practice suggests a strong segregation of explicit and implicit learning processes .
traditionally , the cerebellum has been hypothesized as a critical site for computing movement errors essential for implicit adaptation .
patients with cerebellar pathology exhibit impairments in sensorimotor adaptation tasks , with their performance marked by persistent error and reduced aftereffects [ 811 ] . in most conditions ,
while this may reflect the operation of spared tissue within the cerebellum , it has been proposed that the patients spared learning may be largely driven by the adoption of a cognitive strategy , invoked to offset the impairment in error - based adaptation . when strategic control processes and implicit adaptation work in tandem , it is difficult to isolate the contribution of explicit and implicit processes .
in contrast , the strategic visuomotor rotation task introduced by mazzoni and krakauer is perfectly suited to isolate the effects of explicit and implicit learning processes , given that the task design puts these processes in opposition to one another .
this task has the additional feature that errors related to implicit adaptation progressively increase as training continues , a pattern opposite to that observed in typical studies of motor learning . if cerebellar pathology selectively disrupts implicit adaptive processes that utilize movement errors , then the patients would be expected to show more accurate and stable performance than control participants .
we recruited ten patients ( average age = 49.7 , sd = 13.7 ) with spinocerebellar ataxia ( sca ) and ten age / gender - matched controls ( 57.2 , sd = 7.81 ) with no known neurological conditions ( table 1 ) .
while all of the patients presented clinical evidence consistent with a diagnosis of cerebellar ataxia , the etiology was mixed .
three patients reported a family history of ataxia , but genetic testing had failed to identify a specific subtype .
the other four patients had cerebellar ataxia of unknown origin , termed sporadic adult onset ataxia ( saoa ) , with no known family history .
table 1demographics of the ten patients with cerebellar ataxia and ten control participantsparticipantgenderagehandednesstypeyearsicarsnart iqtrailstmtatmtbataxicscbl1female31rightsaoa14261140.120.43cbl2female38rightsaoa1101041.080.26cbl3male37rightfamily history6161000.310.47cbl4female66rightfamily history16151150.441.19cbl5female52rightsca712231152.351.57cbl6female54rightsca75221130.560.60cbl7female47rightsaoa1261081.744.02cbl8male68rightfamily history8261120.570.08cbl9male38rightsaoa19181080.881.15cbl10female66rightsca68541150.650.20controlscon1female54rightcon2male54rightcon3female55rightcon4female62rightcon5female70rightcon6male51rightcon7female46rightcon8female50rightcon9female65rightcon10male65rightfor the patients ( top ) , the table displays the type of ataxia ( when known ) , the years since initial diagnosis , scores on the icars test of ataxia , and scores on the neuropsychological assessments of higher cognitive function demographics of the ten patients with cerebellar ataxia and ten control participants for the patients ( top ) , the table displays the type of ataxia ( when known ) , the years since initial diagnosis , scores on the icars test of ataxia , and scores on the neuropsychological assessments of higher cognitive function the international cooperative ataxia rating scale ( icars ) was administered to assess the severity of the ataxia and was scored independently by two trained individuals .
the mean icars score was 23.6 ( sd = 11.9 ) , with the individuals exhibiting mild to moderate levels of ataxia . the neurological exam also allowed us to exclude individuals with overt signs of extracerebellar pathology ( e.g. , parkinson - like symptoms ) .
the patients also completed a series of neuropsychological assessments , with the tests selected to provide an assessment of dementia and frontal lobe function given that the task required the retained use of a strategy ( table 1 ) .
this abbreviated battery included the mini - mental state examination ( mmse ) to assess dementia , the tool for real - time assessment of information literacy skills ( trails ) test to assess attention and working memory , and the national adult reading test ( nart ) to assess intelligence .
none of the patients had any indication of dementia ( all mmse scores > 28 ) , and as a group , they exhibited above average intelligence ( nart estimate : mean = 110.3 , sd = 5.15 ) .
as a group , they scored within normal limits on the trails test part a ( mean z score , relative to published norms = 0.15 , sd = 1.14 ) and part b ( mean z = 0.61 , sd = 1.44 ) . the protocol was approved by the university s institutional review board , and participants provided informed consent .
the participants made horizontal reaching movements , sliding their hand along the surface of a table in an attempt to reach a visually displayed target .
lcd computer monitor ( 1,280 1,024 pixel resolution ) horizontally mounted 25.4 cm above the table . with this arrangement ,
the movements were tracked by a 3d motion tracking system ( minibird , ascension technology , burlington , vt , usa ; sampling rate = 138 hz ) with a sensor placed on the tip of the index finger . while the motion tracking system has a spatial resolution of approximately 0.05 cm , the monitor limited the actual resolution to 0.10 cm / pixel . on each trial , eight blue circles , 10 cm from the starting location and separated by 45 , were presented on the monitor . a green circle , the target , appeared at one location ( fig .
feedback was provided by a red cursor that appeared at the position where the hand crossed an invisible ring ( 10 cm radius ) .
following a feedback interval of 1,000 ms , the participants were guided back to the starting position by a white circle whose radius corresponded to the distance of the hand from the starting position .
a 2-cm circular piece of felt was attached on the table to help the participants identify the start position .
when the hand was within 1 cm of the start position , a red cursor appeared at the position of the hand .
once the cursor was at the starting position for 500 ms , the next target appeared .
the ordering of the target locations was pseudorandom such that each target location appeared once every eight trials .
the target , start region , and feedback cursor were all small circles , 0.8 cm in diameter .
1a , b mean trajectory during the baseline ( black ) and strategy - only ( orange ) blocks for a representative control participant ( a ) and patient with ataxia ( b ) .
movements are approximately straight and directed toward the cued green target in the baseline block and to the adjacent ( 45cw ) blue aiming target in the strategy - only block . shading indicates the 95% confidence intervals of the trajectories .
c , d target errors for these two participants across the phases of the experiment : second baseline phase ( black ) , rotation phase ( blue ; between vertical dashed lines ) , washout without feedback ( magenta ) , and washout with feedback ( cyan ) .
the rotation was turned on without warning for two movements ( red ) before the participants were instructed to use a strategy to counteract the rotation .
lower participants performed 244 movements throughout seven phases of the experiment a , b mean trajectory during the baseline ( black ) and strategy - only ( orange ) blocks for a representative control participant ( a ) and patient with ataxia ( b ) .
movements are approximately straight and directed toward the cued green target in the baseline block and to the adjacent ( 45cw ) blue aiming target in the strategy - only block .
c , d target errors for these two participants across the phases of the experiment : second baseline phase ( black ) , rotation phase ( blue ; between vertical dashed lines ) , washout without feedback ( magenta ) , and washout with feedback ( cyan ) .
the rotation was turned on without warning for two movements ( red ) before the participants were instructed to use a strategy to counteract the rotation .
lower participants performed 244 movements throughout seven phases of the experiment participants made a total of 244 movements , divided into a series of blocks ( fig .
for the first three blocks , no rotation was imposed . in an initial baseline block of 24 trials ,
the participants were then taught to use a 45 clockwise ( cw ) strategy . for this strategy - only block of 24 trials ,
they were instructed to aim to the blue circle ( aiming target ) that was adjacent in the clockwise direction from the cued , green target .
the red feedback cursor was presented at the true position at which the hand intersected the target ring ( i.e. , near the aiming target ) .
this strategy - only block was included to make sure that participants understood the aiming instructions that would be required when the rotation was introduced later in the experiment .
following this block , participants completed a second baseline block of 24 trials in which they again aimed for the cued , green target .
for these trials , the position of the feedback cursor was shifted by 45 counterclockwise ( ccw rotation ) from the actual hand position .
the rotation was introduced without warning and was highly salient given that the red feedback circle now appeared close to the blue circle located ccw from the cued , green target .
after two rotation - only trials , the participants were informed that they could cancel out the rotation by using the strategy that they had learned in the strategy - only block .
that is , to offset the rotation , they should reach to the blue target 45cw to the green target .
the rotation+strategy block consisted of 80 trials , ten to each of the eight targets .
participants were told that the rotation was no longer going to be applied and that they should again aim to the green target .
this allowed us to assess the magnitude of adaptation in the absence of a strategy and without further trial - by - trial learning .
following this , the participants performed 80 more trials in which the red feedback was visible , allowing for deadaptation .
kinematic information was analyzed with matlab ( mathworks , natick , ma , usa ) .
endpoint error was computed as the angle of the hand at 10 cm , relative to a straight line connecting the starting position and the target ( green circle except for the strategy - only block ) . to quantify peak drift on an individual basis
, we averaged the error over each set of eight movements ( one movement per target ) .
peak drift was defined as the bin with the maximum angular error during the rotation block .
movement onset was defined by identifying the maximum velocity and scanning the kinematic record backward to identify the last sign reversal in the velocity record .
movement time was defined as the interval between movement onset and when the hand crossed the virtual target ring . as a measure of movement curvature
, we computed the absolute area between the actual hand path and a straight - line path from the start position to the target .
our estimates of the variance are reported as the 95% confidence interval of the mean .
we recruited ten patients ( average age = 49.7 , sd = 13.7 ) with spinocerebellar ataxia ( sca ) and ten age / gender - matched controls ( 57.2 , sd = 7.81 ) with no known neurological conditions ( table 1 ) .
while all of the patients presented clinical evidence consistent with a diagnosis of cerebellar ataxia , the etiology was mixed .
three patients reported a family history of ataxia , but genetic testing had failed to identify a specific subtype .
the other four patients had cerebellar ataxia of unknown origin , termed sporadic adult onset ataxia ( saoa ) , with no known family history .
table 1demographics of the ten patients with cerebellar ataxia and ten control participantsparticipantgenderagehandednesstypeyearsicarsnart iqtrailstmtatmtbataxicscbl1female31rightsaoa14261140.120.43cbl2female38rightsaoa1101041.080.26cbl3male37rightfamily history6161000.310.47cbl4female66rightfamily history16151150.441.19cbl5female52rightsca712231152.351.57cbl6female54rightsca75221130.560.60cbl7female47rightsaoa1261081.744.02cbl8male68rightfamily history8261120.570.08cbl9male38rightsaoa19181080.881.15cbl10female66rightsca68541150.650.20controlscon1female54rightcon2male54rightcon3female55rightcon4female62rightcon5female70rightcon6male51rightcon7female46rightcon8female50rightcon9female65rightcon10male65rightfor the patients ( top ) , the table displays the type of ataxia ( when known ) , the years since initial diagnosis , scores on the icars test of ataxia , and scores on the neuropsychological assessments of higher cognitive function demographics of the ten patients with cerebellar ataxia and ten control participants for the patients ( top ) , the table displays the type of ataxia ( when known ) , the years since initial diagnosis , scores on the icars test of ataxia , and scores on the neuropsychological assessments of higher cognitive function the international cooperative ataxia rating scale ( icars ) was administered to assess the severity of the ataxia and was scored independently by two trained individuals .
the mean icars score was 23.6 ( sd = 11.9 ) , with the individuals exhibiting mild to moderate levels of ataxia . the neurological exam also allowed us to exclude individuals with overt signs of extracerebellar pathology ( e.g. , parkinson - like symptoms ) .
the patients also completed a series of neuropsychological assessments , with the tests selected to provide an assessment of dementia and frontal lobe function given that the task required the retained use of a strategy ( table 1 ) .
this abbreviated battery included the mini - mental state examination ( mmse ) to assess dementia , the tool for real - time assessment of information literacy skills ( trails ) test to assess attention and working memory , and the national adult reading test ( nart ) to assess intelligence .
none of the patients had any indication of dementia ( all mmse scores > 28 ) , and as a group , they exhibited above average intelligence ( nart estimate : mean = 110.3 , sd = 5.15 ) .
as a group , they scored within normal limits on the trails test part a ( mean z score , relative to published norms = 0.15 , sd = 1.14 ) and part b ( mean z = 0.61 , sd = 1.44 ) . the protocol was approved by the university s institutional review board , and participants provided informed consent .
the participants made horizontal reaching movements , sliding their hand along the surface of a table in an attempt to reach a visually displayed target .
lcd computer monitor ( 1,280 1,024 pixel resolution ) horizontally mounted 25.4 cm above the table . with this arrangement ,
the movements were tracked by a 3d motion tracking system ( minibird , ascension technology , burlington , vt , usa ; sampling rate = 138 hz ) with a sensor placed on the tip of the index finger . while the motion tracking system has a spatial resolution of approximately 0.05 cm , the monitor limited the actual resolution to 0.10 cm / pixel . on each trial , eight blue circles , 10 cm from the starting location and separated by 45 , were presented on the monitor . a green circle , the target , appeared at one location ( fig . 1a ) .
feedback was provided by a red cursor that appeared at the position where the hand crossed an invisible ring ( 10 cm radius ) .
the feedback cursor served as the only source of on - line feedback . following a feedback interval of 1,000 ms ,
the participants were guided back to the starting position by a white circle whose radius corresponded to the distance of the hand from the starting position .
a 2-cm circular piece of felt was attached on the table to help the participants identify the start position .
when the hand was within 1 cm of the start position , a red cursor appeared at the position of the hand .
once the cursor was at the starting position for 500 ms , the next target appeared .
the ordering of the target locations was pseudorandom such that each target location appeared once every eight trials .
the target , start region , and feedback cursor were all small circles , 0.8 cm in diameter .
1a , b mean trajectory during the baseline ( black ) and strategy - only ( orange ) blocks for a representative control participant ( a ) and patient with ataxia ( b ) .
movements are approximately straight and directed toward the cued green target in the baseline block and to the adjacent ( 45cw ) blue aiming target in the strategy - only block . shading indicates the 95% confidence intervals of the trajectories .
c , d target errors for these two participants across the phases of the experiment : second baseline phase ( black ) , rotation phase ( blue ; between vertical dashed lines ) , washout without feedback ( magenta ) , and washout with feedback ( cyan ) . the rotation was turned on without warning for two movements ( red ) before the participants were instructed to use a strategy to counteract the rotation .
lower participants performed 244 movements throughout seven phases of the experiment a , b mean trajectory during the baseline ( black ) and strategy - only ( orange ) blocks for a representative control participant ( a ) and patient with ataxia ( b ) .
movements are approximately straight and directed toward the cued green target in the baseline block and to the adjacent ( 45cw ) blue aiming target in the strategy - only block . shading indicates the 95% confidence intervals of the trajectories .
c , d target errors for these two participants across the phases of the experiment : second baseline phase ( black ) , rotation phase ( blue ; between vertical dashed lines ) , washout without feedback ( magenta ) , and washout with feedback ( cyan ) . the rotation was turned on without warning for two movements ( red ) before the participants were instructed to use a strategy to counteract the rotation .
lower participants performed 244 movements throughout seven phases of the experiment participants made a total of 244 movements , divided into a series of blocks ( fig .
for the first three blocks , no rotation was imposed . in an initial baseline block of 24 trials ,
the participants were then taught to use a 45 clockwise ( cw ) strategy . for this strategy - only block of 24 trials ,
they were instructed to aim to the blue circle ( aiming target ) that was adjacent in the clockwise direction from the cued , green target .
the red feedback cursor was presented at the true position at which the hand intersected the target ring ( i.e. , near the aiming target ) .
this strategy - only block was included to make sure that participants understood the aiming instructions that would be required when the rotation was introduced later in the experiment .
following this block , participants completed a second baseline block of 24 trials in which they again aimed for the cued , green target .
for these trials , the position of the feedback cursor was shifted by 45 counterclockwise ( ccw rotation ) from the actual hand position .
the rotation was introduced without warning and was highly salient given that the red feedback circle now appeared close to the blue circle located ccw from the cued , green target .
after two rotation - only trials , the participants were informed that they could cancel out the rotation by using the strategy that they had learned in the strategy - only block .
that is , to offset the rotation , they should reach to the blue target 45cw to the green target .
the rotation+strategy block consisted of 80 trials , ten to each of the eight targets .
participants were told that the rotation was no longer going to be applied and that they should again aim to the green target .
this allowed us to assess the magnitude of adaptation in the absence of a strategy and without further trial - by - trial learning . following this
, the participants performed 80 more trials in which the red feedback was visible , allowing for deadaptation .
kinematic information was analyzed with matlab ( mathworks , natick , ma , usa ) .
endpoint error was computed as the angle of the hand at 10 cm , relative to a straight line connecting the starting position and the target ( green circle except for the strategy - only block ) . to quantify peak drift on an individual basis
, we averaged the error over each set of eight movements ( one movement per target ) .
peak drift was defined as the bin with the maximum angular error during the rotation block .
movement onset was defined by identifying the maximum velocity and scanning the kinematic record backward to identify the last sign reversal in the velocity record .
movement time was defined as the interval between movement onset and when the hand crossed the virtual target ring . as a measure of movement curvature , we computed the absolute area between the actual hand path and a straight - line path from the start position to the target .
our estimates of the variance are reported as the 95% confidence interval of the mean .
as a group , the ataxics tended to move slightly slower than controls ( 312 57.6 vs. 273 45.3 ms ) , but this difference was not significant ( f1 , 18 = 1.8 , p = 0.20 ) .
movements were approximately straight for both groups , with a slight bias in the ccw direction . in the baseline block ,
in which no rotation was present and endpoint feedback was veridical , there was no difference in endpoint accuracy between the patients and controls ( f1 , 18 = 1.10 , p = 0.31 ) , and the degree of curvature was only marginally larger in the ataxic group compared to the controls ( f1 , 18 = 3.17 , p = 0.09 ) .
participants had little difficulty in adopting the 45cw strategy , indicating that they were able to understand and implement the instructions .
averaging over the last eight movements of the strategy - only block , the mean headings for the ataxic patients and controls were 43.3 1.5 and 44.5 1.4 , respectively ( f1 , 18 = 1.47 , p = 0.24 ) .
figure 1a , b shows the mean trajectories during the baseline ( black ) and strategy - only ( orange ) blocks for a representative control participant and individual with ataxia . after the strategy - only block , participants completed a second round of baseline movements ( fig .
the visuomotor rotation was then introduced without warning . as expected , this resulted in an error of approximately 45 ( in cursor space ) for both groups ( fig .
after two movements with this rotation , we instructed the participants that they could counteract the rotation - induced displacement and thus minimize their error , by adopting an explicit corrective strategy of aiming to the blue circle located 45cw from the target .
the mean endpoint error over the first eight reaches was 2.5 1.7 and 1.9 2.0 for the patients and controls , respectively .
the increase in endpoint error was manifested as a drift in the direction of the strategy reaching a maximum of 11.3 2.2 in the cw direction ( t9 = 9.80 , p < 0.001 ) . while the ataxic patients also exhibited drift , with the error rising to 5.9 1.9 in the cw direction ( t9 = 6.13 , p < 0.001 ) , the magnitude of this effect was approximately half that observed for the controls ( f1 , 18 = 12.9 , p = 0.002 ) .
thus , given their reduced drift , their overall performance during the rotation + strategy block , as measured by endpoint error , was less for the patients with ataxia compared to the controls ( f1 , 18 = 6.02 , p = 0.02 ) .
2a mean target error across the experimental session for each group ( filled = ataxic ; open = controls ) .
1 . b drift rate as estimated from regression analysis over the rotation + strategy phase .
the individual data are shown as empty circles for the control participants ( left ) and filled circles for the individuals with ataxia ( right ) a mean target error across the experimental session for each group ( filled = ataxic ; open = controls ) .
1 . b drift rate as estimated from regression analysis over the rotation + strategy phase .
the individual data are shown as empty circles for the control participants ( left ) and filled circles for the individuals with ataxia ( right ) given that drift occurred in a gradual and relatively continuous manner during the 80 trials of the rotation+strategy block ( see also mazzoni and krakauer ) , we fit the data from this block with a linear function to quantify the rate of drift as well as the initial bias ( i.e. , the intercept of the regression ) .
figure 2b displays the individual values for drift rate , as well as the group means .
the drift rate for the control group was significantly greater than zero ( t9 = 3.92 , p = 0.004 ) ; the rate was only marginally greater than zero for the ataxic group ( t9 = 2.09 , p = 0.066 ) .
a comparison of the two groups revealed a reliable increase in drift rate for the controls ( t18 = 2.45 , p = 0.025 ) .
there was no difference between the groups in terms of the initial bias ( t18 = 0.83 , p = 0.42 ) .
after the rotation+strategy block , the participants were told that the rotation had been turned off and that they should now move directly to the green target . to assess the degree of implicit adaptation in the absence of further learning
the movement heading of the ataxia patients was 0.3 1.6. this aftereffect is significant when compared to the baseline heading ( t9 = 3.23 , p = 0.01 ) , but not when compared to the target ( t9 = 0.38 , p = 0.71 ) .
the aftereffect for the control group was larger , averaging 6.2 2.4 , a significant shift when compared to the baseline ( t9 = 7.21 , p < 0.001 ) or target ( t9 = 5.18 , p < 0.001 ) .
a comparison between the two groups confirmed that the aftereffect was significantly greater for the controls compared to the patients ( f1 , 18 = 16.7 , p < 0.001 ) .
learning curves on a range of motor tasks exhibit two stereotypical phases , an initial rapid decrease in movement errors followed by a gradual phase in which performance continues to improve until reaching asymptote . here , we bypassed the rapid phase of this process by providing an explicit strategy that allowed participants to immediately counteract the visuomotor rotation .
this strategy allowed participants to immediately succeed in meeting the task goal . nonetheless , the processes underlying learning in the gradual phase continued to operate , at least for the control participants .
this obligatory motor adaptation led to a reverse learning curve in which task performance degraded with continued training , similar to that observed in young control participants .
motor adaptation is most likely a combination of explicit and implicit processes when participants are aware of movement errors .
our participants were all aware of the rotation and successfully able to employ a strategy that allowed them to compensate for the rotation .
the drift , reflecting a gradual deterioration in performance during extended training with the strategy , arises from the operation of implicit processes
. less clear is participants awareness of this drift and any adjustments they may have made to compensate for the drift . by the end of training , the drift was substantial in most of the participants in the control group ( over 10 ) .
the participants may have become aware of their poor performance and modified their strategy in an attempt to offset the drift .
indeed , as the errors increased , some of the participants verbalized their frustration with missing the target and one reported modifying his strategy to reach to an implicit location that was slightly less than 45 in the cw direction .
the patients with cerebellar degeneration were also able to employ the explicit strategy to counteract the visuomotor rotation .
in contrast to the controls , the performance of these individuals remained relatively stable over the course of training .
both of these observations are consistent with the hypothesis that the contribution of the cerebellum in this task is limited to those processes associated with implicit adaptation based on movement errors . in the absence of implicit adaptation ,
the patients were able to maintain accurate performance throughout training by using a stable strategy .
2b , there was considerable individual variability in drift rate for both the controls and patients .
we did not observe an effect of either age or gender on drift rate for either the controls or ataxics . within the patient group ,
drift rate did not correlate with number of years since ataxia onset ( r = 0.08 , p = 0.40 ) and showed only a weak trend to be positively related to the severity of ataxia as assessed by the icars score ( r = 0.21 , p = 0.18 ) . while various cognitive factors [ 1719 ] such as spatial working memory capacity have been shown to account for individual differences in adaptation tasks that do not entail explicit strategies , we failed to observe any correlations between drift rate and the various neuropsychological measures in our patient group .
previous research has demonstrated that patients with damage to the cerebellum are impaired across a range of tasks involving sensorimotor adaptation , including reaching in force fields [ 10 , 21 ] , prism adaptation , and visuomotor rotations [ 10 , 11 ] .
our results are in accord with these findings , providing a novel and , in some ways , a cleaner demonstration of a cerebellar - related deficit in adaptation given that drift provides an uncontaminated signature of implicit learning . in previous studies , an impairment in motor adaptation was associated with poor task performance and , correspondingly , persistent error signals .
this negative feedback might lead to volitional changes in performance , making it difficult to discern the locus of impairment . in the current study
, the learning deficit is revealed by task performance that is actually better than that exhibited by the control group . as such
, a deficit in error - based learning is inferred by error - free performance .
moreover , the current work provides compelling evidence of a strong dissociation between processes involved in strategic learning and those involved in implicit adaptation , linking the cerebellar contribution solely to the latter component .
previous work had suggested these two learning systems may work in tandem [ 5 , 22 , 23 ] , perhaps with explicit strategies providing a means to bootstrap adaptive processes . when these processes are pitted against one another as in the current task ,
the control data show that the implicit system continues to operate , even when it is maladaptive .
indeed , the control participants were puzzled to observe their performance deteriorate over time . when given the explicit strategy ,
in contrast , if patients with cerebellar degeneration are not provided with an explicit strategy , they show poor adaptation [ 8 , 10 , 11 ] .
this raises a puzzling question : if patients with cerebellar degeneration can effectively use an explicit strategy when instructed , why do they generally fail to spontaneously develop compensatory strategies ?
this paradox suggests that , while an explicit strategy does not influence implicit adaptation , the converse may not be true : implicit processes may influence explicit strategies .
typically the induced visual errors in visuomotor rotation studies are quite large , ranging from 30 to 60 [ 10 , 11 ] , and the patients are aware of their poor performance .
however , given the complex rotational pattern of the errors , generating a successful strategy may not be obvious .
the error pattern would need to be maintained in working memory to decipher the appropriate strategy .
sequence - learning deficits associated with cerebellar degeneration have been attributed to an impairment in working memory processes for maintaining stimulus - response representations .
a similar involvement of working memory may be present in visuomotor rotation and force field adaptation tasks when there are large errors .
thus , damage to the cerebellum may not only disrupt implicit adaptation but may also disrupt the generation of cognitive strategies , assuming that this error information is a prerequisite for the self - generation of a compensatory strategy .
this hypothesis offers one account of why patients with cerebellar degeneration show a greater impairment in learning to compensate for an abrupt and large force field perturbation , compared to when the perturbation is introduced gradually .
importantly , when an appropriate strategy is explicitly provided , this interaction between implicit and explicit systems is no longer required . in sum
, the current results suggest that implicit and explicit processes may not be independent , but rather that implicit mechanisms can inform processes involved in explicit control .
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### Summary:
: in sensorimotor adaptation , explicit cognitive strategies are thought to be unnecessary because the motor system implicitly corrects performance throughout training .
this seemingly automatic process involves computing an error between the planned movement and actual feedback of the movement . when explicitly provided with an effective strategy to overcome an experimentally induced visual perturbation , people are immediately successful and regain good task performance .
however , as training continues , their accuracy gets worse over time .
this counterintuitive result has been attributed to the independence of implicit motor processes and explicit cognitive strategies .
the cerebellum has been hypothesized to be critical for the computation of the motor error signals that are necessary for implicit adaptation .
we explored this hypothesis by testing patients with cerebellar degeneration on a motor learning task that puts the explicit and implicit systems in conflict .
given this , we predicted that the patients would be better than controls in maintaining an effective strategy assuming strategic and adaptive processes are functionally and neurally independent .
consistent with this prediction , the patients were easily able to implement an explicit cognitive strategy and showed minimal interference from undesirable motor adaptation throughout training .
these results further reveal the critical role of the cerebellum in an implicit adaptive process based on movement errors and suggest an asymmetrical interaction of implicit and explicit processes .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: gingival fibromatosis ( gf ) is a heterogeneous group of disorders characterized by progressive enlargement of the gingiva caused by an increase in submucosal connective tissue elements .
the etiology and pathogenesis of gingival hyperplasia are still not well established , however it could be directly linked to three factors : individual susceptibility , local factors ( dental plaque , caries , and iatrogenic factors ) and the action of chemical substances and their metabolites .
the condition is not painful until the tissue enlarges to partially cover the occlusal surface and becomes traumatized during mastication . due to massive gingival enlargement
, an affected child usually develops an abnormal swallowing pattern and experiences difficulty with speech and mastication . along with these features
all these factors will favor accumulation of materia alba and plaque , which further complicates the existing hyperplastic tissue .
acute pain associated with gingival hyperplasia leads to loss of masticatory ability and difficulty in swallowing food .
therefore , these patients have a tendency to swallow partially crushed food which eventually causes gastric disturbances .
the number of patients with this oral lesion have greatly increased in the last three decades .
hereditary gf ( hgf ) is a rare disease , affecting only one in 750,000 people while it can develop as an isolated disorder or a feature of a syndrome .
unlike in hgf and iatrogenic gf , in idiopathic gf ( igf ) , no causative agent can be identified and a family history is always lacking .
a 13-year - old female patient reported to the department of periodontics with a chief complaint of swollen gums involving all her teeth since last three years preventing proper speech , articulation , and mastication , causing inadequate lip apposition and poor esthetics .
she did not give any history of drugs intake , fever , anorexia , weight loss , seizures , hearing loss , nor was having any physical or mental disorder . also familial and postnatal history was non - contributory .
extra - oral examination revealed that the patient has incompetent everted lips and a convex profile .
an intraoral examination revealed generalized , diffused , nodular enlargement of the gingiva involving the upper and lower arches , which were pink in color , and had a firm and fibrous consistency [ figure 1 ] .
the teeth were barely visible as the enlarged gingiva covered till the incisal / occlusal third of the teeth .
punch biopsy was carried out which revealed bulbous increase in the connective tissue , which was relatively avascular and had densely arranged collagen - fiber bundles , numerous fibroblasts , and mild chronic inflammatory cells .
the overlying epithelium exhibited hyperplasia and had elongated rete ridges suggesting histological diagnosis of fibroepithelial hyperplasia .
on the basis of medical , family , drug history , clinical and histological findings , it was diagnosed as idiopathic gingival enlargement .
after completion of phase i treatment , a quadrant - wise gingivectomy was performed under local anesthesia using four different techniques . in first quadrant , ledge and wedge technique
was performed [ figure 3 ] followed by external bevel gingivectomy in second quadrant after ten days [ figure 4 ] .
ten days later , surgery using an electrocautery device with a medium size , loop electrode was performed in third quadrant [ figure 5 ] .
a soft tissue diode laser was used for gingivectomy in the fourth quadrant [ figure 6 ] .
also the patient acceptance towards the treatment was better with these two rather than the conventional approach [ figure 7 ] .
first quadrant - ledge and wedge technique second quadrant - external bevel gingivectomy third quadrant - electrocautery fourth quadrant - diode laser
extra - oral examination revealed that the patient has incompetent everted lips and a convex profile .
an intraoral examination revealed generalized , diffused , nodular enlargement of the gingiva involving the upper and lower arches , which were pink in color , and had a firm and fibrous consistency [ figure 1 ] .
the teeth were barely visible as the enlarged gingiva covered till the incisal / occlusal third of the teeth .
punch biopsy was carried out which revealed bulbous increase in the connective tissue , which was relatively avascular and had densely arranged collagen - fiber bundles , numerous fibroblasts , and mild chronic inflammatory cells .
the overlying epithelium exhibited hyperplasia and had elongated rete ridges suggesting histological diagnosis of fibroepithelial hyperplasia .
on the basis of medical , family , drug history , clinical and histological findings , it was diagnosed as idiopathic gingival enlargement .
after completion of phase i treatment , a quadrant - wise gingivectomy was performed under local anesthesia using four different techniques . in first quadrant , ledge and wedge technique
was performed [ figure 3 ] followed by external bevel gingivectomy in second quadrant after ten days [ figure 4 ] .
ten days later , surgery using an electrocautery device with a medium size , loop electrode was performed in third quadrant [ figure 5 ] .
a soft tissue diode laser was used for gingivectomy in the fourth quadrant [ figure 6 ] .
also the patient acceptance towards the treatment was better with these two rather than the conventional approach [ figure 7 ] .
first quadrant - ledge and wedge technique second quadrant - external bevel gingivectomy third quadrant - electrocautery fourth quadrant - diode laser
though the genetic mechanism is not well understood , the majority of the reported cases have attributed the condition of fibrous enlargement of gingiva to hereditary factors .
gingival hyperplasia can occur after therapy with drugs like phenytoin , cyclosporine , nifedipine , and nitrendipine .
the incidence of gingival enlargement caused by phenytoin , an anticonvulsant used in the treatment of epilepsy varies from 384.5% . whereas , cyclosporine a fairly potent immunosuppressive agent , used to prevent organ transplant rejection and to treat several disease of autoimmune origin , induced gingival enlargement in 30% of the cases .
nifedipine , which is a calcium channel blocker used in the treatment of acute and chronic coronary insufficiency , including angina pectoris and refractory hypertension and nitrendipine an analog of nifedipine have also been reported to induced gingival enlargement .
although gingival tissue may appear normal at birth , hyperplastic gf may become evident with the eruption of primary or permanent dentition , suggesting a trauma - induced tissue reaction during the eruption .
it has been suggested that gingival enlargement may be due to nutritional and hormonal factors ; however , these have not been completely substantiated .
the constant increase in the tissue mass can result in delayed eruption and displacement of teeth , arch deformity , spacing , and migration of teeth .
the condition is not painful until the tissue enlarges to partially cover the occlusal surface of the molars and become traumatized during mastication , which was observed in the present case . due to massive gingival enlargement
, an affected child usually develops abnormal swallowing pattern and experiences difficulty in speech and mastication . along with these features
all these will favor accumulation of materia alba and plaque , which further complicates the existing hyperplastic tissue .
it is not known if plaque control measures are effective in this condition ; however , it is a good practice to maintain the plaque control following gingivectomy procedure .
histologically , the gingival hyperplasia is mainly due to an increase and thickening of mature collagen bundles in the connective tissue stroma .
various modalities of treatment had been proposed including radical treatment with extraction of the involved teeth , which was reported not to favor a recurrence of the growth .
the only treatment of choice in this condition was gingivectomy to satisfy the patient 's esthetics .
though the tissue appeared to be pale and firm , the surgical procedure was complicated with excessive hemorrhage .
since recurrence could be expected within a few months after surgery and may return to the original condition within few years , the patient may have to undergo repeated gingivectomy procedures .
even though recurrence can not be predicted , the psychological and functional benefits far outweigh the risk of recurrence . oral hygiene and the superimposition of plaque accumulation have a crucial effect on the prognosis of gf .
long - term follow - up will be required to evaluate the predictability of the different surgical techniques .
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### Summary:
: idiopathic gingival enlargement is a proliferative fibrous lesion of the gingival tissue that causes esthetic and functional problems .
both genetically and pharmacologically induced forms of gingival enlargement exist .
this case report addresses the diagnosis and treatment of a case of idiopathic gingival enlargement in a 13-year - old female . the patient presented with generalized diffuse gingival enlargement involving the maxillary and mandibular arches extending on buccal and lingual / palatal surfaces and covering incisal / occlusal third of the tooth resulting in difficulty in speech and mastication since last three years .
patient also gave a history of surgical treatment being carried out four years back in upper anterior region suggesting of recurrence .
biopsy report confirmed the diagnosis of gingival hyperplasia .
gingivectomy was carried out in all four quadrants by using four different methods .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: constipation is a common health problem in childhood resulting in 3% of general pediatric and 25% of pediatric gastroenterology outpatient clinics visits .
factors underlying functional constipation are multiple as withholding stool , problems during toilet training and lack of fiber . in these children warning signs and symptoms should be questioned because it is important to distinguish functional and secondary constipation . moreover , even though constipation has a high prevalence , long term follow up results are limited . therefore , in this study we evaluated the clinical features and follow up data of children with functional and secondary constipation .
the study included 335 constipated children who were evaluated between february 2007 and february 2011 at dr .
age , gender , age of onset , previous treatments , response to the previous treatment , frequency of defecation , family history , abdominal pain , rectal bleeding , abdominal distension , stool withholding behaviour , fibre intake , aetiology of constipation , anthropometric findings , response to our treatment and relapses were noted .
constipated children were divided into 2 groups as functional and secondary according to history , physical exam and laboratory findings .
data analyses were performed using spss for windows , version 15.0 ( spss inc . ,
chicago , usa ) . means standard deviations ( sd ) were calculated for measurable variables .
an independent t test assessed the relationship between continuous variables and malnutrition , whereas the test was used for differences in proportions .
constipation had started at a mean age of 2.22.9 years ( median age 1.0 year ) in 335 children ( male / female : 167/168 , mean age : 4.33.5 years ) enrolled .
of these , 305 ( 91% ) were accepted to have functional constipation ( group 1 ) .
rest of the children ( 9% ) had an underlying disease and formed the group of secondary constipation ( group 2 ) ( table 1 ) .
aetiology of constipation in 335 children there was no significant difference with regard to sex and mean age between these groups ( p=0.2 , p=0.5 , respectively ) .
median age of onset was 1 year in group 1 and 0.25 years in group 2 , which was significantly lower ( p=0.02 ) .
however , these differences were not significant ( p=0.191 and p=0.479 , respectively ) . family history of constipation was significantly higher in group 1 ( 41% vs. 17% , p=0.015 ) .
malnutrition was found 18% in group 1 and 56% in group 2 ( p<0.001 ) .
obesity ratio was similar in both groups ( 6% in group 1 vs. 11% in group 2 , p=0.404 ) .
clinical findings of children with functional ( group 1 ) and secondary ( group 2 ) constipation demographic and anthropometric findings of children with functional and secondary constipation most of the patients had received treatment before ( 67% in group 1 , 70% in group 2 ) .
only 48% of these patients in group 1 and 38% in group 2 had succeeded .
some patients relapsed during follow - up ( 30% in group 1 vs. 44% in group 2 , p=0.715 ) .
peak incidence in childhood constipation is reported to be before 4 years of age , especially at the toilet training age .
secondary constipation is stated to be less than 10% similar to our result . even though the secondary constipation is not frequent
abdominal pain and stool withholding were more common in functional constipation group even this difference was not significant .
in other studies abdominal pain is seen in a wide range like 10 - 70% which also covers our result . however , abdominal pain is a subjective symptom .
family history is also frequent ( 13.9 - 39.3% ) in children with functional constipation .
the present study family history was present in 40.9% of children with functional constipation and it is found helpful in distinguishing functional and secondary constipation . failure to thrive is an alarm symptom to recognize organic causes . in our study also , children with secondary constipation had failure to thrive .
response rates were higher afterwards . we suppose that understanding the course of the disease and supporting the diet is important in this difference . however , there are relapses also .
relapse rates in the present study were similar to the results of van ginkel et al .
however , follow - up period is not long enough to give long - term results .
if a constipated child has a family history of constipation but does not have failure to thrive and constipation begins at an older age , functional constipation is more probable .
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### Summary:
: objectivewe aimed to evaluate clinical features and follow - up data of children with functional and secondary constipation.methodshospital records of 335 constipated children were evaluated .
children were divided into 2 groups as functional and secondary , and were compared with regard to clinical and anthropometric data.findingsof 335 children ( m / f 167/168 , mean age 4.33.5 years ) 91% had functional constipation ( group 1 ) .
family history of constipation was significantly higher in group 1 .
malnutrition was found in 18% of group 1 , 56% in group 2 ( p < 0.001).conclusionif a constipated child has a family history of constipation but does not have failure to thrive and constipation begins at an older age , functional constipation is more probable .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: in 2002 , an exact and efficient
helical cone - beam reconstruction method was developed by katsevich [ 1 , 2 ] , which is
a significant breakthrough in the area of helical / spiral cone - beam ct .
the
katsevich formula is in a filtered backprojection ( fbp ) format using data from
a pi - arc corresponding to the so - called pi - segment . by interchanging
the order of the hilbert
filtering and backprojection , zou and pan proposed a backprojection filtration
( bpf ) formula in the standard helical scanning case .
for important biomedical applications
including bolus - chasing ct angiography and electron - beam
ct / micro - ct , our group obtained the
first proofs of the general validities of both the bpf and fbp formulae in the
case of cone - beam scanning along a general smooth scanning trajectory [ 69 ] .
the
importance of performing exact image reconstruction from the minimum amount of
data has been recognized for a long time .
the first landmark achievement is the
well - known fan - beam half - scan formula .
a recent milestone is the two - step hilbert
transform method developed by noo et
al . .
in their framework , an object image on a
pi - line / chord can be exactly reconstructed if the intersection between the
chord and the object is completely covered by a field of view ( fov ) . very lately , defrise et al .
proposed an enhanced data
completeness condition that the image on a chord in the fov can be exactly
reconstructed if one end of the chord in the object is covered by the fov .
inspired by the tremendous biomedical
implications including local cardiac ct at minimum dose , local dental ct with
high accuracy , ct guided procedures , nano - ct , and so on , we recently proved , using
analytic continuation , that the interior problem can be exactly solved if a subregion
in an region of interest ( roi ) in the fov is known [ 19 , 20 ] , while the conventional
wisdom is that the interior problem does not have a unique solution .
a
natural question is whether our exact interior reconstruction method [ 19 , 20 ] can be extended to the interior
reconstruction of a volume of interest ( voi ) ?
, we prove the feasibility of the exact 3d
interior reconstruction using the bpf and fbp approaches , respectively . in the fourth section
the basic setting of our previous work is cone - beam
scanning along a general smooth trajectory
( 1)={(s)s}.
as shown
in figure 1 , a generalized pi - line of r3 is defined as the line through r and is intersecting the scanning
trajectory at two points (sb ) and (st ) on with sb < st ,
where sb = sb(r ) and st = st(r ) are the parameter values corresponding to these two points . at the same
time , the pi - segment ( also called a chord ) l is defined as the segment of the pi - line
between (sb ) and (st ) ,
the pi - arc is the part of the trajectory between (sb ) and (st ) ,
and the pi - interval is [ sb , st ] .
suppose that an object function f(r ) is constrained in a compact support 3 .
for any unit vector ,
let us define a cone - beam projection of f(r ) from a source point (s ) on the trajectory by
( 2)df((s),):=0f((s)+t)dt .
then , we define a unit vector (s , r ) as the one pointing to rl from (s ) on the trajectory : ( 3)(r , s):=r(s)|r(s)| . we also
need a unit vector along the chord : ( 4)e:=(st)(sb)|(st)(sb)| .
assume that there are three points a , b , c on the chord l with b situating between a and c. suppose that ( i ) the projection data df((s),(r , s ) ) are known and df((s),(r , s))0 , both for any s[sb , st ] and for any r on the line - segment ac ( and its small neighborhood ) , and ( ii ) f(r ) is known on the line - segment ab. then , the function f(r ) can be exactly and stably reconstructed on the line - segment bc. we have several remarks on theorem 1 .
our
condition ( i ) implies that the cone - beam projection data are both
longitudinally and transversely truncated but the derivative ( /q)df((q),(r , s))|q = s is available
for any s[sb , st ] and for any r on line - segment ac .
this is the 3d interior reconstruction problem which does not have a
unique solution according to the conventional wisdom .
our condition ( ii )
demands prior information for the interior reconstruction which regularizes the
ill - posedness of the interior reconstruction and make its solution accurate and
robust .
as discussed in our
earlier paper , we may assume that the known
data are on another
subinterval of the line - segment ac ,
or a union of such intervals .
in
practice , we may find that the function f(r ) is known inside a subregion of the voi ,
such as air around a tooth , water in a device , or metal in a semiconductor .
then , the exact interior reconstruction of the unknown parts of the voi becomes
feasible if their corresponding chords intersect with the known voi .
our
generalized bpf algorithm [ 6 , 7 ] requires the backprojection of projection data
derivative ( /q)df((q),)|q = s on a fixed chord and the inverse hilbert transform
along the 1d chord .
recall that the
backprojection at rl can be expressed as [ 6 , 7 ] ( 5)g(r):=sbstq(df((q),(r , s ) ) df((q),(r , s)))|q = sds|r(s)| . condition ( i ) implies that g(r ) is available on the line - segment ac. if we setup a local 1d
coordinate system on the chord l ,
theorem 1 can be reduced to the following 1d case . as shown in figure 2 , assume that e1<a < b < c < e2 and the 1d function f(x ) is supported on the interval [ e1,e2 ] .
f(x ) can be exactly reconstructed on ( b , c ) if ( i ) the hilbert transform g(x ) of the function is known on ( a , c ) ; ( ii ) f(x ) is known on ( a , b ) ; and ( iii ) the constant e1e2f(x)dx is known theorem 2
is exactly what we proved in our previous paper . hence , we complete the proof of
theorem 1 in the bpf framework .
for an
arbitrary smooth scanning curve (s ) on the pi - interval [ sb , st ] and any point r on the chord l from (sb ) to (st ) ,
the exact fbp reconstruction formula can be expressed as
( 6)f(r)=122sbstds|r(s)|pv 02qdf((q),(s , r,))|q = sdsin , where pv
represents a principal value integral , and (s , r, ) represents the
filtering direction which is taken in the pi - segment direction and defined as cos+sine with the unit directions =(r , s ) and e=((e(e))/|e(e)| ) ,
that is , (s , r, ) supposes a clockwise rotation in the plane
determined by l and (r , s ) ,
centered at (s ) with (s , r,0)=(r , s ) ( see figure 1 ) . for a fixed (s ) ,
the filtering plane remains unchanged for all rl .
as shown in figure 3
, we can change the variable to so that the direction for =0 now points to the direction e ,
and the filtering direction is still specified clockwise .
let (r , s ) denote the angle from e ( =0 ) to (r , s ) .
then , ( 6 ) can be rewritten as ( 7)f(r)=122sbstds|r(s)|pv qdf((q),(s,))|q = sdsin((r , s ) ) .
note that (s , r, ) now is changed to (s, ) which is independent of rl ,
and the value of (r , s ) is negative .
our condition ( i ) implies that ( 8)pv(a , s)(c , s)qdf((q),(s,))|q = sdsin((r , s ) ) is known for
any s[sb , st ] and for any r on the line - segment ac. to reconstruct f(r ) on the line - segment bc ,
we need to know that ( 9)h(r)=122sbstds|r(s)|pv [,],[(a , s),(c , s ) ] qdf((q),(s,))|q = sdsin((r , s ) ) for r on the line - segment bc.
in fact , the inner integral of ( 9 ) is an ordinary integral for r on the line - segment ac.
let rp(s ) denote the point on l such that ( rp(s)(s ) ) is perpendicular to l ,
as shown in figure 4 .
then , sin ((r , s))=sin cos ( (r , s))cos sin ( (r , s ) ) with ( 10)sin((r , s))=|rp(s)(s)||r(s)|,cos((r , s))=|rrp(s)||r(s)| , where =1 if r is on the (st ) side of rp(s ) and =1 if r is on the (sb ) side of rp(s ) .
if we use complex plane coordinates ( see figure 4 ) with the origin (sb ) and the positive direction from (sb ) to (st ) ,
then we have ( 11)cos((r , s))=rrp(s)|r(s)| .
then , h(r ) in ( 9 ) becomes ( 12)h(r)=122sbstds[,],[(a , s),(c , s ) ] qdf((q),(s,))|q = s dsin (rrp(s))+cos |rp(s)(s)| .
note that
the denominator under d is nonzero for r on ac in the real axis .
therefore , if we replace r by z in ( 12 ) , h(z ) is an analytic function on the complex plane
with cuts along the real axis from to a and from c to + .
as a result , we can always take derivatives
with respect to z under integration on the right side of
( 12 ) , and the proof follows the same arguments as in the proof of
cauchy s integral theorem . by condition ( ii ) , f(r ) is known on the line - segment ab. hence , ( 13)f(r)=122sbstds|r(s)|pv (a , s)(c , s)qdf((q),(s,))|q = s dsin((r , s))+h(r ) is known for r on the line - segment ab.
assumption ( i ) and ( 8) imply that the first term on the right side of
( 13 )
is also known .
therefore , h(z ) is known for any z on the line - segment ab.
then , by analytic continuation , h(z ) on the line - segment bc can be uniquely determined by its value on the
line - segment ab.
that is , ( 9 ) is known for r on the line - segment bc.
by assumption ( i ) , ( 8) is known for r on the line - segment bc.
this gives us the exact and stable reconstruction of f(r ) on the line - segment bc by ( 7 ) .
first , these arguments work for the generalized pi - line
filtering direction only .
if the filtering direction is not in the pi - line
direction , neighboring points on the same pi - line will require different
filtering integrals .
in this case , currently we do not know how to link a
filtering integral to another filtering integral for the interior
reconstruction .
second , the translation
from (r , s ) to rrp(s ) is a crucial step .
without such a step , one
can not deal with the effect of the outer integral in ( 9 ) .
with that change ,
while we have proved that the exact and stable 3d interior
reconstruction is feasible from data focusing on a voi and collected along a
general smooth scanning trajectory , we believe that our results can be also
extended to the case of discontinuous scanning trajectories . the general exact
cone - beam reconstruction results were reported for both continuous and
discontinuous trajectories [ 68 , 12 , 13 ] .
similarly , we can use the same tricks such as in [ 12 , 13 ] to formulate more general
results .
we will elaborate this type of
ideas further in the future , such as for triple - source cone - beam ct [ 22 , 23 ] . because the closed - form method for analytic continuity is unavailable ,
we adapted a projection onto convex set ( pocs ) method and a singular value decomposition
( svd ) method for exact 2d interior reconstruction ,
and these methods can be further adapted for exact 3d interior reconstruction
and should have the same noise characteristics . moreover
, the bpf and fbp formulations will lead
to different numerical implementations for exact 3d interior reconstruction
when an analytic continuity method is given . according to our theorem
, the function value
of f(r ) must be known in some subregions of a voi to be reconstructed . for
practical applications and further research , we may use and add other
constraints or prior information into the interior reconstruction process such
as an iterative reconstruction procedure .
these additional constraints may be included but not be limited to mean and other moment
values , histogram features , maximum / minimum values of subregions or involved
components , and low - resolution images related to the voi ( subregions or
neighbors ) . even if we do not know the
exact function value of f(r ) in a subregion or we do not necessarily need
exact reconstruction , we can still utilize our analytically obtained guidelines
to construct approximate reconstruction algorithms .
in addition to ct - specific interior reconstruction techniques ,
we recognize that our approach for interior reconstruction can be readily
applied for mri , spect , pet , and other geometric optic - based imaging modes .
furthermore , we feel that our exact interior
reconstruction results can be extended into the case of the exponential attenuated
radon transform [ 24 , 25 ] .
specifically , we can use iterative algorithms to produce superior images
in the same spirit of the exact interior ct reconstruction .
our general hypothesis is that we can start
with a generalized hilbert transform of attenuated radon data and reach similar
conclusions by analytic continuation .
while analytic algorithms may be developed
for the uniformly attenuation spect / pet , iterative algorithms ( e.g. , pocs )
should be feasible for exact 3d interior spect / pet reconstruction in the case
of non - uniformly attenuation background . in the ct field , the most popular imaging model assumes a monochromatic
source and a motionless subject .
. however , our results are
also relevant to polychromatic and/or dynamic imaging . by utilizing truly local data instead of
global data
, we may achieve better temporal resolution , higher image contrast ,
less image artifacts , and so on .
this
aspect seems deserving more research efforts as well . in conclusion , using the bpf and fbp approaches , respectively ,
we have proved that the 3d exact interior reconstruction is feasible from both longitudinally
and transversely truncated data
collected along any general scanning trajectory only through an internal voi .
our previous reconstruction algorithms for
exact 2d interior reconstruction can be directly applied in the 3d case .
our results can take other mathematical forms ,
can be extended to other imaging fields , and have tremendous application
potentials .
|
### Summary:
: using the backprojection filtration ( bpf ) and filtered backprojection ( fbp ) approaches , respectively , we prove that with cone - beam ct the interior problem can be exactly solved by analytic continuation .
the prior knowledge we assume is that a volume of interest ( voi ) in an object to be reconstructed is known in a subregion of the voi .
our derivations are based on the so - called generalized pi - segment ( chord ) . the available projection onto convex set ( pocs ) algorithm and singular value decomposition ( svd ) method
can be applied to perform the exact interior reconstruction .
these results have many implications in the ct field and can be extended to other tomographic modalities , such as spect / pet , mri .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: acute coronary syndromes ( acs ) are a manifestation of ischemic heart disease with high morbidity and are a leading cause of mortality in industrialized countries .
according to the universal definition of myocardial infarction , elevated cardiac troponin is one of the key diagnostic components for the diagnosis of acute myocardial infarction ( ami ) .
high - sensitivity troponin t ( hs - tnt ) assay does not provide information on the mechanism of cell damage despite its high sensitivity in the detection of myocardial necrosis .
accordingly , patients with chest pain , elevated markers of myocardial cell damage , and ecg changes are typically referred to invasive coronary angiography . however , a proportion of coronary angiograms , ranging from 4% to 7% , are revealed to be culprit - free , angiographically normal , epicardial coronary arteries .
acute chest pain in non - acute coronary syndrome ( non - acs ) patients may be the clinical manifestation of a variety of pathologies , including myocarditis , pulmonary or coronary artery embolism , stress cardiomyopathy ( takotsubo cardiomyopathy , ttc ) , and myocardial ischemia originating from microvascular dysfunction . in these patients
therefore , an accurate diagnosis in this group is crucial to achieve accurate risk stratification and to choose the best treatment strategy .
cardiac magnetic resonance ( cmr ) has been shown to be ideally suited for myocardial tissue characterization and is able to detect and differentiate pathologic changes at the level of myocardium .
however , cmr is of limited availability across europe . the present study aimed at the evaluation of the additional value of cmr over commonly available non - cmr standard tests , including hs - tnt assay , for the differentiation of myocardial injury in patients with acs and non - obstructed coronary arteries
patients admitted with an initial diagnosis of acs and having normal coronary arteries at coronary angiogram were prospectively enrolled in this multicenter , observational study .
enrollment was performed in 2 tertiary cardiology centers , the 2 department of cardiology , zabrze , silesian medical university of katowice ( sum ) , poland and the department of cardiology , centre hospitalier universitaire vaudois ( chuv ) , lausanne , switzerland between january 2009 and july 2013 .
inclusion criteria were : 1 ) acute retrosternal chest pain during the last 24 h , 2 ) elevated hs - tnt level ( > 14 ng / l ) at admission or after 6 h , and 3 ) nonsignificant coronary stenosis on coronary angiogram ( stenosis < 30% ) as analyzed by 2 independent invasive cardiologists .
exclusion criteria were : 1 ) history of coronary revascularization , 2 ) past myocardial infarction , 3 ) hypertensive heart disease , 4 ) tachyarrhythmia , 5 ) peripheral artery disease , 6 ) history of stroke , 7 ) coronary vasospasm , 8) renal insufficiency ( creatinine > 200mol / l ) , and 9 ) recent septicemia . during hospitalization a clinical examination , ecg , and echocardiography were obtained for every patient .
baseline blood samples were analyzed for full blood count , c - reactive protein ( crp ) , hs - tnt , creatine kinase myocardial bound ( ck - mb ) , and lipid profile .
the measurement of hs - tnt was conducted on the cobas e 411 immunoanalyzer , which is based on electrochemiluminescence technology ( with detection limit of 310000 ng / l , 99 percentile level of 14 ng / l , and 10% coefficient of variation level of 13 ng / l ) according to the manufacturer instructions ( roche diagnostics , mannheim germany ) .
all patients were referred to the hospital with a suspicion of ami and underwent an initial work - up with past medical history , current symptoms , clinical , electrocardiographic and echocardiographic examination , hs - tnt level , and coronary angiogram .
the infection was defined as symptoms of recent ( < 14 days ) respiratory or gastro - intestinal infection with or without fever .
after exclusion of ami with a culprit - free coronary angiogram , patients were reclassified and referred for cmr with a suspicion of either ttc ( based on mayo clinic criteria ) or myocarditis ( based on european society of cardiology position statement ) .
all procedures were conducted according to current clinical standards of care and no additional consent was obtained regarding ethical concerns .
final diagnosis was based on the distribution pattern of myocardial injury as identified by the late gadolinium enhancement ( lge ) in cmr .
cmr studies were performed using a ge signa mr scanner ( sum , poland ) , a siemens magnetom symphony ( until 2009 ) , or a magnetom aera ( starting in 2009 ) mr scanner ( chuv , switzerland ) .
the cmr protocol included sequences for left ventricular ( lv ) volumes , function , and mass .
lv function and mass were assessed using a stack of standard ecg - gated , steady - state , free precession ( ssfp ) , short axis images covering the lv from base to apex . recommended major diagnostic cmr criteria for myocarditis were primarily based on the findings on lge , a marker of incomplete washout of contrast medium from myocardium , late after the injection ( 1020 min after the intravenous administration of conventional extracellular gadolinium chelate at a dose of 0.150.2 mmol / kg ) . in a subset of patients ( see below ) , edema - sensitive t2-weighted images ( t2-ratio ) ( using a triple inversion - recovery sequence with inversion pulses , including blood flow and fat suppression ) and global t1 enhancement ( early gadolinium enhancement [ ege ] obtained from spin echo imaging techniques and defined as an increased normalized uptake of gadolinium chelate early [ ~3 min ] after its intravenous administration ) were also assessed . to efficiently null the signal of viable myocardium
abnormalities were analyzed from short axis view , 2- , 3- , and 4-chamber views , and localized based on the american heart association 17-segment model .
ami was diagnosed if subendocardial signal enhancement in the distribution of a coronary artery was detected on lge sequences ( with or without a corresponding positive finding on t2-weighted images and/or mvo ) ( figure 1 ) .
myocarditis was diagnosed if subepicardial and/or patchy lge lesions were detected in the lv myocardium according to previously published studies ( figure 2 ) . when scan logistics were favorable , t2-weighted and t1-weighted sequences were also acquired to calculate t2-ratio and t1-global enhancement as described elsewhere ( n=24 , sum , poland ) . cmr was considered normal if there were no lge , mvo , or t2 intensity abnormalities , and if left and right ventricular function were normal .
in the patients with suspected ttc ( based on normal coronary arteries in coronary angiogram and typical wall motion abnormalities on baseline echocardiography ) , the diagnosis of ttc was maintained after the cmr study , if myocarditis and typical infarct pattern in lge was excluded by cmr , even when regional wall motion abnormalities were no longer present .
data at 30 days were obtained by phone calls or were retrieved from medical records .
data at 6 months were gathered during a control visit in the outpatient unit , which included basic physical examination , echocardiographic examination , and a review of medical treatment . a combined clinical end - point included death of cardiovascular origin , non - fatal ami , heart failure ( de novo according to framingham criteria or decompensation of existing heart failure ) , and electrocardiographically documented ventricular tachyarrhythmia .
values are presented as means standard deviation or median ( 25 ; 75 percentile ) as appropriate .
the comparison of variables between groups was performed using t - test or mann - whitney u test and kruskal - wallis test for continuous variables and chi - square test for categorical variables .
tulsa , ok , usa ) and graphpad prism software version 6.00 ( graphpad , la jolla , california , usa ) .
patients admitted with an initial diagnosis of acs and having normal coronary arteries at coronary angiogram were prospectively enrolled in this multicenter , observational study .
enrollment was performed in 2 tertiary cardiology centers , the 2 department of cardiology , zabrze , silesian medical university of katowice ( sum ) , poland and the department of cardiology , centre hospitalier universitaire vaudois ( chuv ) , lausanne , switzerland between january 2009 and july 2013 .
inclusion criteria were : 1 ) acute retrosternal chest pain during the last 24 h , 2 ) elevated hs - tnt level ( > 14 ng / l ) at admission or after 6 h , and 3 ) nonsignificant coronary stenosis on coronary angiogram ( stenosis < 30% ) as analyzed by 2 independent invasive cardiologists .
exclusion criteria were : 1 ) history of coronary revascularization , 2 ) past myocardial infarction , 3 ) hypertensive heart disease , 4 ) tachyarrhythmia , 5 ) peripheral artery disease , 6 ) history of stroke , 7 ) coronary vasospasm , 8) renal insufficiency ( creatinine > 200mol / l ) , and 9 ) recent septicemia . during hospitalization a clinical examination , ecg , and echocardiography were obtained for every patient .
baseline blood samples were analyzed for full blood count , c - reactive protein ( crp ) , hs - tnt , creatine kinase myocardial bound ( ck - mb ) , and lipid profile .
the measurement of hs - tnt was conducted on the cobas e 411 immunoanalyzer , which is based on electrochemiluminescence technology ( with detection limit of 310000 ng / l , 99 percentile level of 14 ng / l , and 10% coefficient of variation level of 13 ng / l ) according to the manufacturer instructions ( roche diagnostics , mannheim germany ) .
all patients were referred to the hospital with a suspicion of ami and underwent an initial work - up with past medical history , current symptoms , clinical , electrocardiographic and echocardiographic examination , hs - tnt level , and coronary angiogram .
the infection was defined as symptoms of recent ( < 14 days ) respiratory or gastro - intestinal infection with or without fever .
after exclusion of ami with a culprit - free coronary angiogram , patients were reclassified and referred for cmr with a suspicion of either ttc ( based on mayo clinic criteria ) or myocarditis ( based on european society of cardiology position statement ) .
all procedures were conducted according to current clinical standards of care and no additional consent was obtained regarding ethical concerns .
final diagnosis was based on the distribution pattern of myocardial injury as identified by the late gadolinium enhancement ( lge ) in cmr .
cmr studies were performed using a ge signa mr scanner ( sum , poland ) , a siemens magnetom symphony ( until 2009 ) , or a magnetom aera ( starting in 2009 ) mr scanner ( chuv , switzerland ) .
the cmr protocol included sequences for left ventricular ( lv ) volumes , function , and mass .
lv function and mass were assessed using a stack of standard ecg - gated , steady - state , free precession ( ssfp ) , short axis images covering the lv from base to apex . recommended major diagnostic cmr criteria for myocarditis were primarily based on the findings on lge , a marker of incomplete washout of contrast medium from myocardium , late after the injection ( 1020 min after the intravenous administration of conventional extracellular gadolinium chelate at a dose of 0.150.2 mmol / kg ) . in a subset of patients ( see below ) , edema - sensitive t2-weighted images ( t2-ratio ) ( using a triple inversion - recovery sequence with inversion pulses , including blood flow and fat suppression ) and global t1 enhancement ( early gadolinium enhancement [ ege ] obtained from spin echo imaging techniques and defined as an increased normalized uptake of gadolinium chelate early [ ~3 min ] after its intravenous administration ) were also assessed . to efficiently null the signal of viable myocardium
abnormalities were analyzed from short axis view , 2- , 3- , and 4-chamber views , and localized based on the american heart association 17-segment model .
ami was diagnosed if subendocardial signal enhancement in the distribution of a coronary artery was detected on lge sequences ( with or without a corresponding positive finding on t2-weighted images and/or mvo ) ( figure 1 ) .
myocarditis was diagnosed if subepicardial and/or patchy lge lesions were detected in the lv myocardium according to previously published studies ( figure 2 ) . when scan logistics were favorable , t2-weighted and t1-weighted sequences
were also acquired to calculate t2-ratio and t1-global enhancement as described elsewhere ( n=24 , sum , poland ) . cmr was considered normal if there were no lge , mvo , or t2 intensity abnormalities , and if left and right ventricular function were normal . in the patients with suspected ttc ( based on normal coronary arteries in coronary angiogram and typical wall motion abnormalities on baseline echocardiography ) , the diagnosis of ttc
was maintained after the cmr study , if myocarditis and typical infarct pattern in lge was excluded by cmr , even when regional wall motion abnormalities were no longer present .
data at 30 days were obtained by phone calls or were retrieved from medical records .
data at 6 months were gathered during a control visit in the outpatient unit , which included basic physical examination , echocardiographic examination , and a review of medical treatment . a combined clinical end - point included death of cardiovascular origin , non - fatal ami , heart failure ( de novo according to framingham criteria or decompensation of existing heart failure ) , and electrocardiographically documented ventricular tachyarrhythmia .
values are presented as means standard deviation or median ( 25 ; 75 percentile ) as appropriate .
the comparison of variables between groups was performed using t - test or mann - whitney u test and kruskal - wallis test for continuous variables and chi - square test for categorical variables .
tulsa , ok , usa ) and graphpad prism software version 6.00 ( graphpad , la jolla , california , usa ) .
from january 2009 to july 2013 , 5110 patients were admitted to the emergency departments with chest pain and were identified with elevated levels of cardiac biomarkers . of these , 75 patients ( 1.5% ) had a normal coronary angiogram and were eligible for the study .
the mean age was 40.014.6 years , 31 patients ( 79% ) were male , and 21 patients ( 28% ) presented with a recent history of infection .
after initial clinical assessment using standard tests and provisional exclusion of ami by coronary angiogram , 69 patients ( 92% ) had suspected myocarditis and 6 patients ( 8% ) had suspected ttc ( figure 3 ) .
patients in these 2 diagnostic categories did not differ regarding cardiovascular risk factors or baseline ecg .
patients in the ttc group were older ( p=0.03 ) and all were female ( p<0.001 ) .
median lvef was lower for ttc patients than in myocarditis patients ( 48% vs. 59% , respectively , p<0.001 ) .
no differences were found regarding wall motion abnormalities ( wma ) , chamber diameters , or pericardial effusion .
the biomarkers of myocardial necrosis for the total cohort were elevated but did not differ between groups ( p=0.67 for hs - tnt , p=0.51 for ck - mb ) . in patients in the ttc group ,
lower values of erythrocytes count , hemoglobin and hematocrit and higher values of high - density lipoprotein ( hdl ) were observed ( table 1 ) .
cmr was performed in all 75 patients , with a mean delay of 12.8 days after the onset of cardiac symptoms .
cmr showed diagnostic changes in 79% of cases ( 59 patients ) and was normal in 21% ( 16 patients ) ( figure 3 ) .
out of the 16 patients with negative lge findings , in 6 patients t2-ratio and t1 global enhancement were also determined . in only 1 patient out of those ( 1/6 patients ) , a borderline positive t1 global enhancement of 3.4 was found ( normal < 2.9 ) , while the t2 ratio of 1.3 was also within normal limits ( normal < 2.0 ) .
therefore , this patient was categorized as normal , i.e. non - injured myocardium as assessed by lge (= myocarditis negative ) . out of the 49 patients with lge findings positive for myocarditis , in 18 patients t2-ratio and t1 global enhancement
out of these 18 lge - positive patients , t2-ratio and t1 global enhancement were positive in 8 and 7 patients , respectively . in
the patients included into the study ( i.e. , patients with acute chest pain , elevated markers of myocardial necrosis , and normal coronary arteries ) , the diagnosis of the standard diagnostic tests ( clinical examination , ecg , echocardiography , biomarkers , and coronary angiogram ) was correct in only 66% of patients ( 50 patients ) based on the final results provided by cmr as the gold standard ( 47 out of 69 suspected and 3 ttc out of 6 suspected ) . with the initial assessment ,
specifically , the diagnosis was changed in 9 patients ( 12% ) , and suspected myocardial disease was excluded in another 16 patients ( 21% ) . out of 69 patients with initially suspected myocarditis , the diagnosis was confirmed in 47 patients ( 68% ) , reclassified to ami in 6 patients ( 9% ) and to non - injured myocardium in 16 patients ( 23% ) . among 6 patients with suspected ttc
, the diagnosis was confirmed in 3 ( 50% ) , reclassified to myocarditis in 2 ( 33% ) , and to ami in 1 ( 17% ) . in summary , the final diagnosis after cmr was unrecognized ami in 7 patients ( 9% ) , myocarditis in 49 patients ( 65% ) , ttc in 3 patients ( 4% ) , and non - injured myocardium in 16 patients ( 21% ) ( figure 3 ) .
no differences in ecg , echocardiographic characteristics , and biomarkers were found between those groups ( table 2 ) .
groups differed regarding age ( older patients in the ttc group and younger patients in the myocarditis group , p=0.002 ) and sex ( with 86% of males in the myocarditis group and no males in the ttc group , p<0.001 ) .
no clinical endpoints were reported for the 30-day and 6-month follow - up . at the 6-month follow - up ,
2% ( range 22;20 ) for the total population and 3% ( range 22;20 ) , 1% ( range 16;8 ) and 4% ( range 3;7 ) for the myocarditis , ami , and non - injured myocardium group , respectively , p=0.91 .
the mean age was 40.014.6 years , 31 patients ( 79% ) were male , and 21 patients ( 28% ) presented with a recent history of infection .
after initial clinical assessment using standard tests and provisional exclusion of ami by coronary angiogram , 69 patients ( 92% ) had suspected myocarditis and 6 patients ( 8% ) had suspected ttc ( figure 3 ) .
patients in these 2 diagnostic categories did not differ regarding cardiovascular risk factors or baseline ecg .
patients in the ttc group were older ( p=0.03 ) and all were female ( p<0.001 ) .
median lvef was lower for ttc patients than in myocarditis patients ( 48% vs. 59% , respectively , p<0.001 ) .
no differences were found regarding wall motion abnormalities ( wma ) , chamber diameters , or pericardial effusion .
the biomarkers of myocardial necrosis for the total cohort were elevated but did not differ between groups ( p=0.67 for hs - tnt , p=0.51 for ck - mb ) . in patients in the ttc group ,
lower values of erythrocytes count , hemoglobin and hematocrit and higher values of high - density lipoprotein ( hdl ) were observed ( table 1 ) .
cmr was performed in all 75 patients , with a mean delay of 12.8 days after the onset of cardiac symptoms .
cmr showed diagnostic changes in 79% of cases ( 59 patients ) and was normal in 21% ( 16 patients ) ( figure 3 ) .
out of the 16 patients with negative lge findings , in 6 patients t2-ratio and t1 global enhancement were also determined . in only 1 patient out of those ( 1/6 patients ) , a borderline positive t1 global enhancement of 3.4 was found ( normal < 2.9 ) , while the t2 ratio of 1.3 was also within normal limits ( normal < 2.0 ) .
therefore , this patient was categorized as normal , i.e. non - injured myocardium as assessed by lge (= myocarditis negative ) . out of the 49 patients with lge findings positive for myocarditis , in 18 patients t2-ratio and t1 global enhancement
out of these 18 lge - positive patients , t2-ratio and t1 global enhancement were positive in 8 and 7 patients , respectively . in
the patients included into the study ( i.e. , patients with acute chest pain , elevated markers of myocardial necrosis , and normal coronary arteries ) , the diagnosis of the standard diagnostic tests ( clinical examination , ecg , echocardiography , biomarkers , and coronary angiogram ) was correct in only 66% of patients ( 50 patients ) based on the final results provided by cmr as the gold standard ( 47 out of 69 suspected and 3 ttc out of 6 suspected ) . with the initial assessment ,
specifically , the diagnosis was changed in 9 patients ( 12% ) , and suspected myocardial disease was excluded in another 16 patients ( 21% ) . out of 69 patients with initially suspected myocarditis , the diagnosis was confirmed in 47 patients ( 68% ) , reclassified to ami in 6 patients ( 9% ) and to non - injured myocardium in 16 patients ( 23% ) . among 6 patients with suspected ttc
, the diagnosis was confirmed in 3 ( 50% ) , reclassified to myocarditis in 2 ( 33% ) , and to ami in 1 ( 17% ) . in summary , the final diagnosis after cmr was unrecognized ami in 7 patients ( 9% ) , myocarditis in 49 patients ( 65% ) , ttc in 3 patients ( 4% ) , and non - injured myocardium in 16 patients ( 21% ) ( figure 3 ) .
no differences in ecg , echocardiographic characteristics , and biomarkers were found between those groups ( table 2 ) .
groups differed regarding age ( older patients in the ttc group and younger patients in the myocarditis group , p=0.002 ) and sex ( with 86% of males in the myocarditis group and no males in the ttc group , p<0.001 ) .
no clinical endpoints were reported for the 30-day and 6-month follow - up . at the 6-month follow - up ,
no significant echocardiographic changes were observed when compared with the initial examination . the median change in lvef as assessed by echocardiography was
2% ( range 22;20 ) for the total population and 3% ( range 22;20 ) , 1% ( range 16;8 ) and 4% ( range 3;7 ) for the myocarditis , ami , and non - injured myocardium group , respectively , p=0.91 .
patients with chest pain , elevated troponin , and normal coronary arteries constitute a heterogeneous group with unclear prognosis . in several studies these patients had similar or even worse prognosis than patients with ami receiving revascularization therapy [ 1820 ] whereas other authors reported an evolution without adverse events .
establishing the correct diagnosis is therefore crucial to ensure that patients are correctly risk - stratified and receive adequate treatment .
our data suggest that the standard diagnostic workup with ecg , biomarkers , and echocardiography is insufficient in this setting , and that a large proportion of patients presenting with acute coronary syndrome , elevated troponin , and normal coronary angiogram have probable myocarditis .
the sensitivity of cmr to detect myocarditis ranges from 60% to 90% [ 2426 ] , depending on localization of the pathological process and lge in the myocardium , the cmr sequence used , wall thickness , the challenging comparison between histological segments with cmr locations , the technique of histopathological analysis used , and patient selection .
endomyocardial biopsy is the gold standard test to diagnose myocarditis , with a recent position paper of the esc favoring the systematic use of endomyocardial biopsy in this particular setting , but its use is currently restricted to specific clinical situations because of its invasive nature and the potential complications associated with this procedure . in the present study , cmr was performed according to the current recommendations .
, 65% of patients received the final diagnosis of myocarditis and 9% of the study population was diagnosed with unrecognized ami .
this is in contrast to previous data in which cmr yielded a higher rate of ami in patients with acs presentation and culprit - free coronary angiogram , but it is in line with other reports showing that most patients admitted with chest pain , high troponin , and normal coronary angiogram were finally diagnosed with myocarditis . of notice ,
the diagnosis of myocarditis was based on lge assessment only in the majority of cases with 32% ratio of co - evaluation with t1 global enhancement and t2-ratio , which should be mentioned in the context of assessing the rate of myocarditis / ami in the studied population .
one might have expected to find a higher proportion of ischemia - induced myocardial damage ( lge positive areas ) with cmr in the population diagnosed with elevated hs - tnt as the marker for myocardial damage .
previous studies reported a higher incidence of myocardial necrosis despite the absence of significant ( > 30% ) epicardial coronary stenosis .
however , these studies also included patients with minimal atheromatosis in coronary angiogram and a positive history of coronary artery disease ( cad ) .
conversely , in our cohort , patients with a positive history of cad were excluded and the majority of patients had completely smooth coronary arteries in angiography ( figure 4 ) with no case showing diffuse cad ( mild pathological changes were found in only 8 patients ) .
this is reflected in the low ( 1.5% ) incidence of fulfilling the criteria for culprit - free angiograms .
thus , in the earlier studies cad was more advanced than in our study , most likely explaining the lower incidence of necrotic lesions detected by cmr in our study . out of the 8 patients with mild pathological changes in the coronary angiogram , 1 was diagnosed with ami . a retrospective analysis of the angiogram in this patient with ami revealed an occluded thin diagonal branch ( < 1 mm ) , which was missed at first , possibly responsible for the localized transmural zone of lge on cmr .
some authors suggest that cmr could be chosen even before coronary angiography as the primary investigation if supported by relevant clinical findings .
others raised the problem of cardiovascular risk underestimation and demonstrated that the incidence of ami in young adults is not marginal . in the present population ,
young patients ( < 40 years old ) constituted 55% of the myocarditis group and 14% of the ami group ( median 58 vs. 37 years , respectively , p=0.02 ) .
although young patients are being diagnosed with myocarditis 4 times more frequently than older patients , their 14% contribution to the ami group is important . therefore , also in young patients
, cmr should not be preferred over coronary angiography , with the latter remaining the diagnostic method of choice for a definite exclusion of cad in the setting of acute chest pain .
considering the relatively weak diagnostic yield of standard tests , cmr should be strongly advised in cases of acute chest pain , elevated troponin , and normal coronary arteries .
the study hypothesis was built and driven by a threatening diversity in the statistics of cmr utilization across europe .
it is known that in western european regions , cmr has a utilization rate of 13% and the regional diversity in cmr availability is important . in switzerland ,
a single university hospital ( chuv , lausanne ) reports approximately 1500 exams per year ( per ~0.51 million inhabitants ) , while an annual rate of 250 cmr examinations is reported in the silesian region of poland for a population of over 4.6 million inhabitants ( data from the silesian department of the national health insurance service , 2013 ) . and
finally , in romania , cmr is still rarely available in some regions ( e.g. , no cmr was available until 2013 in jassy , with a population of > 300 000 ) . in the era of minimizing invasive diagnostic procedures and the tendency to perform evidence - based medicine
, cmr emerges as the most appropriate diagnostic method , counterbalancing the financial , social , and personal costs of a misdiagnosed patient .
the number of enrolled patients was rather low and was not sufficient to achieve statistical significance for the comparison of a large number of variables between groups .
although included patients mainly had smooth coronary arteries on coronary angiography , the lack of routine application of intravascular ultrasound or coronary optical coherence tomography has to be mentioned . due to independent technical conditions ,
the time window of cmr was broad and the results provided could led to under - diagnosis of the characteristic transient pattern of ttc or lower frequency of abnormalities indicative of myocarditis ( edema and lge ) .
the number of enrolled patients was rather low and was not sufficient to achieve statistical significance for the comparison of a large number of variables between groups .
although included patients mainly had smooth coronary arteries on coronary angiography , the lack of routine application of intravascular ultrasound or coronary optical coherence tomography has to be mentioned . due to independent technical conditions ,
the time window of cmr was broad and the results provided could led to under - diagnosis of the characteristic transient pattern of ttc or lower frequency of abnormalities indicative of myocarditis ( edema and lge ) .
the study results suggest the high diagnostic yield of cmr in patients with an acute coronary syndrome and a culprit - free angiogram .
the diagnostic performance of commonly available non - cmr - based tests in this setting is insufficient and leads to a 9% missed diagnosis of ami if not verified by cmr .
the evaluation of patients with chest pain , elevated troponin , and normal coronary arteries should be complemented by a cmr examination if available .
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### Summary:
: backgroundin spite of robust knowledge about underlying ischemic myocardial damage , acute coronary syndromes ( acs ) with culprit - free angiograms raise diagnostic concerns . the present study aimed to evaluate the additional value of cardiac magnetic resonance ( cmr ) over commonly available non - cmr standard tests , for the differentiation of myocardial injury in patients with acs and non - obstructed coronary arteries.material/methodspatients with acs , elevated hs - tnt , and a culprit - free angiogram
were prospectively enrolled into the study between january 2009 and july 2013 .
after initial evaluation with standard tests ( ecg , echocardiography , hs - tnt ) and provisional exclusion of acute myocardial infarction ( ami ) in coronary angiogram , patients were referred for cmr with the suspicion of myocarditis or takotsubo cardiomyopathy ( ttc ) . according to the result of cmr , patients were reclassified as having myocarditis , ami , ttc , or non - injured myocardium as assessed by late gadolinium enhancement.resultsout of 5110 patients admitted with acs , 75 had normal coronary angiograms and entered the study ; 69 of them ( 92% ) were suspected for myocarditis and 6 ( 8% ) for ttc .
after cmr , 49 patients were finally diagnosed with myocarditis ( 65% ) , 3 with ttc ( 4% ) , 7 with ami ( 9% ) , and 16 ( 21% ) with non - injured myocardium .
the provisional diagnosis was changed or excluded in 23 patients ( 31% ) , with a 9% rate of unrecognized ami.conclusionsthe study results suggest that the evaluation of patients with acs and culprit - free angiogram should be complemented by a cmr examination , if available , because the initial work - up with non - cmr tests leads to a significant proportion of misdiagnosed ami .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: therefore , liver function integrity is essential to maintain a physiological metabolism of carbohydrates , lipids , and amino acids .
lipids are insoluble in water , thus they are carried along the plasma with proteins .
lipoproteins are globular , high - molecular - weight particles consisting of a core which contains non - polar lipids , triglycerides , and cholesterol esters , and surrounded by a polar surface coat , made of a single layer of phospholipids , unesterified cholesterol , and specific proteins , the so - called apolipoproteins.[47 ] apolipoproteins , which are synthesized by liver and gut , are expressed on the surface of lipoproteins and , besides ensuring the structural stability , they influence lipoprotein metabolism by activating specific enzymes and binding to cellular receptors . since the liver plays a crucial role in lipid and lipoprotein metabolism , the significant impairment of the hepatic function occurring during chronic liver diseases , including hepatocellular carcinoma ( hcc ) , can influence plasma lipid profiles .
hcc is a challenging malignancy of global importance and is associated with a high rate of mortality .
nowadays , hcc is representing the fifth most common cancer all over the world and the third most frequent cause of mortality amongst oncological patients .
it is responsible for more than 500 000 deaths with over 600 000 new worldwide cases yearly .
more than 95% of patients with hcc have an underlying chronic liver disease which is most often associated with virus hepatitis b and c. hcc is now the leading cause of death among cirrhotic patients .
the best pathogenetic hypothesis points out a process with several stages . in this process , mature hepatocytes acquire further genetic alterations in a microenvironment where the coexistence of hepatic necrosis , inflammation and regeneration leads to the selection of monoclonal populations and the formation of dysplastic nodules .
the staging systems for hcc take into account the severity of concomitant liver disease and the degree of the residual liver function , which are major conditioning elements for prognosis .
the systems so far proposed to measure the liver function are not fully accepted by everyone , therefore the research is still aimed at developing new methods of measurement
. a greater number of reports on hcc have shown abnormal plasma patterns of lipids and lipoproteins.[31618 ] this review is focused on the pathophysiological significance and the clinical impact given by fluctuations in lipoprotein(a ) ( lp(a ) ) plasma levels observed during hcc .
lipoprotein(a ) , also called lp(a ) , is a lipoprotein subclass ; it is a suis generis molecule consisting of a low - density lipoprotein ( ldl)-like particle whose apob-100 is covalently bound to the apoprotein(a ) ( apo(a ) ) through a disulfide bridge .
it was first described more than 40 years ago by berg though it still looks like a mysterious molecule , as its physiological role has not been revealed yet .
there is an analogy between the apo(a ) and the plasminogen genes : they both have coding sequences for loop structures , stabilized by intrachain disulfide bonds , the so - called kringle ( k ) domains .
apo(a ) contains 10 distinct subclasses of plasminogen kringle iv - like domains ( kiv1kiv10 ) . while apo(a )
kiv types 1 and 310 are present as single copies , the kringle iv type 2 domain ( kiv2 ) is present in a variable number of identically repeated copies and it is the molecular basis for the observed isoform size heterogeneity of lp(a ) .
the heterogeneity of apo(a ) explains a large fraction of the variability of plasma lp(a ) concentrations , and there is a clear negative correlation between the molecular weight of apo(a ) and the plasma lp(a ) concentration.[2224 ] the two main lp(a ) subunits , apo(a ) and apob-100 , are independently processed and released by the liver to form covalent particles within the extracellular compartment .
the final assembly of lp(a ) occurs trough a two - step mechanism where a noncovalent interaction between apo(a ) and apob-100 precedes the disulfide linkage formation .
lp(a ) catabolism still remains unclear , but there is evidence against a great involvement of ldl receptors in this process . the most widely used methods to measure lp(a ) in the clinical laboratory are the commercially available immunoassays ( immunoturbidimetric analysis and elisa method ) .
lp(a ) plasma levels are extremely variable among individuals , from less than 0.2 to more than 200 mg / dl , and their distribution does not follow a gaussian type curve
. approximately 90% of the population have serum lp(a ) values lower than 300 mg / l though values above 20000 mg / l have occasionally been found .
although lp(a ) circulating concentrations are mostly determined by genetic factors , they may display more or less significant fluctuations , under different physiological and pathological situations or pharmacological agents .
reported that lp(a ) concentrations were significantly higher among the acute phase response patients ( infections , postoperative , tumors , and other diseases ) than among the controls .
the clinical interest around lp(a ) largely springs from the recognition of it as a cardiovascular risk factor .
although it is not counted among the major traditional risk factors , increased lp(a ) levels have shown a correlation with cardiovascular disease in several studies.[3234 ] moreover , recent data indicate that lp(a ) is a cardiovascular risk factor independent of traditional ones , such as ldl cholesterol , low hdl cholesterol levels , hypertension , diabetes mellitus , obesity , sedentary , and smoking . in some cancer types , apart from hcc , lp(a )
plasma levels have been found to be elevated , but in general few data are still available about lp(a ) concentrations in cancer patients .
since the majority of hccs occur in patients with liver cirrhosis , the evaluation of the liver function plays a central role in the fields of therapeutic decision , tumor staging , and prognosis .
liver function can be assessed readily by routine laboratory tests ( alanine and aspartate aminotransferase , albumin and bilirubin serum levels , prothrombin and international normalized ratio ( inr ) values , platelet and white cell counts , blood ammonia level , ferritin ) , but several factors make the changes in concentration of this analytes difficult to interpret when considered individually . the child - pugh classification has incorporated some of these routine laboratory tests , representing thus the first systematic approach to determine the index of the residual liver function .
however , it is based on some subjective parameters such as ascites and encephalopathy that make the assessment less accurate . the model for end - stage liver disease ( meld ) score , which includes the international normalized ratio ( inr ) and serum bilirubin and creatinine levels in the calculation , has recently emerged as a very valuable method for the assessment of residual liver function .
meld score has been shown to have significant advantages in clinical practice , especially in those patients who are candidates for liver transplantation .
for example , serum creatinine levels and inr show significant discrepancies using different laboratory methodologies .
several studies have reported that the addition of other prognostic factors to those evaluated by meld score may increase accuracy in evaluating liver function and prognosis.[4648 ] other methods of liver function estimation , based on the principle of clearance of substrate by the liver , have been developed .
the substrates include indocyanin green , lidocaine , galactose , aminopyrine aminoacid , and methacetin .
there are also tests based on the principle of energy production by the liver , such as arterial ketone body ratio and akbr , and others based on the number of receptors for asialoglycoprotein ( asgp - r ; technetium-99m - galactosyl human serum albumin ; 99mtc - gsa scan ) .
nevertheless , an accurate , yet practical and cost - effective method of liver function evaluation has not been clearly defined .
the formation of lipoproteins is a complex and gradual process that begins in the rough endoplasmic reticulum where apolipoproteins are synthesized . in the smooth endoplasmic reticulum
, the newly formed lipoproteins get to the tanks of golgi apparatus where they buy the carbohydrate component required for their secretion .
the modification and disposal of the lipid material depends on the liver which can send the circulating lipid material in the form of ketone bodies , triglycerides , phospholipids , and cholesterol , the three last ones being linked to lipoproteins.[75154 ] the liver is the cardinal organ for lp(a ) synthesis .
apo(a ) is synthesized by the hepatocytes as a low molecular mass precursor , and then modified in the endoplasmic reticulum and transferred in the golgi apparatus .
it is unclear if the final assembly of lp(a ) takes place inside or outside the cell , probably on the hepatocyte surface , and from there lp(a ) is released into the circulation .
several studies have shown an association between lp(a ) plasma levels and chronic liver diseases .
it has been demonstrated that serum lp(a ) levels in patients with chronic liver diseases , induced by hepatitis viral infections , are significantly reduced when compared to healthy controls.[16555860 ] malaguarnera et al . reported a significant increase of lp(a ) levels occurring after the treatment in patients with chronic active hepatitis c. only patients who responded fully presented a significant increase in the values of lp(a ) .
these findings suggest that increased levels of lp(a ) represent an expression of improved liver function .
since the liver is the organ that synthesizes lp(a ) , reduced level of lp(a ) during chronic liver diseases may be attributed to the relative decrease in the synthesis by a damaged liver . in the course of hcc and/or cirrhosis , circulating lp(a ) have displayed abnormal patterns .
thus , it is conceivable that the status of hepatic cellular impairments , various cytokines delivered during the disease , and hormone environment may influence the metabolic pathway of lp(a ) .
lp(a ) plasma levels are influenced early when liver function is impaired , because the half - life of lp(a ) is about 3.3 - 3.9 days in human plasma .
lp(a ) plasma levels , at variance with the other lipoproteins , are not affected by dietary changes . while basili et al . found elevated levels of lp(a ) in hcc patients , in three different case control studies lp(a ) plasma levels showed a significant decrease in patients with hcc and liver cirrhosis than among the controls . moreover
, motta et al . noticed a significant negative correlation between lp(a ) and child - pugh degrees , -fetoprotein and ferritin values as well as a positive one with albumin and cholinesterase levels calling for a role of lp(a ) as a marker of liver disease also in hcc .
with its complexity , lp(a ) could act as a marker of residual liver function .
its structure is indeed an expression of lipid ( ldl - like particle ) and protein ( apob-100 ) metabolism , and of coagulation state ( apo(a ) ) as well . since in the overall population lp(a ) blood concentrations are extremely variable from a subject to another , cohort studies would be more appropriate than case control studies at evaluating the relationship between lp(a ) and hcc .
in such a way , it would be possible to evaluate the fluctuations of lp(a ) levels over time , with serial measurements with the progression of the disease and the consequent deterioration of the liver function .
the presence of hbv or hcv infection , generalized inflammatory state or other conditions could be confounding factors though they have not been analyzed separately in any study .
lp(a ) may supply useful additional information for a more complete assessment and monitoring of the liver function in patients with hcc and liver cirrhosis .
further investigations are needed in order to verify lp(a ) accuracy at measuring the residual liver function in hcc patients , especially in comparison with other methods of liver function evaluation .
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### Summary:
: the residual liver function is a major clinical index in hepatocellular carcinoma ( hcc ) patients .
as the liver plays a crucial role in lipid and lipoprotein metabolism , the significant impairment of the hepatic function occurring during chronic liver diseases , such as hcc , can influence plasma lipoprotein profiles .
although , lipoprotein(a ) ( lp(a ) ) circulating concentrations are mostly determined by genetic factors , in the majority of reports they have shown a correlation with the hepatic status and a significant decrease in hcc and liver cirrhosis patients than among the controls .
in such a way , lp(a ) may represent a new additional and useful marker for a more complete assessment and monitoring of the liver function in patients with hcc and liver cirrhosis .
further studies are needed in order to evaluate the clinical significance of lp(a ) in hcc .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: despite improvements in medical and surgical treatment , infective endocarditis ( ie ) remains a serious disease that carries considerable mortality and morbidity.1)2)3)4 ) the early surgery versus conventional treatment in infective endocarditis ( ease ) trial previously demonstrated that early surgery in patients with ie and large vegetations significantly reduced the composite end point of all - cause death and embolic events during hospitalization when compared with conventional treatment.5 ) however , there was no significant difference in all - cause mortality rates at 6 months and more patients treated with early surgery received valve replacement than patients who were treated conventionally.5 ) long - term risks of mortality and morbidity in ie survivors who underwent early surgery or experienced systemic embolic events remain controversial.4)6)7)8)9 ) this study reports the long - term outcomes of the ease trial .
the ease trial design has been previously reported.5 ) briefly , we enrolled consecutive patients who were at high risk for embolisms and had a left - sided , native valve ie .
for all patients suspected of ie , blood cultures were obtained and a transthoracic echocardiography was performed within 24 hours after hospitalization .
patients with definite ie according to the modified duke criteria10 ) were eligible for enrollment if they had severe mitral or aortic valve disease and a vegetation diameter > 10 mm . in line with the 2006 american college of cardiology / american heart association guidelines on surgical indications for ie,11 )
the exclusion criteria were defined as patients with moderate to severe congestive heart failure ( chf ) , ie complicated by heart block , annular or aortic abscess , or destructive penetrating lesions requiring urgent surgery , fungal endocarditis , those who were not candidates for early surgery on the basis of age > 80 years , coexisting major embolic stroke with a risk of hemorrhagic transformation at the time of diagnosis , and/or poor medical status , such as the presence of malignancy .
patients with prosthetic valve ie , right - sided vegetations , small vegetations with a diameter 10 mm and patients referred from other hospitals more than 7 days after the diagnosis of ie were also excluded .
patients were randomly assigned on a 1:1 basis to early surgery or conventional treatment using an interactive web response system .
the protocol specified that patients assigned to the early surgery group should undergo surgery within 48 hours of randomization .
patients assigned to the conventional treatment group were treated according to the current guidelines,11)12)13 ) and surgery was performed only if complications requiring surgery developed during medical treatment or if symptoms persisted after the completion of antibiotic therapy . the institutional review board at each participating center approved the study protocol and written informed consent was obtained from all patients prior to randomization .
all patients were followed during hospitalization at 4 weeks , 6 weeks , 3 months , 6 months , and 1 year and at 6-month intervals thereafter .
patients were asked to call a study coordinator if they experienced any symptoms during follow - up .
data were obtained to the time of death or until march 2015 , and follow - up was complete for all patients .
the pre - specified end points were all - cause death , embolic events , recurrence of ie and repeat hospitalizations due to development of chf that occurred during follow - up .
an embolic event was defined as a systemic embolism fulfilling prespecified criteria : the acute onset of clinical symptoms or signs of embolism , and the occurrence of new lesions confirmed by follow - up imaging studies .
an experienced neurologist confirmed a specific diagnosis of cerebral embolism according to additional magnetic resonance imaging of the brain .
estimates of cumulative event rates were calculated by the kaplan - meier method and compared with the use of the log - rank test . for the kaplan - meier analysis
hazard ratios with 95% confidence intervals were derived with the use of the cox proportional hazards model . all
reported p values are two - sided , and a value of p<0.05 was considered statistically significant .
the ease trial design has been previously reported.5 ) briefly , we enrolled consecutive patients who were at high risk for embolisms and had a left - sided , native valve ie .
for all patients suspected of ie , blood cultures were obtained and a transthoracic echocardiography was performed within 24 hours after hospitalization .
patients with definite ie according to the modified duke criteria10 ) were eligible for enrollment if they had severe mitral or aortic valve disease and a vegetation diameter > 10 mm . in line with the 2006 american college of cardiology / american heart association guidelines on surgical indications for ie,11 )
the exclusion criteria were defined as patients with moderate to severe congestive heart failure ( chf ) , ie complicated by heart block , annular or aortic abscess , or destructive penetrating lesions requiring urgent surgery , fungal endocarditis , those who were not candidates for early surgery on the basis of age > 80 years , coexisting major embolic stroke with a risk of hemorrhagic transformation at the time of diagnosis , and/or poor medical status , such as the presence of malignancy .
patients with prosthetic valve ie , right - sided vegetations , small vegetations with a diameter 10 mm and patients referred from other hospitals more than 7 days after the diagnosis of ie were also excluded .
patients were randomly assigned on a 1:1 basis to early surgery or conventional treatment using an interactive web response system .
the protocol specified that patients assigned to the early surgery group should undergo surgery within 48 hours of randomization .
patients assigned to the conventional treatment group were treated according to the current guidelines,11)12)13 ) and surgery was performed only if complications requiring surgery developed during medical treatment or if symptoms persisted after the completion of antibiotic therapy . the institutional review board at each participating center approved the study protocol and written informed consent was obtained from all patients prior to randomization .
all patients were followed during hospitalization at 4 weeks , 6 weeks , 3 months , 6 months , and 1 year and at 6-month intervals thereafter .
patients were asked to call a study coordinator if they experienced any symptoms during follow - up .
data were obtained to the time of death or until march 2015 , and follow - up was complete for all patients .
the pre - specified end points were all - cause death , embolic events , recurrence of ie and repeat hospitalizations due to development of chf that occurred during follow - up .
an embolic event was defined as a systemic embolism fulfilling prespecified criteria : the acute onset of clinical symptoms or signs of embolism , and the occurrence of new lesions confirmed by follow - up imaging studies .
an experienced neurologist confirmed a specific diagnosis of cerebral embolism according to additional magnetic resonance imaging of the brain .
estimates of cumulative event rates were calculated by the kaplan - meier method and compared with the use of the log - rank test . for the kaplan - meier analysis
hazard ratios with 95% confidence intervals were derived with the use of the cox proportional hazards model .
all reported p values are two - sided , and a value of p<0.05 was considered statistically significant .
a total of 76 patients with left - sided ie who were potential candidates for early preemptive surgery were randomized ; 37 were assigned to early surgery and 39 to conventional treatment ( fig .
1 ) . the treatment groups were generally well balanced with regard to baseline clinical characteristics .
the mitral valve was involved in 45 patients , the aortic valve in 22 , and both valves in 9 .
the median diameter of vegetation was 12 mm ( interquartile range , 11 to 17 ) .
the most common pathogens in both groups were viridians streptococci ( 30% ) , other streptococci ( 30% ) and staphylococcus aureus ( 11% ) .
all patients in the early surgery group underwent valve surgery within 48 hours after randomization ; the median time between randomization and surgery was 24 hours ( interquartile range , 7 to 45 ) .
of the 39 patients assigned to the conventional treatment group , 30 ( 77% ) patients underwent surgery during the initial hospitalization ( n=27 ) or during follow - up ( n=3 ) .
all patients with involvement of the aortic valve underwent valve replacement , but among patients with involvement of the mitral valve , 6 ( 35% ) of the 17 in the conventional group underwent valve replacement , as compared with 14 ( 64% ) of the 22 in the early surgery group .
there was 1 in - hospital death , each in the early surgery group and in the conventional treatment group . during median follow - up of 5.8 years ( interquartile range , 4.8 to 7.1 ) , 3 deaths occurred in the early surgery group and 4 deaths in the conventional treatment group .
the causes of death were malignancy ( n=1 ) , trauma ( n=1 ) , acute renal failure ( n=1 ) and sudden death ( n=1 ) in the early surgery group , and malignancy ( n=1 ) , cerebral infarction ( n=2 ) and sudden death ( n=2 ) in the conventional treatment group .
there was no significant difference between the early surgery and conventional treatment groups in all - cause mortality at 4 years ( 8.1% and 7.7% , respectively ; hazard ratio 1.04 ; 95% ci , 0.21 to 5.15 ; p=0.96 ) ( fig .
there were no embolic events in the early surgery group and 8 embolic events in the conventional treatment group during hospitalization . during follow - up , no embolic event or recurrence of ie occurred in the early surgery group and 2 embolic events and 1 recurrence of ie in the conventional treatment group .
the rate of the composite end point of death from any cause , embolic events or recurrence of ie at 4 years was 8.1% in the early surgery group and 30.8% in the conventional treatment group ( hazard ratio , 0.22 ; 95% ci , 0.06 - 0.78 ; p=0.02 ) .
the estimated actuarial rate of end points at 7 years was significantly lower in the early surgery group than in the conventional treatment group ( p=0.007 by log - rank test ) ( fig .
a total of 76 patients with left - sided ie who were potential candidates for early preemptive surgery were randomized ; 37 were assigned to early surgery and 39 to conventional treatment ( fig .
1 ) . the treatment groups were generally well balanced with regard to baseline clinical characteristics .
the mitral valve was involved in 45 patients , the aortic valve in 22 , and both valves in 9 .
the median diameter of vegetation was 12 mm ( interquartile range , 11 to 17 ) .
the most common pathogens in both groups were viridians streptococci ( 30% ) , other streptococci ( 30% ) and staphylococcus aureus ( 11% ) .
all patients in the early surgery group underwent valve surgery within 48 hours after randomization ; the median time between randomization and surgery was 24 hours ( interquartile range , 7 to 45 ) .
of the 39 patients assigned to the conventional treatment group , 30 ( 77% ) patients underwent surgery during the initial hospitalization ( n=27 ) or during follow - up ( n=3 ) .
all patients with involvement of the aortic valve underwent valve replacement , but among patients with involvement of the mitral valve , 6 ( 35% ) of the 17 in the conventional group underwent valve replacement , as compared with 14 ( 64% ) of the 22 in the early surgery group .
there was 1 in - hospital death , each in the early surgery group and in the conventional treatment group . during median follow - up of 5.8 years ( interquartile range , 4.8 to 7.1 ) , 3 deaths occurred in the early surgery group and 4 deaths in the conventional treatment group .
the causes of death were malignancy ( n=1 ) , trauma ( n=1 ) , acute renal failure ( n=1 ) and sudden death ( n=1 ) in the early surgery group , and malignancy ( n=1 ) , cerebral infarction ( n=2 ) and sudden death ( n=2 ) in the conventional treatment group .
there was no significant difference between the early surgery and conventional treatment groups in all - cause mortality at 4 years ( 8.1% and 7.7% , respectively ; hazard ratio 1.04 ; 95% ci , 0.21 to 5.15 ; p=0.96 ) ( fig .
there were no embolic events in the early surgery group and 8 embolic events in the conventional treatment group during hospitalization . during follow - up , no embolic event or recurrence of ie occurred in the early surgery group and 2 embolic events and 1 recurrence of ie in the conventional treatment group .
the rate of the composite end point of death from any cause , embolic events or recurrence of ie at 4 years was 8.1% in the early surgery group and 30.8% in the conventional treatment group ( hazard ratio , 0.22 ; 95% ci , 0.06 - 0.78 ; p=0.02 ) .
the estimated actuarial rate of end points at 7 years was significantly lower in the early surgery group than in the conventional treatment group ( p=0.007 by log - rank test ) ( fig .
in this randomized trial involving ie patients complicated with severe valve disease and large vegetations , early surgery significantly reduced the composite end point of death from any cause and embolic events during hospitalization , and the substantial benefit for early surgery was sustained throughout the follow - up period extending up to 7 years .
after six months , the event - free survival curves remained parallel and late clinical outcomes were excellent in both groups .
long - term clinical outcome in ie survivors remain controversial.4)6)7)8)9 ) in a prospective , population - based study of left - sided ie , the in - hospital mortality rate was 19% and increased to 41% at 5 years.6 ) the crude survival rate at 1 and 5 years was 90% and 70% in an observational cohort study , and it was significantly worse compared with expected survival.7 ) a nationwide cohort study in sweden showed that long - term relative mortality risk in ie survivors continued to increase , even up to 5 years.8 ) a recent nationwide population - based study in taiwan also demonstrated that the risk of long - term major adverse cardiac events and all - cause mortality substantially increased in ie survivors.4 ) in contrast , a dutch cohort study of patients who were operated on for ie showed that ie survivors had a survival rate similar to the general population.9 ) in this study , more than 80% of our patients underwent valve surgery and long - term mortality was substantially lower than previously reported , whereas only 13% of the sweden cohort and only 14% of the taiwan cohort underwent valve surgery.4)8 ) our aggressive surgical approach may be related to the lower risk of long - term mortality and morbidity .
more patients in the early surgery group received valve replacement than those in the conventional treatment group,5 ) and the timing of surgery might be related to the differences in rates of repair . on the other hand
, a higher rate of valve replacement in the early surgery group did not result in an increase in thromboembolism and recurrence of ie associated with prosthetic valves .
our results suggest that a surgeon 's ability to completely excise infected tissues and careful long - term monitoring is more important in controlling infection and preventing adverse cardiovascular events after surgery than the actual type of surgery ( repair versus replacement ) .
first , the trial was a limited study in scope , in that it excluded those with moderate to severe heart failure , major stroke , prosthetic valve endocarditis or aortic abscess . however , the limitation related to our exclusion criteria is inherent to a randomized clinical trial conducted in infective endocarditis . according to guidelines,13)14 )
early surgery is recommended to patients with moderate to severe chf or to those with uncontrolled infection such as prosthetic valve endocarditis or aortic abscess .
in addition , medical treatment is preferred to early surgery in those with major stroke or intracerebral hemorrhage,15 ) and random assignment of such patients to a treatment arm of early surgery or medical treatment is against the principle of clinical equipoise that forms the ethical basis for a randomized trial.16 ) thus , those with specific indications of early surgery or medical treatment were excluded in this trial .
second , our study had insufficient power to evaluate the effect of early surgery on long - term survival .
third , the operative mortality was very low in the study , and the study patients had low operative risks .
the results of the study may not be applicable to patients with high operative risks . in this randomized trial , the beneficial effect of early surgery in patients with ie and large vegetations
was maintained during long - term follow - up , and late clinical outcome after surgery was excellent in survivors of ie .
in this randomized trial , the beneficial effect of early surgery in patients with ie and large vegetations was maintained during long - term follow - up , and late clinical outcome after surgery was excellent in survivors of ie .
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### Summary:
: background and objectivescompared with conventional treatment , early surgery significantly reduced the composite end point of all - cause death and embolic events during hospitalization , but long - term data in this area are lacking .
this study sought to compare long - term outcomes of early surgery with a conventional treatment strategy in patients with infective endocarditis ( ie ) and large vegetations.subjects and methodsthe early surgery versus conventional treatment in infective endocarditis ( ease ) trial randomly assigned patients with left - sided ie , severe valve disease and large vegetation to early surgery ( 37 patients ) or conventional treatment groups ( 39 patients ) .
the pre - specified end points were all - cause death , embolic events , recurrence of ie and repeat hospitalizations due to the development of congestive heart failure occurring during follow-up.resultsthere were no significant differences between the early surgery and the conventional treatment group in all - cause mortality at 4 years ( 8.1% and 7.7% , respectively ; hazard ratio [ hr ] 1.04 ; 95% ci , 0.21 to 5.15 ; p=0.96 ) .
the rate of the composite end point of death from any cause , embolic events or recurrence of ie at 4 years was 8.1% in the early surgery group and 30.8% in the conventional treatment group ( hr , 0.22 ; 95% ci , 0.06 - 0.78 ; p=0.02 ) .
the estimated actuarial rate of end points at 7 years was significantly lower in the early surgery group than in the conventional treatment group ( log - rank p=0.007).conclusionthere was a substantial benefit in having early surgery for patients with ie and large vegetations whose health was sustained up to 7 years , and late clinical outcome after surgery was excellent in survivors of ie .
( ease clinicaltrials.gov identifier : nct00750373 )
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: it is estimated that chronic hepatitis c ( chc ) affects more than 180 million people worldwide , which is about 3% of the world population ( 1 ) .
an increase in hepatitis c virus ( hcv)-related morbidities and mortalities has been observed in recent years .
in addition , increasing rates of advanced liver disease as a result of hcv infection are expected to be observed in the next decade , and developing countries , which have a higher prevalence of hcv infection , will experience the major burden of end - stage liver diseases ( esld ) throughout the world ( 2 - 4 ) .
therefore , it is obvious that this infection is a major concern of health policy makers .
fortunately , the risk of developing hepatocellular carcinoma ( hcc ) as one of the main complications of hcv infection can be reduced by 75% with successful treatment ( 5 ) , and today , newly introduced treatment strategies have provided opportunities to manage and control this public health concern ( 6 , 7 ) .
in the present study , we conducted an electronic search of available literature published to find pertinent contents reporting novel hcv treatments toward clearance in all hcv infected patient groups and cost benefits of new treatments in the era of daas . to identify articles ,
the search was begun among all peer - reviewed journal indexed in pubmed , scopus and google scholar .
the literature search was done by using the following key words : " hepatitis c virus , hcv , hcv genotypes , special groups , hiv / hcv co - infections , thalassemia , hemophilia , hemodialysis , liver transplantation , mass screening , diagnosis and treatment outcome " .
the search results were investigated carefully , and then most relevant results were strongly considered for including in this study by all authors and consulting the supervisor of the study ( sma ) .
it began with interferon ( ifn ) mono - therapy , with less than 20% sustained virological response ( svr ) .
milestones include the addition of ribavirin ( rbv ) to the treatment protocol and providing pegylated - ifn ( pegifn ) as an alternative treatment ( 8 - 10 ) .
treatment with pegifn / rbv was the standard of care for about 10 years , and it allowed about 50% of subjects with hcv genotype 1 infection to attain svr ( 10 - 12 ) .
the success rate of treatment with this regimen is very dependent on patient characteristics , including age , body mass index , ethnicity , and genetic factors such as polymorphisms near the interferon lambda 3 ( ifnl3 ) gene ( 13 , 14 ) .
viral factors , especially hcv genotype , also affect the response to hcv treatment ( 15 ) , and there are always additional factors that should be taken into account in each treatment approach , including treatment success rate , duration , cost , and side effects . in light of these concerns ,
knowledge of the hcv replication cycle and the role of viral proteins in the virulence of hcv have resulted in targeting of the viral proteins involved in the hcv life cycle to develop new hcv treatments . in 2011 ,
the first generation of direct acting antivirals ( daas ) boceprevir ( boc ) and telaprevir ( tvr ) were introduced and added to the previous pegifn / rbv regimen ( 17 , 18 ) .
these new triple therapy strategies led to higher svr , but they were still ifn - based and had severe adverse effects .
triple therapy with boc or tvr quickly fell out of favor due to the introduction of a new wave of more efficient daas beginning in 2013 , which changed the standards for hcv treatment . in december 2013 , the fda approved sofosbuvir ( sof ) in combination with pegifn / rbv for treatment of hcv genotype 1 infection .
this approach achieved a response rate of over 85% ; however , the presence of unfavorable treatment predictors such as cirrhosis , previous history of treatment , and unfavorable host genetics can influence the success rate of treatment with sof / pegifn / rbv ( 19 ) .
sof in combination with rbv and/or pegifn was also approved for treatment of hcv genotypes 2 , 3 , and 4 , with limited efficacy for hcv genotype 3 ( 20 ) . in october 2014
, the fda approved ledipasvir ( ldv ) in combination with sof for treatment of hcv genotype 1 , which achieved more than 95% efficacy ( 21 , 22 ) .
fortunately , in addition to being more effective than the previous sof / pegifn / rbv regimen , sof / ldv is influenced little by patient characteristics . in december 2014
, the fda approved another ifn - free daa regimen a combination of ombitasvir / paritaprevir - r / dasabuvir ( a three direct acting antiviral , or 3d ) for treatment of hcv genotype 1 infection , with an efficacy rate of over 95% ( 23 ) .
finally , in january 2016 , the fda approved combination therapy with grazoprevir / elbasvir ( gzr / ebr ) , with about a 95% svr rate ( 24 ) .
other regimens containing daas , such as simeprevir ( smv ) and daclatasvir ( dcv ) , have also been approved for treatment of hcv infection since 2013 ( 25 , 26 ) . the use of new treatment strategies has provided opportunities to eradicate hcv infection . however , effective treatment is not enough ; there are still major issues that must be taken into account , some of which we address in this paper .
although an effective treatment regimen is a necessary tool in infection eradication , identifying infected individuals is also of vital importance .
subjects with hcv infection can remain asymptomatic for a long time , so they may be unaware of their infection . during this period , infection can progress to advanced liver disease , and the patient may spread the virus to others . surprisingly , about 75% of patients with hcv in the united states are unaware of being infected ( 27 ) .
another challenge to developing screening strategies for hcv is the occult nature of this infection , which can not be identified with routine diagnostic tests ( 28 , 29 ) .
we believe that health policy makers should design powerful screening programs to identify hcv - infected subjects .
risk factors for hcv infection include intravenous drug use ( ivdu ) , history of unsafe injection practices , use of blood and/or blood products before the introduction of blood donor screening for hcv between 1992 and 1996 ( depending on the national policies of different countries ) , being homeless , and history of imprisonment ( 30 ) .
the prevalence of these risk factors varies among different populations and countries ; population - based studies have determined that different geographical regions have unique risk factors for hcv infection .
for example , baby boomers , persons born between 1945 and 1965 in the united states , account for about 70% of hcv infections in the us ( 31 ) .
in addition , previous parenteral therapy for schistosomiasis is a significant predictor of hcv infection in egypt ( 32 ) .
however , in some countries , further population - based studies are required to determine the special risk factors related to each area .
once this is done , subjects with these risk factors can be recognized as special groups and singled out for screening .
these population - based studies should be conducted alongside the implementation of new prevention and treatment strategies in order to track changes in geographically - based risk factors and changes in the prevalence of hcv among subjects with these risk factors .
these studies will also help in the evaluation of screening strategies . as a result of geographical differences in risk factors and prevalence , a different screening strategy is needed for each country , and this should be supported by governmental and non - governmental organizations .
governments should pay attention to this important issue and fund screening , and health policy makers should design a risk - based , powerful screening method .
furthermore , the quality of these activities and screening methods should be evaluated by research projects and epidemiological population - based studies , which can guide policy makers .
ultimately , medical practitioners and healthcare personnel have an important role in this regard , and they must support screening projects .
risk - based screening strategies can identify about 86% of patients with hcv ( 33 ) .
some patients do not have traditional risk factors and therefore can not be identified by risk - based screening .
therefore , worldwide clinical screening , together with the approach of risk - based screening ( 34 ) , is recommended .
however , the feasibility of such an approach is highly dependent on the economic situation of a given country
. one of the main inconveniences of new treatment strategies is their current high cost .
for example , the cost of a 12-week treatment with sof is 85,000 - 110,000 usd .
new treatment approaches have shorter durations , minimal adverse effects , and higher efficacy ; however , they are very expensive .
strategies should be applied to reduce treatment costs and provide wide access to new treatments , especially in low- and middle - income countries , in which about 80% of patients with chc live ( 5 , 35 , 36 ) .
people with inherited bleeding disorders ( such as hemophilia ) , people with inherited hemoglobin disorders ( such as thalassemia ) , patients under hemodialysis , patients with organ transplantation ( especially liver- and kidney - transplant patients ) and hcv patients co - infected with hiv are some of the groups that need special attention and priority in treatment ( 37 ) .
special patient groups with chc are at increased risk of death or complications ( 38 ) .
a basic question arises here : what considerations need to be made for special patient groups in the era of daas ?
these populations are the most challenging to treat , and they require massive attention . because of faster progression to both esld and hcc in special patients , hcv is a significant cause of morbidity and mortality in these populations ( 39 ) .
hiv / hcv co - infection : hiv and hcv co - infection poses a challenge because it is widespread , particularly among ivdus , and it exhibits lower rates of spontaneous hcv clearance , poor response to treatment of chronic hcv in the pre - daa era , and more rapid progression of hcv - related liver diseases such as cirrhosis and hcc ( 40 ) .
global statistics indicate that four to five million people are co - infected with hiv / hcv ( 41 ) .
adoption of interferon - based hcv treatments ( following the pegifn / rbv and first - generation hcv protease inhibitors ) resulted in lower svr in those with hiv / hcv co - infection than in those with hcv mono - infection ( 40 ) . furthermore
, hcv treatment regimens involve serious adverse effects and pharmacokinetic drug interactions with hiv - antiretroviral drugs ( 42 - 44 ) .
the development and approval of new oral regimens of daas has created an opportunity to improve hcv treatment efficacy and safety for hiv / hcv co - infected patients . however , drug interactions between hcv daas and hiv - antiretroviral agents are still a major problem . for example ,
smv and 3d regimens are contra - indicated in hiv patients receiving many protease inhibitors .
today , sof plays a key role in treating hiv / hcv co - infection ; it has a lower degree of interaction with hiv - antiretroviral drugs .
the combination of sof / ldv or sof / dcv provides high rates of svr in hiv / hcv co - infected patients .
recently , the use of sof / ldv and sof / dcv has been shown to be effective and safe in patients with hiv / hcv co - infection , achieving svr rates of 98% and 96% - 98% , respectively ( 45 , 46 ) .
although there has been much progress in the field of hiv / hcv co - infection treatment , this patient population still needs more attention .
thalassemia and hemophilia : hcv infection is one of the most common infections following the use of blood and blood products among thalassemia and hemophilia patients ( 47 ) . the treatment of thalassemia patients infected with hcv is a very controversial issue . dual therapy with pegifn / rbv , use of protease inhibitors ( boc and tvr ) , and pegifn / rbv - based triple therapy leads to rbv - associated life - threatening anemia in many thalassemia patients ( 48 ) . on the other hand
, the elimination of rbv and the use of low - dose rbv in the treatment of thalassemia patients seems to result in low svr rates ( 49 ) . nevertheless , because of the severe adverse effects of rbv - based treatments in these patients
unfortunately , there are currently no clinical trials evaluating the effect of daa use to treat hcv infection in thalassemia patients .
although the combination of pegifn and rbv is still used in treatment of hcv - infected thalassemia patients ( 15 ) , a few thalassemia cases have been treated with sof - based treatment in our clinic ( middle east liver disease center ) and experienced a favorable treatment response . however , clinical trials with new daas are required to evaluate this approach .
liver failure due to hcv infection is one of the common causes of death in patients with hemophilia .
anti - hcv therapy plays a vital role in the interruption of the hcv infection pathway in order to prevent cirrhosis and hcc .
the current standard of care for treatment of hcv in hemophilia is pegifn / rbv , which achieves svr in 61% of patients ( 51 ) .
however , the side effects of the pegifn / rbv regimen , including thrombocytopenia and excessive bleeding , should be considered .
a recent open - label study showed that out of 14 hemophilia patients infected with hcv and treated with sof / ldv , all achieved svr ( 100% ) ( 52 ) . despite the increasing use of highly effective anti - hcv agents with minimal side effects to treat hemophilia patients , hemophiliacs still constitute a unique patient population that requires special consideration .
hemodialysis : hcv infection is one of the most common infections transmitted by the parenteral route in patients receiving maintenance hemodialysis ( 53 ) . the use of rbv is problematic in this group . receiving an ifn - free and , if possible , rbv - free regimen is a fundamental , urgent need in patients under hemodialysis ( 51 ) . in persons with renal impairment receiving chronic hemodialysis , options for hcv treatment
however , asunaprevir , dcv , smv , gzr / ebr , and 3d regimens are cleared by hepatic metabolism and can be used in patients with renal disease ( 54 ) .
liver transplantation : hepatitis c recurrence is common after liver transplantation when patients are transplanted with detectable viral loads .
recurrence of hcv following liver transplantation may accelerate graft injury , which is difficult to treat with ifn / rbv therapy ( 55 ) . antiviral treatment before transplantation can prevent hcv recurrence .
ifn - based regimens are poorly tolerated and are either ineffectual or contra - indicated in most liver - transplant patients ( 56 ) .
in contrast , sof - based regimens have satisfactory virological response in more than 80% of post - transplant patients ( 57 ) .
favorable response to the currently available therapies and new highly effective treatments for hcv revealed that hcv clearance could be significantly improved in special patient groups .
daa - based therapies stand to achieve a very high rate of treatment success with minimal side effects .
the introduction of new therapeutic agents does not detract from the importance of preventive strategies , including the development of an hcv vaccine ( 58 ) .
it seems that an effective vaccine is achievable in the near future , and as bill gates has said , treatment without prevention is simply unsustainable .
on the other hand , reduction of harmful behaviors should be the main strategy to reduce the prevalence of hcv infection in certain high - risk groups , such as ivdus and inmates ( 27 , 30 ) . furthermore ,
public knowledge and awareness are vital to the eradication of every disease , and ignorance will prevent future eradication of hcv .
it began with interferon ( ifn ) mono - therapy , with less than 20% sustained virological response ( svr ) .
milestones include the addition of ribavirin ( rbv ) to the treatment protocol and providing pegylated - ifn ( pegifn ) as an alternative treatment ( 8 - 10 ) .
treatment with pegifn / rbv was the standard of care for about 10 years , and it allowed about 50% of subjects with hcv genotype 1 infection to attain svr ( 10 - 12 ) .
the success rate of treatment with this regimen is very dependent on patient characteristics , including age , body mass index , ethnicity , and genetic factors such as polymorphisms near the interferon lambda 3 ( ifnl3 ) gene ( 13 , 14 ) .
viral factors , especially hcv genotype , also affect the response to hcv treatment ( 15 ) , and there are always additional factors that should be taken into account in each treatment approach , including treatment success rate , duration , cost , and side effects . in light of these concerns ,
knowledge of the hcv replication cycle and the role of viral proteins in the virulence of hcv have resulted in targeting of the viral proteins involved in the hcv life cycle to develop new hcv treatments . in 2011 ,
the first generation of direct acting antivirals ( daas ) boceprevir ( boc ) and telaprevir ( tvr ) were introduced and added to the previous pegifn / rbv regimen ( 17 , 18 ) .
these new triple therapy strategies led to higher svr , but they were still ifn - based and had severe adverse effects .
triple therapy with boc or tvr quickly fell out of favor due to the introduction of a new wave of more efficient daas beginning in 2013 , which changed the standards for hcv treatment . in december 2013 , the fda approved sofosbuvir ( sof ) in combination with pegifn / rbv for treatment of hcv genotype 1 infection .
this approach achieved a response rate of over 85% ; however , the presence of unfavorable treatment predictors such as cirrhosis , previous history of treatment , and unfavorable host genetics can influence the success rate of treatment with sof / pegifn / rbv ( 19 ) .
sof in combination with rbv and/or pegifn was also approved for treatment of hcv genotypes 2 , 3 , and 4 , with limited efficacy for hcv genotype 3 ( 20 ) . in october 2014
, the fda approved ledipasvir ( ldv ) in combination with sof for treatment of hcv genotype 1 , which achieved more than 95% efficacy ( 21 , 22 ) .
fortunately , in addition to being more effective than the previous sof / pegifn / rbv regimen , sof / ldv is influenced little by patient characteristics . in december 2014
, the fda approved another ifn - free daa regimen a combination of ombitasvir / paritaprevir - r / dasabuvir ( a three direct acting antiviral , or 3d ) for treatment of hcv genotype 1 infection , with an efficacy rate of over 95% ( 23 ) .
finally , in january 2016 , the fda approved combination therapy with grazoprevir / elbasvir ( gzr / ebr ) , with about a 95% svr rate ( 24 ) .
other regimens containing daas , such as simeprevir ( smv ) and daclatasvir ( dcv ) , have also been approved for treatment of hcv infection since 2013 ( 25 , 26 ) .
the use of new treatment strategies has provided opportunities to eradicate hcv infection . however ,
effective treatment is not enough ; there are still major issues that must be taken into account , some of which we address in this paper .
although an effective treatment regimen is a necessary tool in infection eradication , identifying infected individuals is also of vital importance .
subjects with hcv infection can remain asymptomatic for a long time , so they may be unaware of their infection . during this period , infection can progress to advanced liver disease , and the patient may spread the virus to others . surprisingly , about 75% of patients with hcv in the united states are unaware of being infected ( 27 ) .
another challenge to developing screening strategies for hcv is the occult nature of this infection , which can not be identified with routine diagnostic tests ( 28 , 29 ) .
we believe that health policy makers should design powerful screening programs to identify hcv - infected subjects .
risk factors for hcv infection include intravenous drug use ( ivdu ) , history of unsafe injection practices , use of blood and/or blood products before the introduction of blood donor screening for hcv between 1992 and 1996 ( depending on the national policies of different countries ) , being homeless , and history of imprisonment ( 30 ) .
the prevalence of these risk factors varies among different populations and countries ; population - based studies have determined that different geographical regions have unique risk factors for hcv infection .
for example , baby boomers , persons born between 1945 and 1965 in the united states , account for about 70% of hcv infections in the us ( 31 ) .
in addition , previous parenteral therapy for schistosomiasis is a significant predictor of hcv infection in egypt ( 32 ) .
however , in some countries , further population - based studies are required to determine the special risk factors related to each area .
once this is done , subjects with these risk factors can be recognized as special groups and singled out for screening .
these population - based studies should be conducted alongside the implementation of new prevention and treatment strategies in order to track changes in geographically - based risk factors and changes in the prevalence of hcv among subjects with these risk factors .
these studies will also help in the evaluation of screening strategies . as a result of geographical differences in risk factors and prevalence
, a different screening strategy is needed for each country , and this should be supported by governmental and non - governmental organizations .
governments should pay attention to this important issue and fund screening , and health policy makers should design a risk - based , powerful screening method .
furthermore , the quality of these activities and screening methods should be evaluated by research projects and epidemiological population - based studies , which can guide policy makers .
ultimately , medical practitioners and healthcare personnel have an important role in this regard , and they must support screening projects .
risk - based screening strategies can identify about 86% of patients with hcv ( 33 ) .
some patients do not have traditional risk factors and therefore can not be identified by risk - based screening .
therefore , worldwide clinical screening , together with the approach of risk - based screening ( 34 ) , is recommended .
however , the feasibility of such an approach is highly dependent on the economic situation of a given country .
one of the main inconveniences of new treatment strategies is their current high cost . for example , the cost of a 12-week treatment with sof is 85,000 - 110,000 usd .
new treatment approaches have shorter durations , minimal adverse effects , and higher efficacy ; however , they are very expensive .
strategies should be applied to reduce treatment costs and provide wide access to new treatments , especially in low- and middle - income countries , in which about 80% of patients with chc live ( 5 , 35 , 36 ) .
people with inherited bleeding disorders ( such as hemophilia ) , people with inherited hemoglobin disorders ( such as thalassemia ) , patients under hemodialysis , patients with organ transplantation ( especially liver- and kidney - transplant patients ) and hcv patients co - infected with hiv are some of the groups that need special attention and priority in treatment ( 37 ) .
special patient groups with chc are at increased risk of death or complications ( 38 ) .
a basic question arises here : what considerations need to be made for special patient groups in the era of daas ?
these populations are the most challenging to treat , and they require massive attention . because of faster progression to both esld and hcc in special patients , hcv is a significant cause of morbidity and mortality in these populations ( 39 ) .
hiv / hcv co - infection : hiv and hcv co - infection poses a challenge because it is widespread , particularly among ivdus , and it exhibits lower rates of spontaneous hcv clearance , poor response to treatment of chronic hcv in the pre - daa era , and more rapid progression of hcv - related liver diseases such as cirrhosis and hcc ( 40 ) .
global statistics indicate that four to five million people are co - infected with hiv / hcv ( 41 ) .
adoption of interferon - based hcv treatments ( following the pegifn / rbv and first - generation hcv protease inhibitors ) resulted in lower svr in those with hiv / hcv co - infection than in those with hcv mono - infection ( 40 ) .
furthermore , hcv treatment regimens involve serious adverse effects and pharmacokinetic drug interactions with hiv - antiretroviral drugs ( 42 - 44 ) .
the development and approval of new oral regimens of daas has created an opportunity to improve hcv treatment efficacy and safety for hiv / hcv co - infected patients .
however , drug interactions between hcv daas and hiv - antiretroviral agents are still a major problem . for example
, smv and 3d regimens are contra - indicated in hiv patients receiving many protease inhibitors .
today , sof plays a key role in treating hiv / hcv co - infection ; it has a lower degree of interaction with hiv - antiretroviral drugs .
the combination of sof / ldv or sof / dcv provides high rates of svr in hiv / hcv co - infected patients .
recently , the use of sof / ldv and sof / dcv has been shown to be effective and safe in patients with hiv / hcv co - infection , achieving svr rates of 98% and 96% - 98% , respectively ( 45 , 46 ) .
although there has been much progress in the field of hiv / hcv co - infection treatment , this patient population still needs more attention .
thalassemia and hemophilia : hcv infection is one of the most common infections following the use of blood and blood products among thalassemia and hemophilia patients ( 47 ) . the treatment of thalassemia patients infected with hcv is a very controversial issue
. dual therapy with pegifn / rbv , use of protease inhibitors ( boc and tvr ) , and pegifn / rbv - based triple therapy leads to rbv - associated life - threatening anemia in many thalassemia patients ( 48 ) . on the other hand
, the elimination of rbv and the use of low - dose rbv in the treatment of thalassemia patients seems to result in low svr rates ( 49 ) .
nevertheless , because of the severe adverse effects of rbv - based treatments in these patients , it is very important to utilize rbv - free regimens .
unfortunately , there are currently no clinical trials evaluating the effect of daa use to treat hcv infection in thalassemia patients .
although the combination of pegifn and rbv is still used in treatment of hcv - infected thalassemia patients ( 15 ) , a few thalassemia cases have been treated with sof - based treatment in our clinic ( middle east liver disease center ) and experienced a favorable treatment response . however , clinical trials with new daas are required to evaluate this approach .
liver failure due to hcv infection is one of the common causes of death in patients with hemophilia .
anti - hcv therapy plays a vital role in the interruption of the hcv infection pathway in order to prevent cirrhosis and hcc .
the current standard of care for treatment of hcv in hemophilia is pegifn / rbv , which achieves svr in 61% of patients ( 51 ) .
however , the side effects of the pegifn / rbv regimen , including thrombocytopenia and excessive bleeding , should be considered .
a recent open - label study showed that out of 14 hemophilia patients infected with hcv and treated with sof / ldv , all achieved svr ( 100% ) ( 52 ) . despite the increasing use of highly effective anti - hcv agents with minimal side effects to treat hemophilia patients , hemophiliacs still constitute a unique patient population that requires special consideration .
hemodialysis : hcv infection is one of the most common infections transmitted by the parenteral route in patients receiving maintenance hemodialysis ( 53 ) .
receiving an ifn - free and , if possible , rbv - free regimen is a fundamental , urgent need in patients under hemodialysis ( 51 ) . in persons with renal impairment receiving chronic hemodialysis , options for hcv treatment
however , asunaprevir , dcv , smv , gzr / ebr , and 3d regimens are cleared by hepatic metabolism and can be used in patients with renal disease ( 54 ) .
liver transplantation : hepatitis c recurrence is common after liver transplantation when patients are transplanted with detectable viral loads .
recurrence of hcv following liver transplantation may accelerate graft injury , which is difficult to treat with ifn / rbv therapy ( 55 ) . antiviral treatment before transplantation can prevent hcv recurrence .
ifn - based regimens are poorly tolerated and are either ineffectual or contra - indicated in most liver - transplant patients ( 56 ) .
in contrast , sof - based regimens have satisfactory virological response in more than 80% of post - transplant patients ( 57 ) .
favorable response to the currently available therapies and new highly effective treatments for hcv revealed that hcv clearance could be significantly improved in special patient groups .
daa - based therapies stand to achieve a very high rate of treatment success with minimal side effects .
the introduction of new therapeutic agents does not detract from the importance of preventive strategies , including the development of an hcv vaccine ( 58 ) .
it seems that an effective vaccine is achievable in the near future , and as bill gates has said , treatment without prevention is simply unsustainable . studies on vaccine development should be prioritized . on the other hand , reduction of harmful behaviors
should be the main strategy to reduce the prevalence of hcv infection in certain high - risk groups , such as ivdus and inmates ( 27 , 30 ) .
furthermore , public knowledge and awareness are vital to the eradication of every disease , and ignorance will prevent future eradication of hcv .
new treatments have a higher rate of success , less severe side effects , and a shorter duration of therapy . the main goal for the hepatology and infectious disease communities
is the eradication of hcv in the next 20 years ; however , hcv eradication will be an uphill battle .
the next steps are ( 1 ) finding and treating patients with hcv infection in the general population ; ( 2 ) improving the availability and affordability of effective treatments in developing countries , which will bear the majority of the burden of liver diseases in the next decade without proper management ; ( 3 ) combatting hcv infection in special groups , such as patients with thalassemia , hiv / hcv co - infection , kidney disease , and liver - transplant patients ; and ( 4 ) concentration on prevention alongside treatment , always remembering that prevention is better than a cure .
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### Summary:
: contextafter the introduction of safe and highly effective hepatitis c virus ( hcv ) treatments , eradication of hcv in the next 20 years is the ultimate goal . since 2011 , the advent of first generation direct acting antivirals ( daas ) were started and followed by the introduction of a new wave of daas in 2013 which exhibit outstanding efficacy .
it is obvious that the eradication of hepatitis c is not restricted to development of daas.evidence acquisitionan electronic search of available literature published was conducted in all peer - reviewed journal indexed in pubmed , scopus and google scholar .
the literature search was done among articles related treatment of hepatitis c with daas in different patient groups with mass screening of the patients and cost benefit of new treatments as main key words.resultsthere are major steps that should be taken to eradicate hcv , including ( 1 ) the development of screening strategies , particularly for groups such as intravenous drug users and recipients of blood or blood products before the introduction of hcv screening in donors ; ( 2 ) the development of strategies to overcome issues with the high cost of recently introduced treatments ; ( 3 ) special attention to special patient groups , such as hiv / hcv co - infection , hemophilia , thalassemia , hemodialysis , and liver - transplant patients ; and ( 4 ) development of preventive strategies , such as the development of an efficient hcv vaccine , special attention to harm reduction in high - risk groups , and promotion of mass awareness of hcv.conclusionsthe eradication of hcv will require significant governmental financial investment for screening , prevention , and treatment of infected patients .
although , we have a long way to eradication of hcv , the next steps could be including proper planning to patient finding , availability of new treatments to all patients and development of hcv prevention strategies such as vaccines .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: surgery on the trachea is a relatively new phenomenon . prior to the pioneering work of dr .
hermes grillo , conventional wisdom stated that the cartilage of the trachea would not heal properly , so resection of the trachea with reconstruction was not possible .
during the early 1950s , with the development of respiratory intensive care units , patients were managed with mechanical ventilators with endotracheal tubes in place .
these endotracheal tubes had a low volume - high pressure cuff and led to ischemic injury to the tracheal wall from pressure - induced ischemia . when these is - chemic injuries healed , they led to circumferential scarring and narrowing of the affected trachea .
simple dilation of this stricture did not solve the problem , since the injury affected the entire thickness .
grillo began to do experiments in his dog lab to work out the surgical treatment of tracheal stenosis ( fig .
he was able to show that it was possible to resect a portion of the trachea and perform a primary reanastomosis .
after working out the technique in the lab , he successfully applied his tracheal resection and reconstruction techniques to patients who developed tracheal stenosis .
later , this technique was generalized so that it could be applied to any type of tracheal disease that required resection , including tumors .
the upper airway is made up of the hyoid bone , larynx , cricoid , and trachea ( fig .
superior to the true cords is the supraglottic airway , and the inferior area is referred to as the subglottic airway . between the larynx and the trachea is the cricoid , which is important since the laryngeal nerves enter the airway in its posterior portion .
therefore , resection of the entire cricoid is impossible without damaging both recurrent nerves and thereby destroying the protective function of the laryngeal apparatus .
the trachea proper starts just inferior to the cricoid and extends to the main carina , some 1012 cm distal .
the shape of the normal trachea is an extended half circle with the posterior portion nearly flat and made of soft tissue , which comprises the membranous portion .
the anterior portion of the trachea is made up of a series of cartilaginous rings with a membrane between each ring .
the trachea is partially intra - thoracic and partially extrathoracic , as its position in the chest moves superiorly and inferiorly with extension and flexion of the neck , respectively ( fig .
this mobility decreases with age , which is an important consideration in tracheal resection and reconstruction , since this mobility is used to reduce tension on all tracheal anastomoses after resection .
salassa et al . described the blood supply of the trachea in 1977 ( fig .
the inferior thyroid artery , a branch of the subclavian artery , supplies the upper trachea .
distally , various bronchial arteries that come directly off the aorta or intercostal arteries supply the trachea .
since there are no blood vessels on the anterior or posterior surface of the trachea , the trachea can be mobilized extensively , based on the lateral attachments .
once the blood vessels enter the lateral aspects of the trachea , they send smaller vessels to the anterior and posterior surfaces , which then feed the mucosal tissue .
the intrathoracic and extrathoracic portions of the trachea have physiological differences with respect to airflow when the lumen is narrowed . in extrathoracic
stenosis , when patients inhale , the pressure in the trachea falls , meaning that the atmospheric pressure compresses the airway more , further limiting the airflow through the trachea .
this can be seen clearly on an inspiratory flow volume loop , which shows a characteristic plateau ( fig .
5 ) . in cases of tracheal narrowing that are intrathoracic , or in the distal airway
, expiration increases the pressure in the chest , thereby further collapsing the intrathoracic trachea , which leads to decreased flow through the narrowed area of the trachea .
this results in a plateau on the flow volume loop on the expiratory phase of the examination .
patients with a tracheal tumor or tracheal stenosis usually exhibit severe symptoms of upper airway obstruction , but only after the obstruction blocks over 70% of the cross - sectional airway of the lumen .
as the narrowing becomes more severe , the symptoms become more obvious and eventually manifest as shortness of breath with almost any activity .
the presence of stridor indicates a severe obstruction that should be dealt with immediately . after a through history and physical examination
, radiographic imaging can be performed to identify the location and extent of the tracheal pathology . in the past
, tomograms with a copper filter were used to delineate the pathology ; however , with the advent of multiplanar computerized tomography , the older methods became obsolete .
a computed tomography scan with multiple views can show the lesion and its relationships to the surrounding structures ( fig .
as mentioned above , pulmonary function testing shows a characteristic plateau on the inspiratory or expiratory portion of the flow volume loop , depending on the location of the obstruction .
rigid bronchoscopy is critical for examining the airway and obtaining accurate measurements of the location of the tumor .
usually done under general anesthesia , care must be taken to keep the patient spontaneously breathing in case intubation past the lesion can not be accomplished .
this is usually done using a breath - down technique , whereby the patient s own breathing deepens the level of anesthesia .
once the rigid bronchoscope is inserted , measurements are taken to establish the location of the carina , the distal aspect of the tumor or stenosis , the proximal aspect of the tumor or stenosis , and the location of the cricoid .
these measurements allow simple calculations of the amount of the trachea that must be resected and the location of the lesion in the trachea ( fig .
biopsy is not always necessary , since the lesion will need to be removed if possible regardless of the pathologic diagnosis ( fig .
if a tracheal tumor is present , it should not be completely removed , since locating what should be removed at a subsequent resection will be difficult .
if tracheal stenosis is present , the trachea can be dilated with a rigid bronchoscope to allow for elective resection and reconstruction in the subsequent few weeks .
tumors in the proximal two thirds of the trachea can be approached via a collar incision , and those in the distal third can be approached by right thoracotomy .
anesthetic considerations are always important , since during the resection , the anesthesiological team will cede control of the airway to the surgical team , which always causes a bit of anxiety .
almost all patients can have a small endotracheal tube passed distal to the lesion , allowing surgery to be safely initiated .
if there is concern about a severe obstruction , a rigid bronchoscope can either core out a tumor or dilate a stenosis , allowing the endotracheal tube to pass .
after the trachea is opened , an endotracheal tube can be passed into the distal end of the trachea and cross - table ventilation is performed .
the use of cardiopulmonary bypass or jet ventilation is rarely necessary . for tumors in the proximal third of the trachea ,
the thyroid is divided in the midline and the anterior trachea is freed from the surrounding attachments .
once the tumor or stenosis is localized , dissection around the trachea is performed only at the level of the area to be removed ( fig .
an endotracheal tube is placed distally for ventilation , and the initial endotracheal tube is withdrawn into the glottis area . attaching a catheter to the end of the original endotracheal tube facilitates its replacement after the anastomosis is completed .
the portion of the trachea that will be removed is resected , and the proximal and distal margins are checked with frozen sections as appropriate .
traction sutures of 3 - 0 vicryl are placed at the 3-oclock and 6-oclock positions on both the proximal and distal ends of the remaining trachea .
an end - to - end anastomosis is performed using 4 - 0 vicryl ( fig .
the trachea can be divided into four quadrants to make organization of the anastomosis easier .
once the sutures are placed , the distal airway is suctioned of any blood or debris , and the original endotracheal tube is passed through the anastomosis and into the distal airway . the patient s neck is flexed and the ends of the trachea are brought together .
if too much tension is present , a laryngeal release maneuver can be performed , but this will interfere with the swallowing mechanism for about three weeks , so it should not be done unless necessary .
bronchoscopy should be performed to examine the anastomotic area , and if found to be deficient , the anastomosis should be redone .
a small drain is placed in the neck area , and the soft tissue and skin are closed . in order to keep the neck in flexion , a stout stich is placed from the mentum to the sternum ( fig .
patients are extubated in the operating room and should be breathing freely without stridor after extubation .
postoperatively , patients are kept nil per os for 24 hours , then fed a diet as tolerated , watching carefully for any signs of aspiration . on the seventh postoperative day
, a bronchoscopy is done and if all looks well , the chin stitch is removed and the patient is discharged from the hospital .
additional treatment of malignancies depends on the pathology , but in general , nothing else is required , with the exception of radiation therapy for adenoid cystic carcinomas .
grillo et al . reported the results of all of their tracheal work , including 503 patients from 1965 through 1992 .
they had good or satisfactory results in 93.7% of patients , failure ( requiring a tracheostomy ) in 3.9% , and death in 2.4% .
surgery of the trachea is now a standard operation for a well - trained general thoracic surgeon . with careful attention to detail and proper patient selection ,
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### Summary:
: surgical procedures on the trachea have only been undertaken within the past 50 years . knowing the unique blood supply of the trachea and how to reduce tension on any anastomosis are key to a successful outcome .
tracheal conditions requiring surgery usually present with shortness of breath on exertion , and preoperative evaluation involves computed tomography and rigid bronchoscopy .
tracheal resection and reconstruction can be safely performed with excellent outcomes by following a well - described technique .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: multidrug - resistant tuberculosis ( mdr - tb ) , defined as a disease caused by strains of mycobacterium tuberculosis that are resistant to at least isoniazid and rifampin , is recognized as an important global threat ( 1 ) .
current therapy for mdr - tb is the combination of second - line antituberculous drugs , and resectional surgery can be sometimes combined with antituberculous chemotherapy ( 2 , 3 ) . until now
, however , there has been no definite treatment modality in the patients with refractory mdr - tb , who have persistent positive sputum culture for m. tuberculosis despite prolonged antituberculous chemotherapy and who are not candidates for resectional surgery due to extensive bilateral disease .
interferon - gamma ( ifn- ) has been shown to activate monocytes and macrophages against m. tuberculosis in vitro ( 4 - 6 ) .
some clinical efficacy has also been shown for ifn- given systemically to treat disseminated m. avium complex infections in immunocompromised hosts without infection of human immunodeficiency virus ( hiv ) or patients with aids ( 7 , 8) .
in addition , condos et al . reported transient but clinically encouraging improvements in five patients with mdr - tb following one month of ifn- inhalation therapy .
responses included the conversion of sputum smears to negative , delayed growth of cultures , and shrinkage of cavities ( 9 ) .
however , there have been no further reports about long - term effects of ifn- inhalation therapy in the treatment of mdr - tb .
therefore , we studied the effects of ifn- inhalation therapy for six months in the treatment of refractory mdr - tb .
six patients with sputum - smear - positive and culture - positive cavitary mdr - tb that was refractory to antituberculous chemotherapy were evaluated in an open - labeled , nonrandomized observational study .
the study was approved by the institutional review boards , and informed consent was obtained from all patients .
all patients were chronic cases according to the case definition criteria of world health organization ( 10 ) and had a refractory mdr - tb and radiological progression of disease despite adequate chemotherapy for at least six months based on the past drug history and individual susceptibility test results .
no patient was indicated for resectional surgery because of extensive bilateral disease including cavitary lesions .
ifn- inhalation therapy was added to chemotherapeutic regimens only if there was no improvement in the patient 's clinical , microbiological , and radiological conditions .
seoul , republic of korea ) in a dose of two million international units was given via nebulizer three times weekly for six months .
one patient had a computed tomography scan of the chest at baseline and on completion of the ifn- inhalation therapy on the basis of the judgment of the treating clinician .
posterior - anterior chest radiographies and computed tomography scans examined at the baseline and after completion of treatment were reviewed by two experienced chest radiologists .
there were three men and three women . the median duration of disease before ifn- inhalation therapy was 29 months ( range , 7 to 76 ) .
the median number of drugs used previously was 6.5 ( range , 4 to 7 ) .
for the 6-month period of ifn- inhalation therapy , no patient had become sputum - smear negative .
also sputum cultures remained positive for all patients at the end of the ifn- inhalation therapy . in patients 3 and 5 ,
the sputum cultures were negative at the 4th month , but became positive again at the end of 6 months of ifn- inhalation therapy ( table 2 ) .
chest radiographs done at the baseline were compared with those taken after 6 months of ifn- inhalation therapy .
five patients had improvement of infiltration and three patients showed decrease in the size of the cavitary lesions ( table 2 ) .
one patient ( patient 5 ) who was not initially considered as a candidate for surgery successfully received pulmonary resectional surgery after 6 months of ifn- inhalation therapy combined with chemotherapy due to substantial clinical and radiological improvements .
this 27-yr - old immunocompetent male was presented to our hospital with a 6-yr history of refractory pulmonary tuberculosis .
pulmonary tuberculosis had been diagnosed 6 yr ago , at which time he was treated with isoniazid , rifampin , ethambutol , and pyrazinamide .
results of drug susceptibility test showed that isolated m. tuberculosis was resistant to isoniazid and rifampin and had been on various second - line antituberculous drugs since then .
the sputum cultures , however , had remained persistently positive for m. tuberculosis despite a 5-yr history of medical treatment . upon presentation to our hospital , sputum examination showed smear and culture positivity and his chest radiography revealed a large cavity in the right upper lobe and progressive infiltrations in the left upper lobe and both lower lobes ( fig .
recent drug susceptibility test revealed extensive resistance to isoniazid , rifampin , ethambutol , pyrazinamide , streptomycin , and ofloxacin .
prothionamide , cycloserine , para - aminosalicylic acid , levofloxacin , amoxicillin - clavulonic acid , and clarithromycin were prescribed .
six months later , he became clinically worse , with cough , sputum , and anorexia .
sputum smears for acid - fast bacilli were positive , and cultures yielded growth of m. tuberculosis .
the extent of radiographic infiltrations , especially on the left side , had increased ( fig .
at that time , resectional surgery could not be considered due to progressive bilateral lesions .
six months later there was a decrease of cavity size in the right upper lobe and , more importantly , improvement of nodular infiltrates in the left upper lobe and both lower lobes ( fig .
right upper lobectomy and wedge resection of the right lower lobe were successfully performed without perioperative complications .
mdr - tb is a serious life - threatening condition that is associated with a high degree of morbidity and mortality . in 1993 ,
the national jewish center for immunology and respiratory medicine reported 22% mortality attributable to mdr - tb and only 56% of mdr - tb patients were disease free after a mean follow - up period of 51 months ( 12 ) .
recently , the development of modern immunology has led to new investigational therapeutic approach , that is cytokine therapy , in the treatment of mdr - tb .
there is a scientific rationale for the use of ifn- in mdr - tb . by activating macrophages and promoting a range of host immune responses
, ifn- may provide an effective adjunct to antituberculous agents in patients who are not responding to conventional courses of therapy .
ifn- enhances antigen processing and presentation to lymphocytes through the induction of major histocompatibility complex class ii antigens .
it also acts on t lymphocytes , stimulating a differentiation toward a th1-type of immune response ( 6 , 9 , 13 , 14 ) .
ifn- has been used for the prophylactic treatment of chronic granulomatous disease and long - term follow - up of these patients who have received up to 10 yr of ifn- has shown no unexpected toxicity ( 15 ) .
these data indicated that long - term ifn- therapy appears safe and well tolerated in humans .
ifn- has been used successfully as an adjuvant in the treatment of human mycobacterial infections ; leprosy , nontuberculous mycobacterial infection , and tuberculosis ( 7 - 9 , 13 , 16 ) . however
described a patient with acute lymphocytic leukemia in remission who had mdr - tb involving the brain and spinal cord that was steroid - dependent .
subcutaneous ifn- therapy allowed rapid reduction in steroid dose and led to cure without any exacerbation of central nervous system inflammation ( 13 ) .
condos et al . used ifn- aerosol for four weeks in five patients with long - standing mdr - tb refractory to medical treatment ( 9 ) .
sputum acid - fast - bacillus smears became negative and the size of cavitary lesions was reduced in all patients suggesting that ifn- might be useful as an adjunctive therapy in patients with mdr - tb .
with this short course of therapy , culture conversion did not occur and all patients again had positive smears after cessation of ifn-. however , no patient worsened during therapy , and there were no significant systemic or local complaints .
these data suggested that ifn- inhalation therapy could be well tolerated and useful in some patients with mdr - tb .
the six patients described here had persistent mdr - tb that was refractory to appropriate therapy with conventional antituberculous agents .
after the six - month therapy , sputum smears of our patients were persistently positive for the entire six months and sputum cultures were positive at the end of the period in all patients in spite of transient negative conversion in two patients .
these results were not consistent with the results of condos et al . which showed transient clearing of smears in all patients .
the difference between our experience and that of condos et al . may be related to the aerosol dose of ifn- that our patients received ; our patients were taking two million international units of ifn- which were equivalent to 100 g and condos et al . used 500 g of ifn-. in particular , all patients except one patient showed radiological responses .
the most obvious responses were improvements of infiltration such as nodules , reticulonodular opacities , which were noticed in five ( 83% ) patients .
however , reduction in the size of cavitary lesions was observed in only three ( 50% ) patients .
interestingly , one patient showed substantial clinical and radiological improvement and then resectional surgery could be performed . to our knowledge , this is the first reported case of refractory mdr - tb in the lung , which was successfully treated with adjunctive ifn- inhalation therapy combined with surgical management and antituberculous drugs .
this result suggested that ifn- inhalation therapy may play a role of the bridge to pulmonary resection in selected patients who have initially equivocal indication of resectional surgery due to bilateral active disease .
these findings suggested that ifn- inhalation therapy may be a powerful adjunct to conventional therapy , especially in the patients with less destructive parenchymal lesion such as nodular infiltration without cavitary lesions which have a large burden of mycobacterium .
the current study is limited by the small sample size , but the results suggest that ifn- inhalation therapy might be an acceptable adjunctive therapy
. the distinctive role of ifn- in the adjunctive treatment of mdr - tb should be further investigated to determine the criteria of potential candidates and optimal duration of therapy .
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### Summary:
: the aim of this study was to investigate the adjuvant effects of interferon - gamma ( ifn- ) inhalation therapy for six months in the treatment of refractory multidrug - resistant pulmonary tuberculosis ( mdr - tb ) .
aerosolized ifn- was given to six mdr - tb patients with persistent positive smears and cultures despite long - term medical treatment .
the patients received aerosolized two million international units of ifn- three times a week for 6 months while they continued on identical antituberculous chemotherapy . before ifn- inhalation therapy
, the patients received a median of 6.5 ( range , 4 to 7 ) antituberculous drugs for median duration of 29 months ( range,7 to 76 ) .
after ifn- inhalation therapy , sputum smears remained persistently positive in all patients throughout the study period .
sputum cultures were transiently negative at the 4th month in two patients , but became positive again at the end of 6 months of ifn- therapy .
five patients had radiological improvement including three patients who showed a decrease in the size of the cavitary lesions .
resectional surgery could be performed in one patient in whom substantial clinical and radiological improvement was noted after ifn- inhalation therapy .
these results suggest that ifn- inhalation therapy may be effective for some cases of refractory mdr - tb who are otherwise not responding to conventional therapy .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: we followed the preferred reporting items for systematic reviews and meta - analyses ( prisma ) checklist for reporting systematic reviews and meta - analyses ( 14 ) .
we searched medline ( 1966 to january 2010 ) , embase ( 1980 to january 2010 ) , the cochrane central register of controlled trials , and cinahl from inception to january 2010 .
the main search concepts were type 2 diabetes , hemoglobin a1c , long - acting insulin analogs , short - acting insulin analogs , biphasic insulin analogs , glargine , detemir , neutral protamine lispro , lispro , aspart , glulisine , randomized controlled trials , and clinical trials .
we also reviewed reference lists of included articles , the us food and drug administration and european medicines agency web sites for the insulin analogs , as well as web sites of public registries of clinical trials ( clinicaltrials.gov and clinicalstudyresults.org ) .
we included rcts if 1 ) patients aged > 18 years with a diagnosis of type 2 diabetes , as defined by criteria current at the time of the trial ( 15 ) were included ; 2 ) different insulin regimens ( basal , biphasic , prandial or basal - bolus ) using insulin analogs were evaluated ; and 3 ) the proportion of diabetic patients reaching the hba1c goal of 7% was reported .
we included crossover trials with at least 12 weeks of follow - up before and after the crossover phase .
the search had no language restriction ; however , we excluded reviews , editorials , comments , letters , and abstracts .
trials were rejected if the intervention time was <3 months , the number of patients in any arm was < 30 patients , or comparisons were between insulin analogs and conventional insulins within the same or different regimens .
two investigators ( d.g . and k.e . ) identified relevant publications and abstracted the data , and any disagreements were resolved by consensus .
this 5-point quality scale includes points for randomization ( described as randomized , 1 point ; table of random numbers or computer - generated randomization , additional 1 point ) , double - blind ( described as double - blind , 1 point ; use of masking such as identical placebo , additional 1 point ) , and follow - up ( the numbers and reasons for withdrawal in each group are stated ; 1 point ) in the report of an rct .
we gave an additional point if the analysis was by intention - to - treat .
we considered scores of 2 as low quality and a score of 3 as high quality because none of the studies were double - blinded , due to the visibly different properties of the comparators .
we compared four insulin regimens : the biphasic regimen consisted of the biphasic ( premixed ) insulin analogs lispro 25/75 , lispro 50/50 , aspart 30/70 , aspart 50/50 , and aspart 70/30 , with the numbers denoting the percentage of the rapid - acting / the long - acting component;the basal regimen consisted of basal insulin analogs comprising the long - acting insulins glargine , detemir , and lispro / neutral protamine lispro;the prandial regimen consisted of prandial insulin analogs , comprising short - acting insulins lispro , aspart , and glulisine ; andthe basal - bolus regimen consisted of any combination of prandial and basal insulin analogs.no studies comparing basal or prandial with basal - bolus regimens met the inclusion criteria .
the biphasic regimen consisted of the biphasic ( premixed ) insulin analogs lispro 25/75 , lispro 50/50 , aspart 30/70 , aspart 50/50 , and aspart 70/30 , with the numbers denoting the percentage of the rapid - acting / the long - acting component ; the basal regimen consisted of basal insulin analogs comprising the long - acting insulins glargine , detemir , and lispro / neutral protamine lispro ; the prandial regimen consisted of prandial insulin analogs , comprising short - acting insulins lispro , aspart , and glulisine ; and the basal - bolus regimen consisted of any combination of prandial and basal insulin analogs .
the proportion of patients with hba1c < 7% at the end of treatment was the primary outcome .
secondary outcomes were hypoglycemic events and weight gain . statistically , binomial proportion lacks consensus over the calculation of the confidence intervals .
we transformed the proportions into a quantity suitable for the usual fixed and random - effects summaries ( the freeman - tukey variant of the arc sine square root transformed proportion ) ( 17 ) .
the pooled proportion is calculated as a back - transformation of the weighted mean of the transformed proportions , using inverse arc sine variance weights for the fixed - effects model and dersimonian - laird weights ( 18 ) for the random - effects model .
denominators used for calculating the response rate on each treatment group were those reported within original studies as eligible patients coming from randomization .
the association between exposure ( treatments ) and outcome ( proportions of patients with hba1c < 7% ) was measured by the odds ratio ( or ) . when the or and 95% cis were available , we transformed them into logor and calculated the corresponding variance and standard error using the formula proposed by greenland ( 19 ) . when the or was not directly available from the article , we calculated it from tabular data and used the woolf formula to evaluate the standard error of the logor ( 20 ) . if tabular data were not given and only response rate was available , the number of responses was calculated by multiplying the response rate by the number of randomized / eligible patients .
pooled or with 95% ci was estimated , pooling the study - specific estimates by random - effects models fitted using sas ( proc mixed ) software ( sas institute ) with maximum likelihood estimate .
these models provided estimates adjusted for the heterogeneity between studies and the correlation within studies given by the randomized studies with more than two groups .
that is a conservative approach because it raises the variability caused by the correlation within study , providing , as a result , wider and more reliable cis .
heterogeneity of the effect across studies was assessed by q statistics , which is distributed as statistics .
a value of p < 0.10 was used to indicate lack of homogeneity among effects .
i statistics were provided to quantify the percentage of total variation across studies that was attributable to heterogeneity rather than to chance ( 21 ) .
it consists of a funnel - plot regression of log(rr ) or log(or ) on the sample size , weighted by the inverse of the pooled variance . for hypoglycemic events and weight gain , we recorded the mean difference between groups , along with its measure of dispersion . if no measure of dispersion was reported for the between - group difference , we conservatively estimated it by the worst ratio between mean and standard deviation among the available studies .
if a trial reported the number of episodes in each group or reported an event rate in a form other than episodes per patient per 30 days , we converted this information into episodes per patients per 30 days .
we searched medline ( 1966 to january 2010 ) , embase ( 1980 to january 2010 ) , the cochrane central register of controlled trials , and cinahl from inception to january 2010 .
the main search concepts were type 2 diabetes , hemoglobin a1c , long - acting insulin analogs , short - acting insulin analogs , biphasic insulin analogs , glargine , detemir , neutral protamine lispro , lispro , aspart , glulisine , randomized controlled trials , and clinical trials .
we also reviewed reference lists of included articles , the us food and drug administration and european medicines agency web sites for the insulin analogs , as well as web sites of public registries of clinical trials ( clinicaltrials.gov and clinicalstudyresults.org ) .
we included rcts if 1 ) patients aged > 18 years with a diagnosis of type 2 diabetes , as defined by criteria current at the time of the trial ( 15 ) were included ; 2 ) different insulin regimens ( basal , biphasic , prandial or basal - bolus ) using insulin analogs were evaluated ; and 3 ) the proportion of diabetic patients reaching the hba1c goal of 7% was reported .
we included crossover trials with at least 12 weeks of follow - up before and after the crossover phase .
the search had no language restriction ; however , we excluded reviews , editorials , comments , letters , and abstracts .
trials were rejected if the intervention time was <3 months , the number of patients in any arm was < 30 patients , or comparisons were between insulin analogs and conventional insulins within the same or different regimens .
two investigators ( d.g . and k.e . ) identified relevant publications and abstracted the data , and any disagreements were resolved by consensus .
this 5-point quality scale includes points for randomization ( described as randomized , 1 point ; table of random numbers or computer - generated randomization , additional 1 point ) , double - blind ( described as double - blind , 1 point ; use of masking such as identical placebo , additional 1 point ) , and follow - up ( the numbers and reasons for withdrawal in each group are stated ; 1 point ) in the report of an rct .
we gave an additional point if the analysis was by intention - to - treat .
we considered scores of 2 as low quality and a score of 3 as high quality because none of the studies were double - blinded , due to the visibly different properties of the comparators .
we compared four insulin regimens : the biphasic regimen consisted of the biphasic ( premixed ) insulin analogs lispro 25/75 , lispro 50/50 , aspart 30/70 , aspart 50/50 , and aspart 70/30 , with the numbers denoting the percentage of the rapid - acting / the long - acting component;the basal regimen consisted of basal insulin analogs comprising the long - acting insulins glargine , detemir , and lispro / neutral protamine lispro;the prandial regimen consisted of prandial insulin analogs , comprising short - acting insulins lispro , aspart , and glulisine ; andthe basal - bolus regimen consisted of any combination of prandial and basal insulin analogs.no studies comparing basal or prandial with basal - bolus regimens met the inclusion criteria .
the biphasic regimen consisted of the biphasic ( premixed ) insulin analogs lispro 25/75 , lispro 50/50 , aspart 30/70 , aspart 50/50 , and aspart 70/30 , with the numbers denoting the percentage of the rapid - acting / the long - acting component ; the basal regimen consisted of basal insulin analogs comprising the long - acting insulins glargine , detemir , and lispro / neutral protamine lispro ; the prandial regimen consisted of prandial insulin analogs , comprising short - acting insulins lispro , aspart , and glulisine ; and the basal - bolus regimen consisted of any combination of prandial and basal insulin analogs .
the proportion of patients with hba1c < 7% at the end of treatment was the primary outcome .
secondary outcomes were hypoglycemic events and weight gain . statistically , binomial proportion lacks consensus over the calculation of the confidence intervals .
we transformed the proportions into a quantity suitable for the usual fixed and random - effects summaries ( the freeman - tukey variant of the arc sine square root transformed proportion ) ( 17 ) .
the pooled proportion is calculated as a back - transformation of the weighted mean of the transformed proportions , using inverse arc sine variance weights for the fixed - effects model and dersimonian - laird weights ( 18 ) for the random - effects model .
denominators used for calculating the response rate on each treatment group were those reported within original studies as eligible patients coming from randomization .
the association between exposure ( treatments ) and outcome ( proportions of patients with hba1c < 7% ) was measured by the odds ratio ( or ) . when the or and 95% cis were available , we transformed them into logor and calculated the corresponding variance and standard error using the formula proposed by greenland ( 19 ) .
when the or was not directly available from the article , we calculated it from tabular data and used the woolf formula to evaluate the standard error of the logor ( 20 ) . if tabular data were not given and only response rate was available , the number of responses was calculated by multiplying the response rate by the number of randomized / eligible patients . pooled or with 95% ci was estimated , pooling the study - specific estimates by random - effects models fitted using sas ( proc mixed ) software ( sas institute ) with maximum likelihood estimate .
these models provided estimates adjusted for the heterogeneity between studies and the correlation within studies given by the randomized studies with more than two groups .
that is a conservative approach because it raises the variability caused by the correlation within study , providing , as a result , wider and more reliable cis .
heterogeneity of the effect across studies was assessed by q statistics , which is distributed as statistics .
a value of p < 0.10 was used to indicate lack of homogeneity among effects .
i statistics were provided to quantify the percentage of total variation across studies that was attributable to heterogeneity rather than to chance ( 21 ) .
it consists of a funnel - plot regression of log(rr ) or log(or ) on the sample size , weighted by the inverse of the pooled variance . for hypoglycemic events and weight gain , we recorded the mean difference between groups , along with its measure of dispersion . if no measure of dispersion was reported for the between - group difference , we conservatively estimated it by the worst ratio between mean and standard deviation among the available studies .
if a trial reported the number of episodes in each group or reported an event rate in a form other than episodes per patient per 30 days , we converted this information into episodes per patients per 30 days .
we identified 2,650 citations , of which we reviewed 126 ; of these , 16 ( 2338 ) performed comparisons between different insulin regimens and were included in the meta - analysis ( supplementary fig .
all studies were rcts ( table 1 ) : among these , 13 were parallel group and 3 ( 23,24,27 ) were crossover .
the trials enrolled a total of 7,759 patients ( range , 602,091 ) . patients were a mean age of 58.2 years , with slight prevalence of male sex ( 55.6% ) .
the study population had a median hba1c level of 8.6% ( interquartile range 8.49.1% ) .
characteristics of the randomized controlled trials included in the meta - analysis co , crossover group ; p , parallel group ; ohas , oral hypoglycemic agents ; met , metformin ; su , sulfonylurea ; tzd , thiazolidinedione ; itt , intention to treat .
nine trials enrolled insulin - nave patients ( 23,25,2729,31,32,35,37 ) , six enrolled insulin - treated patients ( 24,30,33,34,36,38 ) , and one enrolled mixed patients ( 26 ) .
eleven trials ( 2327,2931,33,35,37 ) adopted combined treatment regimens of oral drugs plus insulin ( whichever regimen ) ; the most - represented oral drugs were metformin , a sulfonylurea , or a glitazone .
most included insulin - nave patients ( 23,25,2730,35,37 ) and adopted combined treatment regimens of oral drugs plus insulin ( 2327,29,30,35,37 ) . compared with basal insulin , patients treated with biphasic insulin had a greater chance to reach the hba1c goal of <
heterogeneity was high ( i = 68% ) but diffuse . compared with basal insulin ,
biphasic insulin was associated with a significant increase in hypoglycemic events ( 0.34 mean events / patient/30 days ) , but significant heterogeneity was observed ( i = 64.9% ) .
exclusion of one trial ( 27 ) with the highest hypoglycemic rate completely eliminated heterogeneity ( i = 0% ; fig .
biphasic insulin was also associated with greater weight gain ( mean difference , 1 kg [ 95% ci 0.281.73 ] ) with high heterogeneity ( i = 85.2% ; fig .
final median ( interquartile range ) insulin dose was 0.5 units / kg ( 0.390.62 ) for biphasic and 0.41 units / kg ( 0.290.55 ) for basal insulin ( p = 0.16 ) .
biphasic versus basal : a : outcome , proportion ( % ) of patients with hba1c < 7% .
n = number of patients in each arm . * mixed - effects model : estimates adjusted for the correlation within studies and heterogeneity between studies ; ^sensitivity analysis .
no difference between treatments was shown for achievement of hba1c goal ( or 1.04 [ 95% ci 0.372.92 ] ; supplementary fig .
2 ) . there was no evidence of publication bias ( p = 0.39 ) .
there was no mean ( 95% ci ) difference in the incidence of hypoglycemia events / patient/30 days ( 0.15 [ 0.57 to 0.27 ] ) or weight gain ( 0.1 kg [ 0.71 to 1.9 ] ) between the two regimens .
for the remaining two trials , no difference in daily insulin dose was observed between the two regimens .
prandial insulin was associated with a nonsignificant chance of achievement the hba1c goal ( or 1.58 [ 95% ci 0.773.23 ] ; supplementary fig .
a sensitivity analysis excluding one trial ( 36 ) gave significant results ( or 2.07 [ 95% ci 1.163.69 ] ) with no evidence of heterogeneity ( i = 0% ) or publication bias ( p = 0.37 ) .
compared with basal insulin , prandial insulin was associated with a nonsignificant increase in the incidence of hypoglycemia , with high heterogeneity ( i = 99.7% ) , which persisted elevated ( i = 97.7% ) after exclusion of one trial .
final median ( interquartile range ) insulin dose was 0.56 units / kg ( 0.510.60 ) for prandial and 0.49 units / kg ( 0.460.51 ) for basal insulin ( p = 0.06 ) .
the inclusion of the 3-year extension of the treating to target in type 2 diabetes ( 4-t ) trial ( 38 ) in the present comparison was justified by the switching of 73.7% of the former original prandial and 81.5% of the basal regimen to a basal - bolus regimen .
compared with biphasic insulin , patients treated with a basal - bolus regimen had a higher chance to reach the hba1c goal ( or , 1.75 [ 95% ci 1.112.77 ] ) , with no evidence of heterogeneity ( i = 0% ; fig .
2 ) . there was no evidence of publication bias ( p = 0.78 ) .
there was no difference in incidence of hypoglycemia and weight gain between the two regimens .
final median ( interquartile range ) insulin dose was 0.78 units / kg ( 0.661.09 ) for biphasic insulin and 0.97 units / kg ( 0.901.29 ) for the basal - bolus regimen ( p = 0.40 ) .
biphasic versus basal - bolus . a : outcome , proportion ( % ) of patients with hba1c < 7% .
n = number of patients in each arm . * mixed - effects model : estimates adjusted for the correlation within studies and heterogeneity between studies .
ten trials ( 2330,35,37 ) were eligible . most included insulin - nave patients ( 23,25,2730,35,37 ) and adopted combined treatment regimens of oral drugs plus insulin ( 2327,29,30,35,37 ) . compared with basal insulin , patients treated with biphasic insulin had a greater chance to reach the hba1c goal of <
1a ) . there was no evidence of publication bias ( p = 0.15 ) .
heterogeneity was high ( i = 68% ) but diffuse . compared with basal insulin ,
biphasic insulin was associated with a significant increase in hypoglycemic events ( 0.34 mean events / patient/30 days ) , but significant heterogeneity was observed ( i = 64.9% ) .
exclusion of one trial ( 27 ) with the highest hypoglycemic rate completely eliminated heterogeneity ( i = 0% ; fig .
biphasic insulin was also associated with greater weight gain ( mean difference , 1 kg [ 95% ci 0.281.73 ] ) with high heterogeneity ( i = 85.2% ; fig .
final median ( interquartile range ) insulin dose was 0.5 units / kg ( 0.390.62 ) for biphasic and 0.41 units / kg ( 0.290.55 ) for basal insulin ( p = 0.16 ) .
biphasic versus basal : a : outcome , proportion ( % ) of patients with hba1c < 7% .
n = number of patients in each arm . * mixed - effects model : estimates adjusted for the correlation within studies and heterogeneity between studies ; ^sensitivity analysis .
no difference between treatments was shown for achievement of hba1c goal ( or 1.04 [ 95% ci 0.372.92 ] ; supplementary fig .
2 ) . there was no evidence of publication bias ( p = 0.39 ) .
there was no mean ( 95% ci ) difference in the incidence of hypoglycemia events / patient/30 days ( 0.15 [ 0.57 to 0.27 ] ) or weight gain ( 0.1 kg [ 0.71 to 1.9 ] ) between the two regimens .
for the remaining two trials , no difference in daily insulin dose was observed between the two regimens .
was associated with a nonsignificant chance of achievement the hba1c goal ( or 1.58 [ 95% ci 0.773.23 ] ; supplementary fig .
an evidence of publication was detected ( p = 0.07 ) . a sensitivity analysis excluding one trial ( 36 ) gave significant results ( or 2.07 [ 95% ci 1.163.69 ] ) with no evidence of heterogeneity ( i = 0% ) or publication bias ( p = 0.37 ) . compared with basal insulin ,
prandial insulin was associated with a nonsignificant increase in the incidence of hypoglycemia , with high heterogeneity ( i = 99.7% ) , which persisted elevated ( i = 97.7% ) after exclusion of one trial .
final median ( interquartile range ) insulin dose was 0.56 units / kg ( 0.510.60 ) for prandial and 0.49 units / kg ( 0.460.51 ) for basal insulin ( p = 0.06 ) .
three studies ( 33,34,38 ) were eligible . all trials included patients who were not insulin - nave .
the inclusion of the 3-year extension of the treating to target in type 2 diabetes ( 4-t ) trial ( 38 ) in the present comparison was justified by the switching of 73.7% of the former original prandial and 81.5% of the basal regimen to a basal - bolus regimen .
compared with biphasic insulin , patients treated with a basal - bolus regimen had a higher chance to reach the hba1c goal ( or , 1.75 [ 95% ci 1.112.77 ] ) , with no evidence of heterogeneity ( i = 0% ; fig .
there was no difference in incidence of hypoglycemia and weight gain between the two regimens .
final median ( interquartile range ) insulin dose was 0.78 units / kg ( 0.661.09 ) for biphasic insulin and 0.97 units / kg ( 0.901.29 ) for the basal - bolus regimen ( p = 0.40 ) .
n = number of patients in each arm . * mixed - effects model : estimates adjusted for the correlation within studies and heterogeneity between studies .
the ultimate goal of treatment of diabetes is improvement in microvascular and macrovascular complications , and death .
most trials included in this analysis were not specifically designed to evaluate these clinical outcomes .
although not ideal , hba1c is the most - used intermediate outcome to optimize glycemic control in a clinical setting .
the ada position statement on standards of medical care in diabetes ( 4 ) insists on the optimal hba1c target of < 7% for most nonpregnant adults , stressing the evidence that microvascular complications are better mitigated with this goal with respect to macrovascular complications ( level of evidence a vs. b , respectively ) .
we found that biphasic and prandial insulin were both associated with a greater proportion of type 2 diabetic patients achieving the hba1c goal of < 7% compared with basal insulin .
the basal - bolus regimen was better than biphasic , and in absolute terms , was the best regimen for the attainment of the hba1c goal .
ultimately , the proportion of patients with a hba1c goal of < 7% using the basal - bolus regimen was 63.5% .
the effect of the different insulin regimens on hypoglycemia was quite similar across different comparisons , with the exception of a greater event rate with the biphasic compared with basal insulin .
biphasic and prandial insulin were both associated with greater weight gain compared with basal insulin , and this effect was also consistent across pooled trials .
biphasic insulin is less effective than basal insulin in decreasing fasting glucose levels but is more effective in decreasing postprandial glucose levels ( 10,11 ) .
our analyses showed biphasic insulin was associated with more hypoglycemia than basal insulin ( 0.34 mean events / patient/30 days ) .
these data are consistent with previous analyses ( 9,10 ) showing that biphasic insulin is more likely to cause hypoglycemia than basal insulin , although in one study ( 10 ) the effect of the different insulin regimens could not be pooled in a meta - analysis .
the overall median incidence of hypoglycemia across all the comparisons was generally low , at 0.4 events / patient/30 days ( range , 04.71 [ interquartile range 0.31.0 ] ) .
biphasic and prandial insulin both caused more weight gain than basal insulin ; however , weight gain was limited , at 1 and 1.94 kg , respectively .
no difference in weight gain was found between biphasic versus prandial insulin or biphasic insulin versus the basal - bolus regimen .
the reduced frequency of insulin injections and glucose monitoring , associated with its inherent simplicity , has led to the basal insulin regimen becoming the first option in initiating insulin therapy in recent guidelines ( 5 ) .
although successful for many patients , at least 60% of patients taking basil insulin were not able to reach the hba1c target .
when the hba1c goal is not attained despite successful basal insulin dose titration , or when titration is limited by hypoglycemia , treatment is generally intensified by addition of prandial or biphasic insulin . according to our analysis
, this escalation in insulin regimens from the simple basal to the complex basal - bolus may result in a further gain in the proportion of type 2 diabetic patients attaining the hba1c goal ( 63.5% with the basal - bolus regimen ) , which still leaves 33% of patients not at the target goal .
the degree of heterogeneity was high for some comparisons , although results in most cases were qualitatively similar across studies in directions of the results .
moreover , sensitivity analysis eliminated heterogeneity in most cases . in addition , there was no evidence of publications bias .
most studies had a short follow - up , and firm conclusions can not be draw about the long - term comparative effectiveness of the various regimens .
any improvements seen in hba1c in these short - term trials may not be sustained over a longer period , although studies with longer follow - up gave similar results . only one long - term study ( mean patient participation after randomization was 963 days ) was specifically designed for assessing cardiovascular outcomes in survivors to a first myocardial infarction comparing basal with biphasic insulin , but the study was stopped for lack of efficacy ( 36 ) .
, our analysis of 7,759 type 2 diabetic patients using insulin analogs indicates that the hba1c target < 7% can be achieved in 35 to 63.5% , depending on the particular insulin regimen .
basal insulin is associated with a lower proportion of diabetic patients at target compared with prandial or biphasic insulin , but with less hypoglycemia and weight gain compared with biphasic insulin .
the best achievement rate is obtained with a basal - bolus regimen compared with biphasic insulin , without further risk of hypoglycemia or weight gain .
more studies are needed to understand better the effect of insulin analogs on long - term diabetes complications .
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### Summary:
: objectiveinsulin analogs are increasingly used in patients with type 2 diabetes .
we compared the effect of basal , biphasic , prandial , and basal - bolus insulin regimens with insulin analogs to reach the hemoglobin a1c
( hba1c ) target of < 7% in people with type 2
diabetes.research design and methodswe conducted an electronic search for randomized controlled trials ( rcts ) involving insulin analogs .
rcts were included if they lasted at least 12 weeks , reported the proportion of diabetic patients reaching the hba1c target of < 7% ( primary outcome ) , and the number of patients in any arm was > 30.resultswe found 16 rcts , with 20 comparisons and 7,759 patients . a greater proportion of patients achieved the hba1c goal of < 7% with both biphasic ( odds ratio 1.88 [ 95% ci 1.382.55 ] ) and prandial ( 2.07 [ 1.163.69 ] ) insulin compared with basal insulin ; this was associated for biphasic insulin with greater hypoglycemia ( event / patient/30 days , mean difference , 0.34 [ range 00.69 ] ) and weight gain in kg ( 1.0 kg [ 0.281.73 ] ) . compared with biphasic insulin ,
the basal - bolus regimen was associated with a greater chance to reach the hba1c goal ( odds ratio 1.75 [ 95% ci 1.112.77 ] ) , with no greater hypoglycemia or weight gain .
the effect of insulin analogs on long - term diabetes complications is still lacking.conclusionsa greater proportion of type 2 diabetic patients can achieve the hba1c goal < 7% with biphasic or prandial insulin compared with basal insulin ; in absolute terms , the basal - bolus regimen was best for the attainment of the hba1c goal .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: one of the most important public health problems is leishmaniasis , which is due to a range of diseases from self - limited cutaneous lesions to the fatal visceral one .
a parasite named leishmanina causes the disease that has many types , which are endemic for special regions like l.amzonesis , l.donovani , and l.mexicana in the latin america . l.tropica the cause of anthroponotic cutaneous leishmaniasis
, acl is particularly prevalent from ( cl ) patients in kerman province , southeastern iran ( 13 ) .
systemic pentavalent antimoniates have been used as the first line therapy of leishmaniasis for more than eighty years . although , the drugs are effective ( about 30% ) ( 4 ) , but their adverse effects such as fatal cardiotoxicity , myalgia , pancreatitis , and elevated serum amylase , lipase and liver enzyme levels etc .
besides , their painful injections are another limitation of the drug , especially in children .
hence , presenting new methods to cure this neglected disease is considered in many investigations .
it is an anti - neoplastic agent and a membrane active phospholipid derivative ( 5,6).the phosphocholine analogue demonstrated in vivo and in vitro activity against different species of leishmania ( 5 ) .
the discovery of using some antifungal agents as a leishmanicidal has been assessed . in 1990s , several studies focused on the effect of antifungal agents such as clotrimazole , ketoconazole and terbinafine on various types of leishmania .
moreover , large multivesicular bodies have been found in the parasites by using the allylamine terbinafine and azole , ketoconazole(7 ) .
terbinafine inhibits the enzyme squalene epoxidase , which converts squalene - to - squalene epoxide , and this reduction in squalene epoxide leads to a decrease in ergosterol formation ( 8) .
furthermore , excess squalene damages cellular membranes and may cause the release of lytic enzymes from vacuoles .
these actions may be responsible for the leishmanicidal effect of terbinafine in vitro ( 8) . except of hepatitis , neutropenia , pancytopenia , stevens - johnson syndrome , loss of taste , erythema multiforme and toxic epidermal necrolysis , there were not any serious side effects for terbinafine ( 9 ) .
the aim of this study was to evaluate the efficacy of oral terbinafine plus cryotherapy versus systemic glucantime plus cryotherapy in the treatment of cl due to l. tropica .
a randomize clinical trial was performed at afzalipour hospital , kerman university of medical sciences , iran , in 201112 .
a sample size of 40 participants per treatment group was planned , a probability of a type i error at alpha = 0.05 and beta=0.1 to determine a 20% difference between topical terbinafine compared with control group .
a total of 80 participants with proven direct smear for cl were enrolled in this trial .
skin scraping was taken from the margin of active lesion , smeared on a glass slide , methanol fixed , giemsa stained and microscopically checked for amastigote stage .
inclusion criteria were as follows : they should not have received any other leishmanicidal treatment during last three months .
pregnant and nursing women and those who had hypersensitivity to trial drugs were dropped out .
all participants were aware of the trial plans and all participants or their parents for those fewer than 18 years of old obtained informed consent .
demographic data including age , sex , and the number , location , type and the size of lesions , the presence of indurations and ulcer , and the duration of lesions were recorded for each patient .
review board and ethics committee of kerman university of medical sciences approved the study , under number k-90/507 .
a simple block randomization list with a block size of 4 was accumulated by a team member who was not involved in the enlistment and follow - up of the patients .
the randomization allocation concealment was carried out by sending the randomization numbers in envelopes to a dermatologist who was responsible for giving the assigned treatment after each patient was enrolled .
this study was an assessor blind trial in which the outcome assessor was unaware of the drugs used by the patients .
group a was treated with 125 mg / kg ibd ( for less than 20 kg body weight ) , 250 mg / kg ibd ( 2040 kg body weight ) , 500 mg / kg ibd ( for more than 40 kg body weight ) oral terbinafine ( lamisil manufactured in novartis in switzerland country with irc number : 122803330 ) for 4 weeks and accompanied with cryotherapy for every 2 weeks . the other group ( b ) was treated with 15 mg / kg / day i m systemic meglumine antimoniate ( glucantime manufactured in haupt pharma in france country with irc number : 1228027161 ) for 3 weeks and using cryotherapy the same as group a. cryotherapy involved the application of liquid nitrogen via a cotton swab for 1025 seconds until the lesion and 12 mm of surrounding normal tissue appeared frozen in both groups .
different modalities of treatment were not given to the same patient in different lesions ( i.e. each patient received oral terbinafine plus cryotherapy , or combined cryotherapy and systemic glucantime ) .
laboratory testing including complete blood count ( cbc ) , urea , creatinine , lft(alkaline phosphatase , alanine aminotransferase , aspartate aminotransferase , bilirubin total ) were performed for all participants at base line , in the middle , and at the end of the treatment course . the improving rate determined by measuring indurations at baseline , in the middle ( day 10 for glucantime group and day14 for terbinafine group ) , and at the end of the study ( day 21 for glucantime group and day 28 for terbinafine group ) .
the size of indurations of the lesions was measured in two perpendicular directions based on sokal method by an independent observer who was not aware of the treatment options . to confirm the complete improvement direct smear
clinical response was determined based on the following criteria :
complete improvement ( decrease in induration size > 75%),partial improvement ( decrease in induration size between 25% and 75%),no improvement ( decrease in induration size < 25% ) .
complete improvement ( decrease in induration size > 75% ) , partial improvement ( decrease in induration size between 25% and 75% ) , no improvement ( decrease in induration size < 25% ) .
all participants were followed for 3 months after completing the project , they were examined every month to assess the recurrence of the lesions at the site of the previous lesions or around them and increasing the size of the lesions after primary partial improvement .
we decided to crossover the patients who did not respond to terbinafine to glucantime group .
while , they did not respond to glucantime , other common remedies were used for them .
having compared demographic and baseline data of subjects in two groups , the data file was converted to the long format in a way that each record showed the data subject in one session .
then , the size of each lesion was computed based on its dimensions . in our analysis , no response to treatment was defined if the size of a lesion decreased less than 25% , partial treatment if decreased between 25% and 75% , and complete treatment if decreased 75% ( complete re - epithelialization ) , compared to its baseline area .
survival curves were calculated using the kaplan meier method , and hazard ratios were estimated using the cox proportional hazards model . in order to compare subjects response to treatments in each group , we used the cox regression model .
two types of models were constructed : 1 ) the event of interest was complete treatment ; 2 ) the event of interest was partial treatment .
since the shape and location of lesions , before treatment was significantly different between the two groups , in cox regression models , they were adjusted for , after computing the crude hazard ratio ( hr ) .
similarly , the confounding effect of sex , the duration , and the size of lesions before treatment were evaluated by this approach .
a randomize clinical trial was performed at afzalipour hospital , kerman university of medical sciences , iran , in 201112 .
a sample size of 40 participants per treatment group was planned , a probability of a type i error at alpha = 0.05 and beta=0.1 to determine a 20% difference between topical terbinafine compared with control group .
a total of 80 participants with proven direct smear for cl were enrolled in this trial .
skin scraping was taken from the margin of active lesion , smeared on a glass slide , methanol fixed , giemsa stained and microscopically checked for amastigote stage .
inclusion criteria were as follows : they should not have received any other leishmanicidal treatment during last three months .
pregnant and nursing women and those who had hypersensitivity to trial drugs were dropped out .
all participants were aware of the trial plans and all participants or their parents for those fewer than 18 years of old obtained informed consent .
demographic data including age , sex , and the number , location , type and the size of lesions , the presence of indurations and ulcer , and the duration of lesions were recorded for each patient .
review board and ethics committee of kerman university of medical sciences approved the study , under number k-90/507 .
a simple block randomization list with a block size of 4 was accumulated by a team member who was not involved in the enlistment and follow - up of the patients .
the randomization allocation concealment was carried out by sending the randomization numbers in envelopes to a dermatologist who was responsible for giving the assigned treatment after each patient was enrolled .
this study was an assessor blind trial in which the outcome assessor was unaware of the drugs used by the patients .
group a was treated with 125 mg / kg ibd ( for less than 20 kg body weight ) , 250 mg / kg ibd ( 2040 kg body weight ) , 500 mg / kg ibd ( for more than 40 kg body weight ) oral terbinafine ( lamisil manufactured in novartis in switzerland country with irc number : 122803330 ) for 4 weeks and accompanied with cryotherapy for every 2 weeks .
the other group ( b ) was treated with 15 mg / kg / day i m systemic meglumine antimoniate ( glucantime manufactured in haupt pharma in france country with irc number : 1228027161 ) for 3 weeks and using cryotherapy the same as group a. cryotherapy involved the application of liquid nitrogen via a cotton swab for 1025 seconds until the lesion and 12 mm of surrounding normal tissue appeared frozen in both groups .
different modalities of treatment were not given to the same patient in different lesions ( i.e. each patient received oral terbinafine plus cryotherapy , or combined cryotherapy and systemic glucantime ) .
laboratory testing including complete blood count ( cbc ) , urea , creatinine , lft(alkaline phosphatase , alanine aminotransferase , aspartate aminotransferase , bilirubin total ) were performed for all participants at base line , in the middle , and at the end of the treatment course . the improving rate determined by measuring indurations at baseline , in the middle ( day 10 for glucantime group and day14 for terbinafine group ) , and at the end of the study ( day 21 for glucantime group and day 28 for terbinafine group ) .
the size of indurations of the lesions was measured in two perpendicular directions based on sokal method by an independent observer who was not aware of the treatment options . to confirm the complete improvement direct smear was done clinically improved for all lesions .
clinical response was determined based on the following criteria :
complete improvement ( decrease in induration size > 75%),partial improvement ( decrease in induration size between 25% and 75%),no improvement ( decrease in induration size < 25% ) .
complete improvement ( decrease in induration size > 75% ) , partial improvement ( decrease in induration size between 25% and 75% ) , no improvement ( decrease in induration size < 25% ) .
all participants were followed for 3 months after completing the project , they were examined every month to assess the recurrence of the lesions at the site of the previous lesions or around them and increasing the size of the lesions after primary partial improvement .
we decided to crossover the patients who did not respond to terbinafine to glucantime group . while
, they did not respond to glucantime , other common remedies were used for them .
having compared demographic and baseline data of subjects in two groups , the data file was converted to the long format in a way that each record showed the data subject in one session .
then , the size of each lesion was computed based on its dimensions . in our analysis , no response to treatment was defined if the size of a lesion decreased less than 25% , partial treatment if decreased between 25% and 75% , and complete treatment if decreased 75% ( complete re - epithelialization ) , compared to its baseline area .
survival curves were calculated using the kaplan meier method , and hazard ratios were estimated using the cox proportional hazards model . in order to compare subjects response to treatments in each group , we used the cox regression model .
two types of models were constructed : 1 ) the event of interest was complete treatment ; 2 ) the event of interest was partial treatment . since the shape and location of lesions , before treatment was significantly different between the two groups , in cox regression models , they were adjusted for , after computing the crude hazard ratio ( hr ) .
similarly , the confounding effect of sex , the duration , and the size of lesions before treatment were evaluated by this approach .
of eighty patients entered to the study , half were in the terbinafine group ( 18 males and 18 females ; the sex of four patients was unknown ) and the other half of participants were in the glucantime group ( 16 males and 18 females ; the sex of six patients was unknown ) . -
no major clinical or laboratory parameter adverse effect was observed in the both groups after treatment .
participants mean age was 18.52 17.3 years and the majority were female ( n= 36 , 51.43% ) .
there was no significant difference between both groups regarding baseline data ( table 1 ) . comparing main characteristics of subjects classified by their received treatments
as total sample size in each group was less than 100 , crude numbers without percent are reported .
patients who had more than one lesion were completely treated if they had one or more lesions that showed symptoms of complete response to treatment ; patients were partially treated if they had no symptom of complete treatment but showed symptoms of partial treatment in one or more lesions .
those who did not show evidence of partial or complete treatment at all were considered as cases with no response to treatment
most participants had one lesion ( terbinafine : n=25 , 62.5% vs. glucantime : n=19 , 47.5% ; p=0.420 ) , the most frequent location of the lesions was on patients face ( terbinafine : n=99 , 45.8% vs. glucantime : n=93 , 50% ;
p=0.035 ) .
the lesions were most frequently in the shape of nodules ( terbinafine : n=123 , 55.4% vs. glucantime : n=78 , 37.5% ; p<0.0001 ) .
figure 1 shows box plot of initial lesion size in glucan - time and terbinafine groups .
median of initial lesion size in glucantime and terbinafine groups / * since each patient could have more than one lesion , lesion codes are more than 80 ( the total number of subjects ) having used cox regression model , we found that the trend of partial treatment in terbinafine group was slower than glucantime group , but this was not statistically significant ( hr= 0.55 , ci 95%= 0.31.1 ; panel 1 , left hand ) .
adjustment for the duration , location , size , and the number of the lesions did not change the pattern .
after adjustment for lesion shape ( papule ) , partial treatment in terbinafine group was significantly much slower than glucantime group ( hr= 0.48 , ci 95%= 0.240.98 ) ( table 2 ) . comparing the crude and adjusted partial and complete response to treatments the trend of complete treatment in terbinafine group was significantly slower than glucantime group ( hr= 0.53 , ci 95%= 0.30.98 ; panel 1 , right hand ) .
adjustment for the duration , location , shape , and the number of the lesions did not change the pattern . in terbinafine versus glucantime group ,
complete treatment was faster in females rather than males ; therefore , after adjustment for sex , complete treatment in terbinafine group became significantly much slower than glucantime group ( hr= 0.36 , ci 95%= 0.190.69 ) .
in contrast , the larger lesions achieved the complete treatment slower ; therefore , adjustment for ulcer size accelerated the speed of complete treatment in terbinafine versus glucantime group up to 15% , but it did not change the direction of the pattern at all . after adjustment for both confounders ( sex and ulcer size ) , the hr did not differ from the crude one but it was not statistically significant anymore ( table 2 ) . a kaplan - meier analysis indicated that the difference in complete and partial treatment between the treatment groups was not significant ( fig .
there are many modalities to treat cl including physical , topical , systemic , immuno - therapy etc . with different efficacies ( 10,11 ) .
although feasibility of miltefosine versus glucantime is applicable , it is expensive compared to glucantime ( 12 ) .
the use of antifungal , to improve the cl lesions has been recently considered , as they are safer than the pentavalent antimoniates .
the mechanism of action of antifungal drugs is inhibition of synthesis of ergosterol , which is found in large amounts in cell wall of leishmania .
the mechanism of action of terbinafine is based on the cell - wall of leishmania destruction , which is rich in ergosterol(13 ) .
vanniersantons et al . demonstrated that antifungal , ketoconazole and terbinafine compound could be effective on leishmania , in vitro ( 7 ) . in an in vivo experimental study , 60 mice were exposed to l. major .
they compared two groups ( control and terbinafine groups ) and terbinafine group was meaningfully treated ( 14 ) .
there has not been any clinical trial conducted in the world about oral terbinafine on cl lesions until 2013 .
there has been only one pilot study on the efficacy of oral terbinafine to treat cl due to l.tropica in saudi arabia . in this study
, they randomly enrolled 27 patients for a pilot study using terbinafine with a dose range of 250500 mg / day for four weeks .
they found that complete and partial response were 28.5% and 43% , respectively ( 15 ) .
comparing to our findings , complete response in this trial is much more than the pilot study and also this is true about partial treatment , but the difference is more comparable in complete response that might be related to the sample size , as this trial had more participants than the pilot one .
another reason might be accompanying the treatment with cryotherapy , which was not performed in the pilot study .
in another study , systemic terbinafine has been used in an hiv - positive patient suffering from new world cl ( 250mg / day for 2 weeks ) , as well ( 16 ) .
we performed the first assessor blind - randomize - clinical trial to compare the efficacy of combination therapy of oral terbinafine and cryotherapy versus systemic glucantime and cryotherapy in cl patients .
our findings confirmed that consuming oral terbinafine in the dose of 125500 mg / day ( depending on patient s body weight ) for four weeks was as effective as systemic glucantime in the dose of 15 mg / kg for three weeks in matter of healing of the acute old world dry type cl , caused by l. tropica .
hence , we suggest oral terbinafine as a second - line therapy , in patients who have hypersensitivity or resistance to systemic glucantime .
as it is non - invasive treatment and painless it would be appropriate option especially for children .
on the other hand adverse effects of glucantime such as pain(16 ) , burning sensation(17,18 ) lymphangitis ( 19 ) , secondary infection(20 ) , nausea , urticaria , necrosis , sporotrichoid lesions ( 20 ) , vomiting , dizziness , dyspnea and anaphylactic shock(1921 ) , limits its use especially in children(22 ) .
some studies have showed that terbinafine is a relatively safe drug ( 15 , 23 ) . a post marketing surveil - lance study regarding terbinafine side effects , finally conclude that terbinafine is a safe drug with limited side effects ( 24 ) .
the main limitation is a lack of placebo arm to address the self - healing observed with time that is mainly due to the ethical limitations .
in addition , we found that oral terbinafine in the treatment of cl is less cost effective than antimoniate drugs .
we suggest using oral terbinafine especially in children in endemic areas ( 25 , 26 ) .
the other limitation is that we did not confirm the results using methods such as pcr .
large sample size , randomization , parasitological and biochemical tests were the strengths of this study .
the clinical implications of our study are that using oral terbinafine indicated similar healing but slower than glucantime for lesions due to l. tropica .
in contrast to glucantime , terbinafine is costly , slow in action . in our study
no adverse effect in both groups were observed but according to the other studies using glucantime caused many adverse effect ( topically or systemically)(22 ) .
investigation in different endemic areas can play a role for assessment the efficacy of terbinafine in other species of leishmania .
hence , it seems that in case of hypersensitivity and/or resistance to pentavalent antimoniate , we may be able to use oral terbinafine . on the other hand the administration of pentavalent antimoniate could be associated with several side effects , although they are still the first - line drugs in the antileishmanial armamentarium .
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### Summary:
: background : leishmaniasis is a parasitic infection that may lead to a variety of manifestations . in iran ,
cutaneous leishmaniasis ( cl ) has a high prevalence .
there are many treatment modalities for cl .
the use of oral terbinafine in the treatment of cl has recently been considered .
the aim of this study was to compare combination of oral terbinafine plus cryotherapy versus systemic meglumine antimoniate plus cryotherapy in cl.methods:patients with proven direct smear for cl were divided randomly in 2 groups of 40 cases . for the first group systemic glucantime prescribed ( i m , 15 mg / kg / day ) for 3 weeks .
for the second group oral terbinafine as two folds of usual dose in the treatment of fungal diseases prescribed [ 125 mg / day for body weight ( bw ) < 20 kg , 250 mg / day for bw 2040 kg , 500 mg / day for bw>40 kg ] for 4 weeks .
both groups received cryotherapy every 2 weeks for 4 weeks .
the patients were followed monthly for 3 months after the treatment.results:partial ( hr= 0.55 , ci 95%= 0.31.1 ) and complete ( hr= 0.53 , ci 95%= 0.30.98 ) clinical improvement in terbinafine group was much slower than glucantime group , although at the end of treatment protocols no significant difference between groups were statistically observed ( p=0.27).conclusion : considering more convenient suitable route of administration and approximately comparable results , it seems that terbinafine can be used as an alternative treatment , especially in the case of allergy or resistance to systemic glucantime .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: asymptomatic infections are frequent in europe , as borrelia - specific antibodies have been observed in 525% of healthy subjects [ 1 , 2 , 3 , 4 ] .
the primary stage is characterized by erythema migrans and can be followed by dissemination of disease , which mainly affects the joints , heart or nervous system [ 4 , 5 , 6 ] , within weeks to months .
neuroborreliosis of the central nervous system ( cns ) is rare , and differentiation from other disorders of the cns with concomitant seropositivity for b. burgdorferi can be difficult . herein , we report a case with positive b. burgdorferi serology and 4 episodes of severe cns manifestations with full recovery each time after sufficient antibiotic treatment .
we illustrate the diagnostic steps and procedures which were valuable for posing the differential diagnosis in this unusual case , taking into account current state - of - the - art procedures for the diagnosis of lyme borreliosis .
a 31-year - old woman presented with a 2-day history of rapidly progressing hypoesthesia of the body below the neck , tetraparesis , gait ataxia , brainstem symptoms , and urinary retention .
fifteen years earlier , in 1996 , she had suffered from a mild paraparesis with hypoesthesia of both legs , which remitted completely after treatment with an oral antibiotic and glucocorticoids .
details were not remembered and neither cerebrospinal fluid ( csf ) analysis nor mri scans had been performed . the second episode occurred 3 years later , in 1999 , with acute urinary retention and a mild - to - moderate sensomotoric deficit below dermatome t6 .
transcranial magnetic motor evoked potentials ( mep ) and somatosensory evoked potentials ( ssep ) were altered .
cerebral and spinal mri scans were normal , but csf analysis showed a lymphocytic pleocytosis of 260 leukocytes/l , and a highly elevated b. burgdorferi csf / serum igg antibody index ( ai ) of 8.0 ( normal < 2.0 ) , leading to the diagnosis of neuroborreliosis with transverse myelitis .
the patient was subsequently treated intravenously for 14 days with ceftriaxone 2 g / day and prednisolone 80 mg / day and recovered completely .
control csf analysis showed a regression of the pleocytosis to 30 leukocytes/l and a reestablishment of the blood - brain barrier ( bbb ) function with an albumin csf / serum quotient of 3.6 compared to 12.8 before treatment . during the third episode in 2008 , the patient developed neck pain , a mild gait ataxia , and paresthesia of both legs .
cerebral and spinal mri scans , mep and ssep were normal , but csf analysis revealed 293 leukocytes/l with a positive b. burgdorferi igm ( eia and western blot ) in serum but not in csf . the ai was reported to be normal .
treatment consisted of intravenous ceftriaxone 2 g / day , which was later switched to oral doxycycline 100 mg bid and notably no corticosteroids .
the patient made a complete clinical recovery , and csf reanalysis after treatment showed a reduction of the pleocytosis to 15 leukocytes/l .
the only other remarkable prior condition was an x - type histiocytosis with a strictly dermal manifestation diagnosed in 1982 , which completely remitted and had not caused any further manifestation since treatment with methotrexate and purinethol .
notably , the patient did not recall a tick bite or erythema migrans at any time . on admission in march 2011 ,
the patient presented with a sustained gaze - evoked nystagmus to the left and an incomplete abducens nerve paralysis .
the patient was not able to stand or walk , but showed moderate ataxia of all limbs .
sensory testing revealed sensory deficits below dermatome c4 , with impaired discrimination of sharp and dull , and essentially no sense of vibration , temperature and position .
a spinal mri scan revealed extensive signal alterations especially in the cervical , but also in the thoracic spinal cord .
some of these lesions comprised 2 or more segments and involved large parts of the cord 's cross section ( fig .
1a , b ) , in combination with moderate swelling at the cervical level and a faint enhancement after intravenous gadolinium administration ( not shown ) .
csf analysis revealed a predominantly lymphocytic pleocytosis of 136 leukocytes/l ; dysfunction of the blood - csf barrier , with an elevated csf / serum albumin quotient of 18.8 ; and an elevated total csf protein of 126 mg / dl .
there were no oligoclonal bands , but a reiber diagram suggested intrathecal synthesis of igm ( igm quotient 11.96 , igm index 0.64 ) but not igg ( igg quotient 12.78 , igg index 0.68 ) .
measles , rubella , and zoster ais ( mrz reaction < 1.3 ) were negative .
csf / serum ais of 52.6 and 18.8 were highly positive for b. burgdorferi igm and igg , respectively , with a b. burgdorferi - specific igm concentration of 18.9 u / ml and an igg concentration of 1.3 u / ml in csf .
western blotting was positive in csf and serum for p41- and ospc - specific igm and igg at day 1 , and revealed an additional positive osp17-igm band in serum at days 7 and 17 ( fig .
quantitative real - time pcrs amplifying the ospa gene and the p41 gene of b. burgdorferi sensu lato were negative in csf .
serology for mycoplasma pneumoniae was positive in serum ( immunohistochemical assay , 1:320 ; enzyme immunoassay , borderline positive ) but not in csf .
a pcr for 16s ribosomal dna was positive , and the amplicon was cloned and sequenced but revealed no mycoplasma - specific sequences .
four months after the episode , serological controls revealed a non - significant rise in m. pneumoniae titer in serum ( immunohistochemical assay 1:640 ) , with persistent negative results in csf .
aquaporin-4 antibodies were negative , as were antinuclear antibodies , antineutrophil cytoplasmic antibodies , anti - dna antibodies , anti - extractable nuclear antigens , hiv- , treponema- , hepatitis b and c serology , and pcr of hsv , cmv , vzv and ebv in the csf .
the evoked potentials gave evidence of an affection of the central pyramidal tract and a demyelinating affection of the somatosensory afferents in both legs , while visual and acoustic evoked potentials were normal .
the patient was treated with intravenous ceftriaxone 2 g / day , acyclovir 3 750 mg / day and methylprednisolone 1 g / day .
the patient 's clinical status ameliorated rapidly ; she started to walk again after 1 week and was out of bed most of the day after 3 weeks .
csf analysis after 7 days of treatment revealed a reduction of leukocytes to 26/l along with a reduction of the total protein to 33 mg / dl and a reconstitution of the blood - csf barrier .
cytological examination of all 3 spinal csf samples showed lymphocytic pleocytosis but no lymphoblasts or other atypical cells .
the csf / serum ai decreased after 7 days of treatment to 34.1 for igm and 12.7 for igg , and after a further 10 days to 17.4 for igm and 15.6 for igg .
ais were negative for borrelia - specific igg and further decreased for igm ( igg negative in serum and csf , igm ai 6.5 ) after 4 months .
the levels of cxcl13 were only slightly elevated in csf and did not rise in the course of the current episode ( 35 pg / ml at onset , 4.2 pg / ml after 7 days , 4.5 pg / ml after another 10 days and 4.5 pg / ml after 4 months ) , which argues against acute neuroborreliosis during this episode .
on admission in march 2011 , the patient presented with a sustained gaze - evoked nystagmus to the left and an incomplete abducens nerve paralysis .
the patient was not able to stand or walk , but showed moderate ataxia of all limbs .
sensory testing revealed sensory deficits below dermatome c4 , with impaired discrimination of sharp and dull , and essentially no sense of vibration , temperature and position .
a spinal mri scan revealed extensive signal alterations especially in the cervical , but also in the thoracic spinal cord .
some of these lesions comprised 2 or more segments and involved large parts of the cord 's cross section ( fig .
1a , b ) , in combination with moderate swelling at the cervical level and a faint enhancement after intravenous gadolinium administration ( not shown ) .
csf analysis revealed a predominantly lymphocytic pleocytosis of 136 leukocytes/l ; dysfunction of the blood - csf barrier , with an elevated csf / serum albumin quotient of 18.8 ; and an elevated total csf protein of 126 mg / dl .
there were no oligoclonal bands , but a reiber diagram suggested intrathecal synthesis of igm ( igm quotient 11.96 , igm index 0.64 ) but not igg ( igg quotient 12.78 , igg index 0.68 ) .
measles , rubella , and zoster ais ( mrz reaction < 1.3 ) were negative .
csf / serum ais of 52.6 and 18.8 were highly positive for b. burgdorferi igm and igg , respectively , with a b. burgdorferi - specific igm concentration of 18.9 u / ml and an igg concentration of 1.3 u / ml in csf .
western blotting was positive in csf and serum for p41- and ospc - specific igm and igg at day 1 , and revealed an additional positive osp17-igm band in serum at days 7 and 17 ( fig .
quantitative real - time pcrs amplifying the ospa gene and the p41 gene of b. burgdorferi sensu lato were negative in csf .
serology for mycoplasma pneumoniae was positive in serum ( immunohistochemical assay , 1:320 ; enzyme immunoassay , borderline positive ) but not in csf .
a pcr for 16s ribosomal dna was positive , and the amplicon was cloned and sequenced but revealed no mycoplasma - specific sequences .
four months after the episode , serological controls revealed a non - significant rise in m. pneumoniae titer in serum ( immunohistochemical assay 1:640 ) , with persistent negative results in csf .
aquaporin-4 antibodies were negative , as were antinuclear antibodies , antineutrophil cytoplasmic antibodies , anti - dna antibodies , anti - extractable nuclear antigens , hiv- , treponema- , hepatitis b and c serology , and pcr of hsv , cmv , vzv and ebv in the csf .
the evoked potentials gave evidence of an affection of the central pyramidal tract and a demyelinating affection of the somatosensory afferents in both legs , while visual and acoustic evoked potentials were normal .
the patient was treated with intravenous ceftriaxone 2 g / day , acyclovir 3 750 mg / day and methylprednisolone 1 g / day .
the patient 's clinical status ameliorated rapidly ; she started to walk again after 1 week and was out of bed most of the day after 3 weeks .
csf analysis after 7 days of treatment revealed a reduction of leukocytes to 26/l along with a reduction of the total protein to 33 mg / dl and a reconstitution of the blood - csf barrier .
cytological examination of all 3 spinal csf samples showed lymphocytic pleocytosis but no lymphoblasts or other atypical cells .
the csf / serum ai decreased after 7 days of treatment to 34.1 for igm and 12.7 for igg , and after a further 10 days to 17.4 for igm and 15.6 for igg .
ais were negative for borrelia - specific igg and further decreased for igm ( igg negative in serum and csf , igm ai 6.5 ) after 4 months .
the levels of cxcl13 were only slightly elevated in csf and did not rise in the course of the current episode ( 35 pg / ml at onset , 4.2 pg / ml after 7 days , 4.5 pg / ml after another 10 days and 4.5 pg / ml after 4 months ) , which argues against acute neuroborreliosis during this episode .
the differential diagnostic for the relapsing spinal syndromes of our patient comprises spinal lymphoma , a spinal manifestation of x - type histiocytosis , neuromyelitis optica , multiple sclerosis ( ms ) or a systemic autoimmune disease . as our patient
presented with only spinal and brainstem symptoms and no supratentorial lesions were detectable in mri , the diagnostic criteria for ms were not fulfilled .
the long asymptomatic course between relapses , the absence of atypical cells in csf , the positive response to antibiotic treatment ( even without corticosteroids in 2008 ) and the serological findings argue against lymphoma .
a relapse of x - type histiocytosis after 14 years without symptoms seems very improbable as the microscopic analysis of csf revealed no evidence of histiocytes , and myelitis as a manifestation of histiocytosis is an extremely rare event , even though it has been previously reported .
the severe pleocytosis and damage to the bbb argue against neuromyelitis optica , ms or vasculitis especially since the visual system was unaffected and aquaporin-4 antibodies , oligoclonal bands , mrz reaction , supratentorial mri and the laboratory screening for vasculitis were negative .
the fact that a positive b. burgdorferi csf / serum ai was found in 3 out of 4 episodes and that csf pleocytosis and clinical symptoms ameliorated in response to antibiotic treatment seems to suggest recurrent episodes of neuroborreliosis .
however , recurrent episodes of borreliosis and even more so neuroborreliosis after sufficient antibiotic treatment such as in this case , are very uncommon . if relapses occur , they are attributed to reinfections or relapses after inadequate antibiotic therapy .
moreover , it needs to be considered that the patient did not recall any previous tick bite or erythema migrans nor does she belong to a part of the population with an increased risk for repeated tick bites .
further , it remains unclear why the ai was negative during the third episode while all other signs and symptoms were similar .
all 4 episodes manifested with a spinal syndrome despite the fact that b. burgdorferi myelitis represents less than 5% of cases with neuroborreliosis in larger studies [ 9 , 10 , 11 ] .
positive csf / serum igg ai can be found after a successfully treated and no longer active neuroborreliosis .
but we would expect continuously positive predominantly igg ais in the case of ai persistence after an acute infection or during a persisting or remitting infection involving the cns . however , this was not the case during the episode in 2008 when the ai was normal or in the current episode when ais returned to normal 3 months after the start of the episode .
increasing ais are not specific for an acute borreliosis as they can also be the result of an unspecific stimulation of the immune system , e.g. by an autoimmune manifestation or a yet unidentified infection in our patient .
ais are calculated as the ratio of specific to total immunoglobulins in csf divided by the ratio of specific to total immunoglobulins in serum .
it is therefore possible that low concentrations of total immunoglobulins in csf give rise to positive ais at rather low specific concentrations in csf , like the borrelia - specific igg concentration of 1.3 u / ml observed in our patient . in line with this ,
therefore , further parameters were needed to resolve the diagnostic dilemma in this case . real - time pcr - based results for b. burgdorferi in csf are often negative , as are cultures , even in the case of active neuroborreliosis ; however , positive results can serve to ascertain the diagnosis .
the level of cxcl13 in csf is a very sensitive parameter for neuroborreliosis and can be of great help , especially in complex cases like ours [ 12 , 13 ] . in several studies using the same ready - made elisa from r&d systems as in our patient
, untreated neuroborreliosis could be differentiated from other neurological disorders with a high sensitivity of above 90% using cutoff values of cxcl13 concentrations in csf of 250 pg / ml , 100 pg / ml or 142 pg / ml . in a prospective trial , where a self - made elisa with different binding properties was used , a sensitivity of 94.1% and a specificity of 96.1% were obtained with a cutoff of 1,229 pg / ml , and sensitivity even reached 100% at a cutoff of 697 pg / ml .
an important finding of this large trial was that the cxcl13 concentration in csf could discriminate neuroborreliosis from ms .
the cxcl13 levels found in ms were only moderately elevated , like in our case .
a reanalysis of the data of this prospective study revealed a negative predictive value of 99% for acute untreated neuroborreliosis ( a. plate , pers .
this large body of evidence clearly indicates a good negative predictive value for the cxcl13 concentration of 35 pg / ml observed in our patient .
thus , the recurrence of episodes despite sufficient antibiotic therapy and the fact that she did not recall a tick bite or erythema migrans and did not belong to a risk group for repeated tick bites strongly argue against acute neuroborreliosis as the cause of our patient 's current episode .
instead , it seems most probable that our patient had suffered from neuroborreliosis in the past , e.g. when she had her first episodes of neurological symptoms in 1996 and/or 1999 , which was effectively treated and cured back then .
we interpret the subsequent episodes in 2008 and 2011 as post - infectious autoimmune - mediated transverse myelitis triggered by the preceding neuroborreliosis .
immune responses specific against cns proteins or myelin have been reported in csf of neuroborreliosis patients [ 17 , 18 , 19 , 20 , 21 , 22 ] , and post - infectious autoimmune mechanisms following lyme borreliosis have been discussed for arthritis and autoimmune polyneuropathy [ 23 , 24 ] . so an autoimmune mechanism caused by molecular mimicry seems a plausible explanation for the relapsing events of myelitis observed in our patient .
the fact that she recovered in 2008 even without steroid treatment does not argue against an autoimmune transverse myelitis , as these disorders are also known to show spontaneous remissions , albeit with a slower recovery than with steroid treatment .
also , the fact that we did not observe more bands in the b. burgdorferi western blot in csf and serum argues against a persistent and relapsing neuroborreliosis , in which we would expect more bands , particularly igg .
the findings are in line with our assumption that our patient had contact with b. burgdorferi before , possibly even neuroborreliosis during one of the first episodes .
thus , the bands detectable in csf and serum during the fourth episode would have been caused by a persistence of specific b cells , which are stimulated in the context of the presumed autoimmune event .
taken together , our case highlights the diagnostic challenges that may occur in patients with inflammatory lesions of the spinal cord and/or positive b. burgdorferi serology .
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### Summary:
: we report the case of a 31-year - old woman with 4 episodes of myelitis with pleocytosis , a positive borrelia burgdorferi serology with positive antibody indices , and full recovery each time after antibiotic and steroid treatment , suggesting neuroborreliosis .
we nevertheless believe that recurrent neuroborreliosis is improbable based on the levels of the chemokine cxcl13 in cerebrospinal fluid and favor the diagnosis of post - infectious autoimmune - mediated transverse myelitis possibly triggered by an initial neuroborreliosis as the cause of the relapses observed in our patient .
we demonstrate the diagnostic steps and procedures which were important in the differential diagnosis of this unusual and challenging case .
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: in 2004 , approximately 4,500 cases of sudden , unexpected infant death ( suid ) occurred in the united states .
a diagnosis of sudden infant death syndrome ( sids ) was made in the majority and it remains the leading cause of postneonatal suid [ 13 ] , although that percentage has been decreasing during the past few years .
some have ascribed this to a diagnostic shift away from sids toward other designations such as undetermined or suffocation [ 47 ] .
this shift has been partially attributed to greater consideration of medical histories and improved death scene investigations .
adherence to widely publicized sids definitions that mandate death scene investigation and postmortem examinations has probably contributed as well [ 8 , 9 ] . in 1991 ,
sids was defined by an expert panel convened by the national institute of child health and human development ( nichd ) as the sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation , including performance of a complete autopsy , examination of the death scene , and review of the clinical history . in 2004 ,
the nichd definition of sids was refined by an international panel of experts as the sudden , unexpected death of an infant under 1 year of age , with onset of the fatal episode apparently occurring during sleep , that remains unexplained after a thorough case investigation , including performance of a complete autopsy , and review of the circumstances of death and the clinical history .
this general definition was then stratified into categories for research purposes and another category , unclassified sudden infant death ( usid ) , was created for other deaths , e.g. , those in which a postmortem examination was not undertaken .
there is increasing consensus that sids is the lethal intersection of the inherently unstable developmental physiology of a young infant rendered vulnerable as a result of an underlying abnormality , such as has been documented in the medullary serotonergic system [ 1013 ] , while exposed to environmental risk factors .
since the technology and resources necessary to identify these subtle neuropathologic abnormalities that have been found in a large percentage of sids cases are unavailable to medical examiners , sids remains a diagnosis of exclusion in the practical world of forensic pathology . in july 2003
, the kentucky medical examiners devised and implemented a classification scheme for suid cases ( table 1 ) with definitions for sids that are at variance with the nichd and san diego definitions .
for example , sids group b in the 2003 ky scheme allows a diagnosis of sids in the absence of a death scene investigation whereas it is a required in the nichd and san diego definitions.table 12003 ky classification for cases of sudden , unexplained infant death [ 19 , p. 344]sudden
infant death syndrome categorydescriptiongroup a(attributed to sids)classic sids including : age 3 weeks to 6 months , sleeping alone in a standard crib , bassinet , playpen or safe - sleeping surface , and performance of a complete autopsy with appropriate laboratory studies , scene investigation , and case history reviewgroup b(consistent with sids)most findings are consistent with sids , however an aspect is either lacking or questionable which may include infant s age < 3weeks or 612 months , bedsharing , unsafe or questionable bedding surface , no scene investigationgroup c(undetermined)cases in which there is no anatomical , toxicological , or metabolic cause of death , although physical or historical evidence eliminates sids as the potential diagnosis .
cases in this category may include a questionable family or social history that can not be reconciled by the examiner , such as evidence or documented history of previous abuse with the same caregiver ; another simultaneous death , i.e. , twins ; a previous sids death in the immediate family ; and trauma not accounted for by resuscitative efforts 2003 ky classification for cases of sudden , unexplained infant death [ 19 , p. 344
] the commonwealth of kentucky ( ky ) has 120 counties , each with its own elected coroner and a fluctuating number of deputy coroners .
the coroners are charged with the responsibility of investigating and certifying the cause and manner of all deaths , including deaths in children less than 18 years old , under their statutory jurisdiction . in infant deaths ,
the coroner in each county conducts the death scene investigation , evaluates the sleep environment , collects evidence , gathers the medical and family history , and involves other investigating agencies when applicable .
the medical examiners , working within four regional offices , request these documents from the coroners to supplement their autopsy findings from which they recommend to the coroner the cause and manner of death that should be placed on the death certificate . in ky , the coroner is the official certifier of death in cases of suid . the hard copy death certificate completed by the coroner
is then sent to the funeral director who submits it to the office of vital statistics .
staff members in ky s vital events unit code specific demographic information from the certificate , such as gender , date of death , age , and cause of death , into the super micar program of the national center for health statistics ( nchs ) .
the information is sent electronically to nchs , which assigns an international statistical classification of diseases and related health problems , tenth revision ( icd-10 ) code based upon the literal text field on the hard copy death certificate .
if sids , whether subclassified as a , b , or c , written as attributed to sids or consistent with sids appears on the ky hard copy death certificate , then the nchs automatically assigns the cause of death as sids with an icd-10 code of r95 .
finally , the nchs sends the hardcopy death certificates back to ky s office of vital statistics who have these codes entered by a data entry vendor .
all information is combined into one record , and the full electronic death certificate file is made available to various agencies ( fig .
. 1suid surveillance system in kentucky suid surveillance system in kentucky in 2006 , the centers for disease control and prevention ( cdc ) funded seven states ( georgia , kentucky , maryland , massachusetts , new mexico , south carolina , and wisconsin ) with the purpose of identifying differences in investigating , recording and collecting statewide suid data in an effort to clarify statewide death certification practices and compare state performances with national expectations .
the ky suid pilot surveillance system was implemented in september 2006 , building upon the infrastructure developed through the national violent death reporting system .
figure 1 shows the flow of information to the state suid database in ky .
we hypothesized that discrepancies in causes of death would be found between the ky medical examiners recommendations for cause of death and that found on the hard copy and electronic death certificates .
thus the aims of our study are : ( 1 ) to compare sids death certifications recommended by the kentucky medical examiners with the stated cause of death text field on the hard copy death certificates and with those cases coded as sids on the electronic death certificate file and ( 2 ) to compare ky and national sids rates .
for our pilot study , death certificate data were collected retrospectively for suid cases that occurred in ky between january 1 , 2004 and december 31 , 2005 .
the causes of death recommended by the medical examiners were compared with those of the coroners on the hard copy death certificates and the icd-10 codes assigned by the nchs .
the electronic death certificate file is the primary source for cause of death reporting to the department for public health .
hard copy death certificates are stored in a vault and are not easily accessible as the retrieval process is labor intensive and limited to office of vital statistics staff .
therefore , initial comparisons were made between the causes of death recommended by the medical examiners and that appearing on the electronic death certificates and then secondarily between medical examiner recommendations and hard copy death certificates .
comparisons were also made between hard copy death and electronic death certificates to determine if there was a lack of agreement between sids groups due to typing error or inadvertent exclusion .
finally , data obtained from the linked birth / infant death data in the cdc s query system wonder were used to compare trends in rates in the u.s . with ky .
proportions were compared using chi - square statistics and agreement among methods was measured by the kappa statistic .
the kappa statistic was used to assess agreement , where 1 = complete disagreement , 0 = random coincidence ( or no agreement beyond that expected by chance ) and 1 = complete agreement .
proportions were compared using chi - square statistics and agreement among methods was measured by the kappa statistic .
the kappa statistic was used to assess agreement , where 1 = complete disagreement , 0 = random coincidence ( or no agreement beyond that expected by chance ) and 1 = complete agreement .
autopsies were performed in 178 ( 89% ) of the total 199 suid cases in 2004 and 2005 .
the medical examiners did not recommend a cause of death to the coroners for the 21 cases that had not undergone autopsy . in 18 cases
there was an autopsy and autopsy report , but the medical examiners final diagnostic pages were unavailable to the suid project . only 74 ( 37.2% ) of the 199 requested hard copy death certificates were received .
medical examiner data for each of the four jurisdictions and the entire state were available for 160 ( 90% ) of the 178 cases undergoing autopsies ( electronic death certificates were available in all 199 cases).table 2comparison of the causes of death ( cod ) recommended by the kentucky medical examiner ( kyme ) and those appearing on the hard copy ( hcdc ) and electronic death ( edc ) certificates , by jurisdiction , 20042005me officeautopsy not performedme final cod page unavailableevaluable casessids group a ( attributed to sids)sids group b ( consistent with sids)kymehcdcedcmehcdcedcjefferson county10 ( 48%)9 ( 50%)55 ( 35%)7 ( 13%)030 ( 55%)27 ( 49%)00frankfort office8 ( 38%)7 ( 39%)74 ( 46%)17 ( 23%)24 ( 100%)51 ( 69%)35 ( 47%)26 ( 96%)1 ( 1%)western office2 ( 10%)1 ( 5.5%)16 ( 10%)3 ( 19%)09 ( 56%)6 ( 38%)1 ( 4%)0northern office1 ( 5%)1 ( 5.5%)15 ( 9%)3 ( 20%)011 ( 73%)8 ( 53%)00total2118160302410176271cases given icd-10 code of r95 on edcone case coded as r95-b on the edc even though an icd-10 code for sids b does not exist comparison of the causes of death ( cod ) recommended by the kentucky medical examiner ( kyme ) and those appearing on the hard copy ( hcdc ) and electronic death ( edc ) certificates , by jurisdiction , 20042005 cases given icd-10 code of r95 on edc one case coded as r95-b on the edc even though an icd-10 code for sids b does not exist the number of autopsies in each jurisdiction is proportional to the size of the population in each of the geographical regions of medical examiner office coverage .
the frankfort and louisville offices have jurisdiction over the two most populous cities in ky while the northern and western offices cover more rural areas , thus accounting for the varying percentage of available medical examiner data .
the number of cases without an autopsy and the number of cases with an autopsy , but not a medical examiner recommendation , varied by less than one case in each of the four jurisdictions suggesting the presented data are valid ( table 2 ) .
this cause of death was recommended in 47.5% of cases by the medical examiners , but appeared on just 36.5% of the hard copy death certificates and only once was sids group b identified among the r95 codes found in the electronic death certificate file ( table 3).table 3kentucky medical examiner recommendations compared to electronic and hard copy death certifications in suid cases , 20042005cause of deathpercent of casesmedical examiner recommendation ( % ) hard copy death certificate ( % ) electronic death certificate ( % ) sids a18.7532.4357.29sids b47.536.490.50hard copy death certificates are available in only 74 caseselectronic death certificates are available for all 199 cases with and without autopsies kentucky medical examiner recommendations compared to electronic and hard copy death certifications in suid cases , 20042005 hard copy death certificates are available in only 74 cases electronic death certificates are available for all 199 cases with and without autopsies sids group a is recommended by the medical examiners as the cause of death at a rate about one half that which appears on the hard copy death certificate ( 18.8 vs. 32.4% , respectively ) . and ,
sids group a is listed as the cause of death on the electronic death certificates three times more commonly than the rate recommended by the medical examiners ( 57.3 vs. 18.8% , respectively ) . in other words ,
the percentage of classic sids cases appearing on kentucky s electronic death certificates was significantly greater ( p < 0.0001 ) than the percentage the medical examiners had designated as classic sids cases .
conversely , sids group b is recommended by the medical examiners in nearly half of the cases compared to less than 1% of the electronic death certificates ( 47.5 vs. 0.50% , respectively ) .
there is slight agreement when the medical examiners recommendations are compared with the hard copy death certificates ( kappa = 0.16 [ 95% ci : 0.078 , 0.39 ] for sids group a and 0.25 for sids group b [ 95% ci : 0.021 , 0.47 ] .
when comparing the overall assessment of suid classification within the medical examiners recommendations with the electronic death certificates , the kappa is 0.39 ; [ 95% ci : 0.31 , 0.47 ] indicating fair agreement ; the kappa for sids group a is 0.24 [ 95% ci : 0.15 , 0.32 ] indicating slight to fair agreement .
the kappa for sids group b is 0.01 [ 95% ci : 0.013 , 0.041 ] indicating poor agreement .
when comparing the hard copy death certificates with the electronic death certificates , the kappa for sids group a is 0.43 [ 95% ci : 0.27 , 0.59 ] and for sids group b is 0.12 [ 95% ci : 0.033 , 0.27 ] , representing fair and unusually low agreement , respectively . although there were no classifications with perfect agreement between the medical examiner recommendations and the death certificates ; substantial agreement occurred with group c / undetermined and with the other suids group .
figures 2 , 3 , 4 , and 5 show infant death rates from 1995 through 2005 in ky and the u.s .
while there is some parallel in overall suid rates over this interval , sids rates have diverged upward in ky and downward in the u.s .
deaths occurring as a result of inflicted injuries remained relatively stable in ky and nationally .
rates of undetermined causes of death went up in 2002 and have remained stable in the u.s .
, however , in ky they began to increase in 1998 peaking in 2002 from which time they declined . in ky rates of suffocation increased in 1998 from which time they leveled off ; in comparison , suffocation rates in the u.s .
2rates of sudden , unexpected infant deaths in kentucky and the u.s . , 19952005fig .
4sids , suffocation , abuse , and undetermined rates in the u.s . , 19952005fig .
5sids , suffocation , abuse , and undetermined rates in ky , 19952005 rates of sudden , unexpected infant deaths in kentucky and the u.s . , 19952005 sids rates in kentucky and the u.s . ,
19952005 sids , suffocation , abuse , and undetermined rates in the u.s . , 19952005 sids , suffocation , abuse , and undetermined rates in ky , 19952005
autopsies were performed in 178 ( 89% ) of the total 199 suid cases in 2004 and 2005 .
the medical examiners did not recommend a cause of death to the coroners for the 21 cases that had not undergone autopsy . in 18 cases
there was an autopsy and autopsy report , but the medical examiners final diagnostic pages were unavailable to the suid project . only 74 ( 37.2% ) of the 199 requested hard copy death certificates were received .
medical examiner data for each of the four jurisdictions and the entire state were available for 160 ( 90% ) of the 178 cases undergoing autopsies ( electronic death certificates were available in all 199 cases).table 2comparison of the causes of death ( cod ) recommended by the kentucky medical examiner ( kyme ) and those appearing on the hard copy ( hcdc ) and electronic death ( edc ) certificates , by jurisdiction , 20042005me officeautopsy not performedme final cod page unavailableevaluable casessids group a ( attributed to sids)sids group b ( consistent with sids)kymehcdcedcmehcdcedcjefferson county10 ( 48%)9 ( 50%)55 ( 35%)7 ( 13%)030 ( 55%)27 ( 49%)00frankfort office8 ( 38%)7 ( 39%)74 ( 46%)17 ( 23%)24 ( 100%)51 ( 69%)35 ( 47%)26 ( 96%)1 ( 1%)western office2 ( 10%)1 ( 5.5%)16 ( 10%)3 ( 19%)09 ( 56%)6 ( 38%)1 ( 4%)0northern office1 ( 5%)1 ( 5.5%)15 ( 9%)3 ( 20%)011 ( 73%)8 ( 53%)00total2118160302410176271cases given icd-10 code of r95 on edcone case coded as r95-b on the edc even though an icd-10 code for sids b does not exist comparison of the causes of death ( cod ) recommended by the kentucky medical examiner ( kyme ) and those appearing on the hard copy ( hcdc ) and electronic death ( edc ) certificates , by jurisdiction , 20042005 cases given icd-10 code of r95 on edc one case coded as r95-b on the edc even though an icd-10 code for sids b does not exist the number of autopsies in each jurisdiction is proportional to the size of the population in each of the geographical regions of medical examiner office coverage .
the frankfort and louisville offices have jurisdiction over the two most populous cities in ky while the northern and western offices cover more rural areas , thus accounting for the varying percentage of available medical examiner data . the number of cases without an autopsy and the number of cases with an autopsy , but not a medical examiner recommendation , varied by less than one case in each of the four jurisdictions suggesting the presented data are valid ( table 2 ) .
the greatest disparity in classification centered on sids group b or consistent with sids .
this cause of death was recommended in 47.5% of cases by the medical examiners , but appeared on just 36.5% of the hard copy death certificates and only once was sids group b identified among the r95 codes found in the electronic death certificate file ( table 3).table 3kentucky medical examiner recommendations compared to electronic and hard copy death certifications in suid cases , 20042005cause of deathpercent of casesmedical examiner recommendation ( % ) hard copy death certificate ( % ) electronic death certificate ( % ) sids a18.7532.4357.29sids b47.536.490.50hard copy death certificates are available in only 74 caseselectronic death certificates are available for all 199 cases with and without autopsies kentucky medical examiner recommendations compared to electronic and hard copy death certifications in suid cases , 20042005 hard copy death certificates are available in only 74 cases electronic death certificates are available for all 199 cases with and without autopsies sids group a is recommended by the medical examiners as the cause of death at a rate about one half that which appears on the hard copy death certificate ( 18.8 vs. 32.4% , respectively ) . and , sids group a is listed as the cause of death on the electronic death certificates three times more commonly than the rate recommended by the medical examiners ( 57.3 vs. 18.8% , respectively ) . in other words ,
the percentage of classic sids cases appearing on kentucky s electronic death certificates was significantly greater ( p < 0.0001 ) than the percentage the medical examiners had designated as classic sids cases .
conversely , sids group b is recommended by the medical examiners in nearly half of the cases compared to less than 1% of the electronic death certificates ( 47.5 vs. 0.50% , respectively ) .
there is slight agreement when the medical examiners recommendations are compared with the hard copy death certificates ( kappa = 0.16 [ 95% ci : 0.078 , 0.39 ] for sids group a and 0.25 for sids group b [ 95% ci : 0.021 , 0.47 ] .
when comparing the overall assessment of suid classification within the medical examiners recommendations with the electronic death certificates , the kappa is 0.39 ; [ 95% ci : 0.31 , 0.47 ] indicating fair agreement ; the kappa for sids group a is 0.24 [ 95% ci : 0.15 , 0.32 ] indicating slight to fair agreement .
the kappa for sids group b is 0.01 [ 95% ci : 0.013 , 0.041 ] indicating poor agreement .
when comparing the hard copy death certificates with the electronic death certificates , the kappa for sids group a is 0.43 [ 95% ci : 0.27 , 0.59 ] and for sids group b is 0.12 [ 95% ci : 0.033 , 0.27 ] , representing fair and unusually low agreement , respectively .
although there were no classifications with perfect agreement between the medical examiner recommendations and the death certificates ; substantial agreement occurred with group c / undetermined and with the other suids group .
figures 2 , 3 , 4 , and 5 show infant death rates from 1995 through 2005 in ky and the u.s .
while there is some parallel in overall suid rates over this interval , sids rates have diverged upward in ky and downward in the u.s .
deaths occurring as a result of inflicted injuries remained relatively stable in ky and nationally . rates of undetermined causes of death went up in 2002 and have remained stable in the u.s .
, however , in ky they began to increase in 1998 peaking in 2002 from which time they declined . in ky rates of suffocation
increased in 1998 from which time they leveled off ; in comparison , suffocation rates in the u.s .
2rates of sudden , unexpected infant deaths in kentucky and the u.s . , 19952005fig .
4sids , suffocation , abuse , and undetermined rates in the u.s . , 19952005fig .
5sids , suffocation , abuse , and undetermined rates in ky , 19952005 rates of sudden , unexpected infant deaths in kentucky and the u.s . , 19952005 sids rates in kentucky and the u.s . ,
19952005 sids , suffocation , abuse , and undetermined rates in the u.s . , 19952005 sids , suffocation , abuse , and undetermined rates in ky , 19952005
in contrast to other states , such as california , for example , where autopsies are mandated by statute and performed on nearly every infant dying suddenly and unexpectedly , autopsies were not performed on approximately 11% of such cases in ky . although coroners are mandated to perform postmortem investigations , the current ky statute does not require an autopsy in which case death certification occurs without the recommendation of a medical examiner .
thus , the likelihood of incorrectly identifying the cause of death , be it sids , other natural causes , or inflicted or accidental injuries , is increased . with incorrect diagnoses , state vital statistics will be skewed . and appropriate counseling for planned future pregnancies may not be provided to the surviving parents . the ky 2003 classification scheme for sids ( table 1 ) is at variance with the widely accepted nichd sids definition published in 1991 as well as the increasingly adopted san diego definition published in 2004 .
consequently , a sudden unexpected infant death not subjected to death scene investigation can be classified as sids in ky under this classification system .
since reports by caretakers regarding the scene are not always accurate , death scene investigation is critically important .
for example , infant deaths caused by asphyxia may not be accompanied by diagnostic postmortem findings yet the scene investigation may identify an unsafe sleep environment that explains the cause of death .
the ky system of death certification begins with the medical examiner giving their cause and manner of death recommendations to the coroner , who has the legal authority to reject them but is still responsible for completing the hard copy death certificate .
the death certification process concludes with nchs that assigns an icd-10 code based on information appearing on the hard copy death certificate .
given the different criteria for sids in the ky , nichd , and san diego definitions , it is not surprising there are significant disparities between the medical examiners recommendations and what is being coded as sids by the nchs . as alluded to above , the combination of the rates in which autopsies are not done in ky , the ky classification scheme for suid cases , and the lack of consistency between the recommendations of the medical examiners and the cause of death appearing on the electronic death certificates inevitably create vital statistics data that are inaccurate and can not be compared with confidence to those from other statewide or national jurisdictions .
this seems to be borne out in diverging rates of infant death from different causes between ky and the u.s ( figs . 2 , 3 , 4 , 5 ) .
further , given the limited resources available to address efforts to reduce rates of infant death , any skewing of vital statistics mortality data allows the possibility if not the probability of misdirecting funds to inappropriate target areas .
it is retrospective and relies solely upon information provided on death forms completed by the medical examiners and the death certificates completed by the coroners and the icd-10 code assigned by the nchs .
investigation variables were inconsistent and often incomplete ; autopsy variables were present much more consistently than death scene information , but autopsies were nt always performed or medical examiner recommendations were not always completed , leaving a deficit in the data . since almost all of the available hard copy death certificates emanated from autopsies performed in the frankfort me office , responsible for central and eastern kentucky , the results are skewed towards them and away from other jurisdictions .
how this may have affected the hard copy death certificate results had the reporting been more consistent is unknown .
the vulnerability of a pilot study , as ours is , to missing and/or inaccurate data is another important limitation given such studies are often used as the basis for a more comprehensive and inclusive surveillance system .
further , the hard copy death certificates more closely reflect the medical examiner s recommendations compared to the electronic death certificates in which almost all cases of the sids group a and b distinctions were lumped together as sids and coded as r95 .
nevertheless , assessment of a pilot study can provide the context in which to assess the feasibility of collecting uniform , statewide or nationwide data and to recommend improvements , efficiency and usefulness to pilot participants and future project participants .
kentucky s statewide pilot project has broader implications than the seemingly provincial study of one state s suid surveillance system .
first , this study provides a detailed state - level data quality evaluation template , which the other seven funded states and potential future states might use to evaluate discrepancies in suid classifications .
secondly , states with decentralized death investigation systems might take this evaluative model and transpose it for replication in all death classifications of all ages . in conclusion
, our study leads to several recommendations , including , first , nationwide adoption of a widely used sids definition , such as that proposed in san diego in 2004 ; second , implementation of legislation to ensure autopsy in all cases of sudden unexpected infant death ; third , the medical examiners recommendations for causes of death should appear on all death certificates under their jurisdiction ; fourth , multidisciplinary pediatric death review teams should prospectively evaluate infant and childhood cases before death certification is recommended ; and last , research into other jurisdictions death certification process is encouraged in order to improve certification of the causes and manners of sudden unexpected infant death .
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### Summary:
: the centers for disease control and prevention funded seven states , including kentucky , to clarify statewide death certification practices in sudden , unexpected infant death and compare state performances with national expectations .
accurate assignment of the cause and manner of death in cases of sudden , unexpected infant death is critical for accurate vital statistics data to direct limited resources to appropriate targets , and to implement optimal and safe risk reduction strategies .
the primary objectives are to ( 1 ) compare suid death certifications recommended by the ky medical examiners with the stated cause of death text field on the hard copy death electronic death certificates and ( 2 ) compare ky and national suid rates .
causes of death for suid cases recommended by the medical examiners and those appearing on the hard copy and electronic death certificates in ky were collected retrospectively for 2004 and 2005 .
medical examiner recommendations were based upon a classification scheme devised by them in 2003 .
coroners hard copy death certificates and the cause of death rates in ky were compared to those occurring nationally .
eleven percent of infants dying suddenly and unexpectedly did not undergo autopsy during the study interval .
the ky 2003 classification scheme for sids is at variance with the nichd and san diego sids definitions .
significant differences in causes of death recommended by medical examiners and those appearing on the hard copy and electronic death certificates were identified .
sids rates increased in ky in contrast to decreasing rates nationally .
nationwide adoption of a widely used sids definition , such as that proposed in san diego in 2004 as well as legislation by states to ensure autopsy in all cases of sudden unexpected infant death are recommended .
medical examiners recommendations for cause of death should appear on death certificates .
multidisciplinary pediatric death review teams prospectively evaluating cases before death certification is recommended .
research into other jurisdictions death certification process is encouraged .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the preclinical large animal study is one of the most important aspects of the assessment of a new valvular prosthesis ( 1 ) .
an appropriate animal model must be large enough to accommodate devices that can be implanted in humans , as both size and geometry influence the fluid mechanics ( 2 ) . in the testing of aortic valvular prostheses in animals ,
the heterotopic mitral position has been the most frequently tested site , because direct aortic implantation is technically demanding .
however , incongruities in the quality of hemodynamic stressors of the aortic and mitral positions exist , and the hemodynamic data derived from the mitral position may not necessarily represent the aortic position .
furthermore , for testing in the mitral position , not only is cardio - pulmonary bypass a prerequisite , but trained persons that can deal with the complexities and operation of these machines are required to be in attendance ( 4 ) ; all of which may add to excessive cost . to address these shortcomings ,
the current study was devised to develop a simple , safe , and cost efficient large animal model for performing site specific hemodynamic assessments in the aortic environment .
ten castrated male hampshire swine , weighing 52.46 kg ( 40 - 60 kg ) were used . the protocol used in this study
all animals received humane care in compliance with the principles stated in the guide for care and use of laboratory animals ( nih publication no .
85 - 23 ) . from 12 hr before surgery , the animals were given free access to only water .
the animals were sedated with an intramuscular injection of ketamine hcl ( 10 - 15 mg / kg ) and placed in the supine position on the operating table .
electrocardiographic leads were positioned for continuous monitoring , and external defibrillation patches were placed on the back for emergent cardiac defibrillation .
an additional intermittent infusion of ketamine was given intravenously via an ear vein as needed .
general anesthesia was maintained with pancuronium bromide ( 2 - 4 mg / hr ) and 1 - 3% enflurane .
the pigs were euthanized with a fatal intracardiac injection of saturated potassium chloride while under anesthesia .
the pulmonary arterial pressure and cardiac output were monitored every 30 min with a swan - ganz catheter passed through the right internal jugular vein . before opening the sternum ,
continuous arterial pressure monitoring was established through the right femoral artery , and through the left internal thoracic artery after sternotomy .
the arterial pressure was continuously monitored and maintained at a mean level of 70 mmhg . to access the mediastinal structures , a standard median sternotomy was performed from the sternal notch to the xyphoid process level . for simultaneous exposure of the descending thoracic aorta ,
an l shaped lateral extension was made leftward from the distal tip of the sternotomy .
two individual vascular conduits of internal diameter 21 mm and length 30 cm were used to construct the composite valved conduit .
jude medical europe , brussels , belgium ) , was sutured to the distal end of the conduit with continuous running suture of polypropylene # 4 - 0 .
a 0.5 cm curtain of the vascular graft material was left distal to the prosthetic valve implantation site .
the second graft conduit was sutured in an end to end fashion with # 4 - 0 polypropylene continuous running suture , to the curtain of graft material distal to the prosthetic graft ( fig .
1 ) . basically , the vascular conduit was selected to closely match that of the prosthetic valve being tested in size .
the conduit was sufficiently large to accommodate the slight variations in the external prosthetic valvular diameter that is seen among different manufacturers for any given valve size .
a 21 fr pediatric arterial perfusion cannula was connected to each end of a 3/8 inch diameter silicone tubing of 1 meter in length to construct an aorta to femoral artery bypass perfusion shunt .
after separating the main pulmonary artery and the ascending aorta a braided nylon umbilical tape was passed under the ascending aorta with the aid of a right - angled kelly .
a single purse - string suture was created just distal to the non - coronary sinus with a braided multifilament # 1 - 0 suture on the posterior aspect of the ascending aorta by pulling on the umbilical tape .
the proximal femoral artery was then exposed for distal cannulation of the shunt . when the activated coagulation time exceeded 200 sec , the ascending aorta
was shunted to the femoral artery with the silicone shunt , as described above . after ensuring good functioning of the aorta to femoral artery shunt , the ascending aorta was partially clamped with a side - biting satinsky clamp just distal to the aorto - femoral shunt .
the proximal end of the composite graft was anastomosed to the side clamped portion of the ascending aorta in an end- to - side fashion with a # 4 - 0 polypropylene running suture . due to the short length of the ascending aorta , clamping of the innominate artery together with
consequently , the innominate artery was partially included in the proximal anastomosis between the ascending aorta and the composite valved conduit .
the distal end of the composite valved conduit was anastomosed in and end - to side manner to the distal descending aorta at the diaphragmatic crux level with a continuous running suture of 4 - 0 polypropylene .
hemodynamic assessment of the native aortic valve was performed before cross clamping the proximal descending thoracic aorta , whereas assessment of the prosthetic aortic valve was performed after cross clamping the proximal descending thoracic aorta .
arterial pressure was monitored directly through the internal mammary and the femoral arteries as described above .
the purpose of monitoring through the internal mammary artery was to check the arterial pressure during the cross clamping of the proximal descending thoracic aorta .
echocardiography was performed using a 7.5-mhz transducer probe connected to a vingmed cfm 725 ultrasound machine .
an air free interface was created by interposing a thoroughly de - aired ultrasound gel - filled sterile latex glove between the probe and the vascular surface .
transvalvular pressure gradients were calculated from the maximal flow velocity across the valve as determined by continuous - wave doppler .
the conduit ( native or graft ) diameter , cardiac output ( co ) , ejection fraction ( ef ) , time velocity integral of pulsed wave doppler ( pwtvi ) , time velocity integral of continuous wave doppler ( cwtvi ) , left ventricular end diastolic dimension ( lvedd ) , left ventricular end systolic dimension ( lvesd ) , stroke volume ( sv ) , and effective orifice area ( eoa ) were calculated .
preoperative baseline cardiac output prior to median sternotomy was obtained by using the thermodilution technique with the swan ganz catheter .
subsequent cardiac output measurements through both the native aortic valve and the graft were calculated directly by echocardiography using the 2d doppler technique .
the time velocity integral of forward systolic flow was determined by pulsed doppler at the left ventricular outflow tract .
this value was then multiplied by the cross sectional area to obtain the stroke volume .
pwtvi or ctvi , measures of flow velocity , were used to calculate the cardiac out - put according to the following formula ; flow ( q)=area ( a)velocity ( v ) cardiac output ( co)=qheart rate / min echocardiographic data were collected preoperatively , postoperatively before drug infusion ( control ) and postoperatively after the infusion of dobutamine at 10 and 20 g / kg / min .
the statistical package , sas 6.12 ( sas institute inc . , cary north carolina , u.s.a . ) was used to perform the analyses .
echo data were compared using the wilcoxon signed rank test between the native aortic valve and prosthetic valve .
ten castrated male hampshire swine , weighing 52.46 kg ( 40 - 60 kg ) were used . the protocol used in this study
all animals received humane care in compliance with the principles stated in the guide for care and use of laboratory animals ( nih publication no .
85 - 23 ) . from 12 hr before surgery , the animals were given free access to only water .
the animals were sedated with an intramuscular injection of ketamine hcl ( 10 - 15 mg / kg ) and placed in the supine position on the operating table .
electrocardiographic leads were positioned for continuous monitoring , and external defibrillation patches were placed on the back for emergent cardiac defibrillation .
an additional intermittent infusion of ketamine was given intravenously via an ear vein as needed .
general anesthesia was maintained with pancuronium bromide ( 2 - 4 mg / hr ) and 1 - 3% enflurane .
the pigs were euthanized with a fatal intracardiac injection of saturated potassium chloride while under anesthesia .
the pulmonary arterial pressure and cardiac output were monitored every 30 min with a swan - ganz catheter passed through the right internal jugular vein . before opening the sternum ,
continuous arterial pressure monitoring was established through the right femoral artery , and through the left internal thoracic artery after sternotomy .
the arterial pressure was continuously monitored and maintained at a mean level of 70 mmhg . to access the mediastinal structures , a standard median sternotomy was performed from the sternal notch to the xyphoid process level . for simultaneous exposure of the descending thoracic aorta ,
an l shaped lateral extension was made leftward from the distal tip of the sternotomy .
two individual vascular conduits of internal diameter 21 mm and length 30 cm were used to construct the composite valved conduit .
jude medical europe , brussels , belgium ) , was sutured to the distal end of the conduit with continuous running suture of polypropylene # 4 - 0 .
a 0.5 cm curtain of the vascular graft material was left distal to the prosthetic valve implantation site .
the second graft conduit was sutured in an end to end fashion with # 4 - 0 polypropylene continuous running suture , to the curtain of graft material distal to the prosthetic graft ( fig .
1 ) . basically , the vascular conduit was selected to closely match that of the prosthetic valve being tested in size .
the conduit was sufficiently large to accommodate the slight variations in the external prosthetic valvular diameter that is seen among different manufacturers for any given valve size .
a 21 fr pediatric arterial perfusion cannula was connected to each end of a 3/8 inch diameter silicone tubing of 1 meter in length to construct an aorta to femoral artery bypass perfusion shunt .
after separating the main pulmonary artery and the ascending aorta a braided nylon umbilical tape was passed under the ascending aorta with the aid of a right - angled kelly .
a single purse - string suture was created just distal to the non - coronary sinus with a braided multifilament # 1 - 0 suture on the posterior aspect of the ascending aorta by pulling on the umbilical tape .
when the activated coagulation time exceeded 200 sec , the ascending aorta was shunted to the femoral artery with the silicone shunt , as described above . after ensuring good functioning of the aorta to femoral artery shunt , the ascending aorta was partially clamped with a side - biting satinsky clamp just distal to the aorto - femoral shunt .
the proximal end of the composite graft was anastomosed to the side clamped portion of the ascending aorta in an end- to - side fashion with a # 4 - 0 polypropylene running suture . due to the short length of the ascending aorta , clamping of the innominate artery together with the ascending aorta with
consequently , the innominate artery was partially included in the proximal anastomosis between the ascending aorta and the composite valved conduit .
the distal end of the composite valved conduit was anastomosed in and end - to side manner to the distal descending aorta at the diaphragmatic crux level with a continuous running suture of 4 - 0 polypropylene .
hemodynamic assessment of the native aortic valve was performed before cross clamping the proximal descending thoracic aorta , whereas assessment of the prosthetic aortic valve was performed after cross clamping the proximal descending thoracic aorta .
arterial pressure was monitored directly through the internal mammary and the femoral arteries as described above .
the purpose of monitoring through the internal mammary artery was to check the arterial pressure during the cross clamping of the proximal descending thoracic aorta .
echocardiography was performed using a 7.5-mhz transducer probe connected to a vingmed cfm 725 ultrasound machine .
an air free interface was created by interposing a thoroughly de - aired ultrasound gel - filled sterile latex glove between the probe and the vascular surface .
transvalvular pressure gradients were calculated from the maximal flow velocity across the valve as determined by continuous - wave doppler .
the conduit ( native or graft ) diameter , cardiac output ( co ) , ejection fraction ( ef ) , time velocity integral of pulsed wave doppler ( pwtvi ) , time velocity integral of continuous wave doppler ( cwtvi ) , left ventricular end diastolic dimension ( lvedd ) , left ventricular end systolic dimension ( lvesd ) , stroke volume ( sv ) , and effective orifice area ( eoa ) were calculated .
preoperative baseline cardiac output prior to median sternotomy was obtained by using the thermodilution technique with the swan ganz catheter .
subsequent cardiac output measurements through both the native aortic valve and the graft were calculated directly by echocardiography using the 2d doppler technique .
the time velocity integral of forward systolic flow was determined by pulsed doppler at the left ventricular outflow tract .
this value was then multiplied by the cross sectional area to obtain the stroke volume .
pwtvi or ctvi , measures of flow velocity , were used to calculate the cardiac out - put according to the following formula ; flow ( q)=area ( a)velocity ( v ) cardiac output ( co)=qheart rate / min echocardiographic data were collected preoperatively , postoperatively before drug infusion ( control ) and postoperatively after the infusion of dobutamine at 10 and 20 g / kg / min .
the statistical package , sas 6.12 ( sas institute inc . , cary north carolina , u.s.a . ) was used to perform the analyses .
echo data were compared using the wilcoxon signed rank test between the native aortic valve and prosthetic valve .
measurements of the heart rate , cardiac output , transvalvular vmax ( m / sec ) , peak gradient ( pg)max ( mmhg ) , and effective orifice area ( eoa cm ) are shown .
no significant differences were detected in , cardiac output , heart rate , and measured flow through the native aortic and prosthetic valves ( p = ns ) .
the transvalvular pressure gradient across the prosthetic valve was documented when it was noted that the difference in the calculated cardiac output between the native aortic annulus and the graft was negligible . the cardiac output and the heart rate increased equally in both the native and the prosthetic valves in a dobutamine dose dependent manner . as the prosthetic valvular diameter was smaller than that of the native aortic valve , the mean eoa was also smaller ( p<0.05 ) .
accordingly , vmax and pg in the resting state were significantly higher in the composite valved conduit than in the native aortic valve ( p<0.05 ) , and this difference was accentuated by incremental dobutamine infusion .
dobutamine in excess of 10 g / kg / min significantly increased vmax and pg versus the resting state in both native and prosthetic valves .
further increase in the dobutamine dosage to 20 g / kg / min produced a further increase in vmax and pg in the prosthetic valve , but not in the native aortic valve .
one of the prerequisites of developing a new cardiac valvular prosthesis is a successful pre - clinical large animal series .
an appropriate animal model may provide information on valve performance , safety , and in vivo hemodynamics ( 1 , 5 ) . however , no suitable animal model is available that can yield such information for a prosthetic aortic valve .
these include sheep , goats , dogs , pigs , calves and primates ( 6 )
. however , due to the unique limitations of each preclinical model , it is imperative to develop an appropriate animal model that best suits the purposes of the experiment at hand ( 7 ) . the physical size and the rapid growth rate of calves present problems for postoperative husbandry and non - invasive valvular functional assessment ( 8 , 9 ) .
goats have been found to be a good model for valve testing , but their availability is often limited ( 10 ) .
the relative susceptibility of dogs to sepsis and thrombosis has marked these animals as less than optimal ( 11 ) .
they have many favorable characteristics for prosthetic valve testing , as their blood pressures , heart rates , cardiac outputs and intra - cardiac pressures are similar to humans ( 12 ) .
standard cardiopulmonary bypass techniques and anesthesia with minor modifications are possible in these animals without difficulty ( 7 ) . however , the sheep is costly and not readily available in korea .
in addition , the short length of the ascending aorta , which is a common feature of cloven - footed animals ( calves , sheep , and goats ) , gives way to the aortic bifurcation a short way downstream of the aortic valve . consequently , prosthetic implantation directly into the aortic annulus is technically challenging ( 13 , 14 ) .
the pig is more advantageous in terms of cost and availability , but it too shares the limitations of cloven footed animals of having a short ascending aortic trunk , a tendency to develop cardiopulmonary bypass complications , and presenting difficulties in terms of accessing the peripheral venous circulation , management and handling ( 7 , 13 , 15 - 17 ) .
nevertheless , numerous reports on mechanical heart valves have been based on data derived from the pig ( 2 , 13 , 18 , 19 ) . after a careful deliberation of various animal studies
, we selected the pig for the current study . thus we undertook the current study to develop a cost efficient , reliable animal model that allows a relatively simple site specific hemodynamic assessment of mechanical prosthetic devices in the arterial environment . during the early part of the current experiment
, several animals died of arrhythmias varying from atrial fibrillation with intractable rapid ventricular response to frank ventricular fibrillation .
these animals were excluded from the current data and only data from those animals ( n=10 ) with the final model were assessed .
these animals did not receive any cardiac manipulation . in another animal , tension pneumothorax developed during tracheostomy after which ventricular fibrillation occurred . in yet another animal , ventricular fibrillation occurred after partial ascending aortic clamping .
it is speculated that a sudden increase in ventricular afterload resulting from the cross clamp caused the ventricular fibrillation .
the side - biting clamp may understandably produce supravalvular aortic stenosis in an unpredictable manner with variable acute after - load augmentation .
intolerable levels of this sudden unprotected afterload increase may have been the cause of death .
subsequently , to relieve the afterload build up , a temporary bypass shunting of the proximal ascending aorta , proximal to the cross clamp to the femoral artery , was performed .
the proximal decompression afforded by this temporary shunt proved to be a key modification , and one that led to the success of the subsequent trials .
the use of an artery to artery shunt as a means of partially bypassing the aorta with a heparin coated shunt is not a novel concept .
aorto - femoral shunting for thoracic aortic and great vessel procedures was described by gott and colleagues ( 20 ) , and the feasibility of implanting an aortic valvular device in the descending thoracic aorta to treat left ventricular outflow tract obstruction with an apicoaortic conduit was described by norman et al .
the concepts underlying these ideas led to the final design of the current experimental model , which involved the use of a composite valved conduit to bypass the aorta from the proximal aorta to the distal aorta with the aid of an aorto - femoral bypass shunt . with the current model , a site - specific functional evaluation of valvular prostheses without cardiopulmonary bypass in the high pressure arterial environment
is possible furthermore , the current model has the potential for successive testing of different valve unit types in a single animal in a cost efficient manner , i.e. , one valve can simply be replaced by another between the two grafts . however , despite these purported advantages , the hemodynamic data must accurately reflect the actual hemodynamic performance of the valvular prosthesis being tested .
the prosthetic valve that was used in this particular experiment had a small and fixed orifice , the latter of which is a common trait of mechanical prostheses .
consequently , a steeper vmax and pressure gradient increase were observed in the prosthetic valve as compared to the native valve .
this was especially evident with dobutamine increment ( table 1 ) . with the native aortic valve serving as the control in each animal , direct hemodynamic assessments and comparisons with the native aortic valve were possible , as the cardiac output and heart rate remained constant when the respective hemodynamic data were being obtained from each site .
although some obligatory sharing or diversion of blood flow to the arch vessel during the hemodynamic evaluation of the composite valved conduit after proximal thoracic aortic cross clamping was inevitable , the differences in the measured cardiac output and flow between the native aortic valve and the valved conduit became insignificant once equilibrium had been reached between the arch vessel and the valved conduit .
therefore , it is our contention that the current model is suitable as a site - specific model for the hemodynamic assessment of valvular prostheses in the aortic position . in terms of limitations , although some sharing of blood flow with the arch vessels during distal aortic clamping was unavoidable during the hemodynamic assessment of the prosthetic valve , the stated objectives of the study were fully satisfied as the differences in the cardiac output between the native valve as compared with the prosthetic valve were insignificant .
therefore , conclusions derived from the direct hemodynamic comparison of the prosthetic and native aortic valves in the current animal study are believed to be valid .
the question of whether the current model should be regarded as being site specific is open to debate as the valvular device was actually implanted in a site other than the actual aortic annulus .
however , it is our contention that functionally , this model is site specific , as the prosthetic aortic valve is continually subjected to the stressors of the high pressure systemic arterial system as is the annulus of the native aortic root .
issues regarding durability , thrombogenicity , calcification and other long term modes of valve failure are beyond the scope of the current model , as these parameters should be persued through a chronic animal series .
nevertheless , the current model proved useful at acquiring acute hemodynamic data relating to valve function . in conclusion ,
the current model was found suitable for acquiring essential information on the hemodynamic performance of a valvular prosthesis , and cost and time efficient by obviating the cardiopulmonary bypass and by offering the potential for multiple valve testing in a single large animal .
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### Summary:
: the objective of this study was to develop a pre - clinical large animal model for the in vivo hemodynamic testing of prosthetic valves in the aortic position without the need for cardiopulmonary bypass .
ten male pigs were used .
a composite valved conduit was constructed in the operating room by implanting a prosthetic valve between two separate pieces of vascular conduits , which bypassed the ascending aorta to the descending aorta . prior to applying a side - biting clamp to the ascending aorta for proximal grafting to the aortic anastomosis , an aorta to femoral artery shunt was placed just proximally to this clamp .
the heart rate , cardiac output , vmax , transvalvular pressure gradient , effective orifice area and incremental dobutamine stress response were assessed .
a dose dependant increase with dobutamine was seen in terms of cardiac output , vmax , and the peak transvalvular pressure gradient both in the native and in the prosthetic valve . however , the increment was much steeper in the prosthetic valve .
no significant differences in cardiac output were noted between the native and the prosthetic valves .
the described pre - clinical porcine model was found suitable for site - specific in - vivo hemodynamic assessment of aortic valvular prosthesis without cardiopulmonary bypass .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: it accounts for 2.8% of new cancers but 6.2% of all cancer deaths as the fourth leading cause of cancer mortality .
the 5-year relative survival rate is 6% , with the least improvements in survival over the past three decades compared to most other cancers .
the dismal prognosis of pancreatic cancer is mainly associated with late diagnosis , in addition to low resection rate , aggressiveness of the cancer , and lack of effective treatment .
therefore , pancreatic cancer must be discovered early to increase the chance of being cured by surgery . a simple model including early clinical symptoms may facilitate the recognition of this almost always fatal disease .
a 50-year - old male presented in 2006 with chest pain , productive cough for 1 week , and progressive lower extremity edema for 1 year .
the past medical history included hypertension , hypothyroid , dyslipidemia , dilated cardiomyopathy , hypothyroidism , chronic obstructive pulmonary disease , morbid obesity , sleep apnea , gastroesophageal reflux disease , depression , and cryptorchidism treated with orchidopexy .
he had a 45-pack - year history of smoking and heroin abuse , and was on methadone maintenance .
physical examination revealed the following : blood pressure 120/72 , heart rate 64 , respiration rate 18 , temperature 97.0f , bilateral lower extremity edema 2 + .
sodium was 135 , potassium 3.8 , chloride 103 , bicarbonate 25 , blood urea nitrogen 17 , creatinine 1.1 , and glucose 103 .
imaging studies and stress test showed no deep venous thrombosis , pulmonary embolism ( pe ) , or myocardial infarction .
he was discharged after stabilization with the primary diagnosis of unstable angina . in 2007 ,
he presented with severe dyspnea , hemoptysis , and retrosternal chest pain radiating towards back , recent weight loss of 20 pounds without alternation in appetite or bowel habits .
gradually , the patient became weaker . in 2012 , he developed exertional dyspnea , gait unsteadiness , tendency to fall , and loss of more than 80 pounds over 6 months , which was attributed to dental and recurrent periodontal diseases . eventually , he became unable to work . in 2013 ,
the ct scan showed abnormalities suggesting malignancy in the distal body and tail of the pancreas , retroperitoneal adenopathy , multiple hepatic masses , as well as thrombi in hepatic , splenic , left renal , and portal veins ( fig .
liver biopsy revealed adenocarcinoma of the pancreatic primary with tumor cells positive for ck 7 , ck 19 , ca19.9 , and negative for cd 56 , s100 , chromogranin , synaptophysin , ck 20 , and hep par 1 .
although it is generally believed to be rapid , the rate of early pancreatic cancer progression might be slower than what it was thought , as estimated in other types of solid cancers .
a recent study illustrated that it takes about 12 years for the initiating mutation to result in the nonmetastatic founder cell ; another 7 years to acquire the metastatic ability , and then 3 more years to cause death .
in other studies , the small pancreatic cancer was demonstrated to have a slow progressive rate .
it takes over 29 months for this cancer to grow into an invasive carcinoma measuring 1 cm in diameter . in small invasive pancreatic carcinoma ,
these findings make it possible to detect the small pancreatic cancer during the relatively long , silent , and most importantly curable period using certain screening methods and provide a significant extension of time to perform effective treatment .
however , owing to the low prevalence and absence of promising treatment approaches , even in early stages , it is currently infeasible to do mass screening for asymptomatic pancreatic cancer in the general population .
still , those limitations do not mitigate the necessity of striving for early diagnosis of pancreatic cancer .
a prediction rule was developed to stratify the risk for pancreatic cancer in patients with chronic pancreatitis , where gender , mass location , mass number , direct bilirubin , and ca 19 - 9 were included in the calculation .
however , a pretest clinical model employing risk factors and symptoms would be plausible to help clinicians to stratify the patients into different risk categories and determine whether further investigation is needed .
weighted noninherited factors including obesity , cigarette smoking , carcinogen exposure , dm , chronic pancreatitis , liver disease , as well as inherited factors such as hereditary pancreatitis and peutz - jeghers syndrome might be used to construct such a model [ 8 , 11 ] .
the thromboembolism , late onset of dm , weight loss , and other changes preceded the diagnosis of pancreatic cancer by 67 years in this case .
thromboembolism is a common complication of cancer , it occurs in 1757% of pancreatic cancer patients .
pancreatic cancer cells can activate platelets , release various procoagulant factors , induce venous or arterial thrombosis , or disseminated intravascular coagulation . in the absence of heart failure , renal insufficiency , or liver disease , the initial pedal edema in the patient was likely due to iliac deep venous thrombosis , which might be missed by the lower extremity venous duplex . as a matter of fact
, diffuse intra - abdominal venous thrombosis was detected by the subsequent ct scan . however , even with the knowledge of the association between cancer and thrombosis , the existence of some known pe risk factors , as in this case morbid obesity and sleep apnea , may discourage the physician from further investigation for other possible etiologies .
dm is a risk factor for ( especially chronic dm > 5 years ) [ 8 , 13 ] or a complication of pancreatic cancer . dm was found in 50% of pancreatic cancer patients , and in over 20% dm occurs during the asymptomatic phase .
about 1% of patients aged 50 years or older who had new - onset dm will develop pancreatic cancer within 3 years after the diagnosis of dm .
patients with pancreatic cancer diagnosed in association with dm had better survival than symptomatic patients , and the cancer was generally resectable if found at the onset of dm .
the new - onset dm in adults requires careful evaluation to exclude malignancy . with a high prevalence of type 2 dm in the general population
, the discovery of a biomarker to distinguish the cancer - related dm and type 2 dm would markedly facilitate this process .
knowledge and recognition of certain early manifestations may lead to further investigation and diagnosis of presymptomatic pancreatic cancer before it becomes incurable .
furthermore , a standardized clinical scoring system based on risk factors and clinical findings would help objectify pretest probability of pancreatic cancer and facilitate the decision making regarding whether and which diagnostic test , for example endoscopic ultrasonography , is needed for individuals with increased risk of pancreatic cancer .
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### Summary:
: the early symptoms of pancreatic cancer are often very vague
. they may precede the diagnosis by years and go unrecognized .
this makes pancreatic cancer one of the cancers with the worst survival rates .
the progression rate of the early phase might be slower than previously thought . here , we report a case where symptoms , including thromboembolism and new - onset diabetes mellitus , preceded the diagnosis of pancreatic cancer by 6 years or longer .
the awareness of the early symptoms of pancreatic cancer is required for being vigilant and further diagnostic tests . a simple clinical model utilizing certain risk factors and symptoms for
pancreatic cancer will help stratify the patients for further screening tests .
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: the original cohort of the dcct consisted of 1,441 men and women 1339 years of age at study entry .
the primary prevention cohort consisted of 726 subjects with no retinopathy , a urinary albumin excretion rate < 40 mg/24 h , and a diabetes duration of 15 years .
the secondary intervention cohort consisted of 715 subjects who had nonproliferative retinopathy , urinary albumin excretion rate 200 mg/24 h , and a diabetes duration of 115 years ( 11 ) .
they entered the dcct trial between 1983 and 1989 and were studied for an average of 6.5 years . in total , 730 patients were randomly assigned to receive conventional diabetes treatment , and 711 were randomized to receive intensive diabetes treatment . in 1993 , the dcct was discontinued due to statistical evidence of a powerful salutary effect of intensive treatment on long - term complications ( 12 ) . at study close - out
, dcct subjects were encouraged to use intensive therapy and invited to join the edic study , a multicenter longitudinal observational study . of the 1,428 surviving members of the original cohort , 1,375 ( 95% ) elected to participate in some or all aspects of the edic study ( 13 ) . at edic year 10 ,
1,365 patients ( 713 men and 652 women ) were invited to complete self - report measures of sexual dysfunction and urological complications ( i.e. , bladder dysfunction and urinary tract infections ) .
a total of 550 ( 84.4% ) of the 652 women completed the uro - edic questionnaire . on the annual anniversary of enrolling in the dcct ,
each edic subject underwent a standardized annual history and physical examination , including a detailed evaluation of overall health , diabetes management , occurrence of diabetes complications , development of new disease , and medications used .
annual evaluations also include resting electrocardiograms , doppler ultrasound measurements of ankle and arm blood pressure ratios , and arm blood pressure .
serum creatinine and a1c are assessed annually using the same methods as in the dcct ( 12,13,14 ) .
lipid profiles and 4-h urine collections for measurement of albumin excretion rate and creatinine clearance are obtained on alternate years using the same methods as in the dcct ( 13 ) .
hypertension was defined as systolic blood pressure 140 mmhg , diastolic blood pressure 90 mmhg , or documented use of antihypertensive agents .
hypercholesterolemia was defined as ldl cholesterol 130 mg / dl or use of lipid - lowering agents .
sexual function was evaluated by an abbreviated version of the female sexual function index ( fsfi ) ( 15 ) .
the fsfi is a widely used , multidimensional , well - validated , self - report measure that assesses sexual function across six domains , including sexual desire , arousal , lubrication , orgasm , satisfaction , and pain ( 15,16,17,18 ) . for the present study , an abbreviated version including 7 of the 19 original fsfi items
was developed ( fsfi - r ) . from each of the domains of sexual desire , arousal , lubrication , orgasm , and pain
the items are 5-point likert - type items , with higher scores reflecting worse sexual functioning .
the fsfi - r total score is the sum of all the items representing each domain of sexual functioning added with the mean score of the two items assessing satisfaction .
the psychometric properties of the fsfi - r were evaluated using an independent sample of 286 women with and 245 women without sexual dysfunction selected from previous validation studies ( 16,17,18 ) .
overall , the abbreviated version of the fsfi was found to have adequate psychometric properties that are essentially equivalent to those of the full - scale measure ( see the online appendix available at http://care.diabetesjournals.org/cgi/content/full/dc08-1164/dc1 ) .
the prevalence of a specific sexual problem was estimated based on a domain - specific item analysis by combining the percentages of women who scored in the two lowest categories on each item [ almost never or never or a few times ( less than half the time ) ] , except for the pain domain where the percentages of women who scored in the highest categories on each item [ almost always or always or most times ( more than half the time ) ] were combined .
for example , the prevalence of dyspareunia ( painful intercourse ) was based on the percentage of women who answered most times ( more than half the time ) or almost always or always to the question
the prevalence of depression was assessed by means of a composite depression variable , which was based on study coordinator ratings of clinical depression , based on dsm - iv criteria , in addition to patient self - reports of use of antidepressant medications and/or psychological counseling for depressive symptoms .
initially , pearson 's tests ( fisher 's exact where appropriate ) were used to assess univariate associations between sexual function scores ( both total and individual domain scores ) and relevant biomedical and psychosocial predictor variables . for continuous measures ,
those variables that were nominally significant at the p < 0.15 level , with respect to overall fsd , with no adjustment for multiple comparisons , were used in a multivariate logistic regression model .
an identical analysis was performed using the same covariates for each of the individual sexual domains , where fsd is a score 2 and no fsd is a score > 2 for each domain item , except for the pain domain , where the opposite was true .
fsd in the satisfaction domain was indicated by a total mean score 2 . due to the model selection and the multiple testing ,
analyses were performed using sas version 8.2 ( sas institute , cary , nc ) .
initially , pearson 's tests ( fisher 's exact where appropriate ) were used to assess univariate associations between sexual function scores ( both total and individual domain scores ) and relevant biomedical and psychosocial predictor variables . for continuous measures ,
those variables that were nominally significant at the p < 0.15 level , with respect to overall fsd , with no adjustment for multiple comparisons , were used in a multivariate logistic regression model .
an identical analysis was performed using the same covariates for each of the individual sexual domains , where fsd is a score 2 and no fsd is a score > 2 for each domain item , except for the pain domain , where the opposite was true .
fsd in the satisfaction domain was indicated by a total mean score 2 . due to the model selection and the multiple testing ,
analyses were performed using sas version 8.2 ( sas institute , cary , nc ) .
the design , methods , baseline findings , and main outcomes of the dcct and edic study ( to date ) have been published elsewhere ( 11,12 ) .
a total of 550 women completed the uro - edic questionnaire ( response rate 84.4% ) .
this cohort had lower triglyceride levels ( p = 0.0389 ) , had lower a1c levels ( p = 0.0029 ) , and smoked less ( p = 0.0060 ) at dcct baseline compared with the total cohort of women who originally entered the dcct . in addition , the sample who completed the survey did not differ on dcct variables at baseline compared with the 102 women who did not participate in the study . in total , 116 women ( 21.0% )
were excluded from the analyses because they did not provide complete data on sexual functioning ( n = 10 ) or reported lack of sexual activity ( n = 52 ) or absence of a sexual partner ( n = 54 ) during the previous 12 months . at the time of the survey , these 116 sexually inactive women differed from the 434 sexually active women in that they were less likely to be married or in a partner relationship ( p < 0.0001 ) , were more often randomized to intensive treatment ( p = 0.0376 ) , had a higher mean age ( p = 0.0004 ) , were more likely to be ( post)menopausal ( p = 0.0415 ) , had a higher bmi ( p = 0.0271 ) , and had an increased prevalence of hypertension ( p = 0.0011 ) .
this report thus describes results obtained from 424 eligible participants : 217 in the conventional and 207 in the intensive treatment groups .
the mean age of the 424 participating women was 42.8 7.1 years with a mean duration of type 1 diabetes of 22.8 5.0 years .
the majority of participants were caucasian ( 97% ) , were married ( 81% ) , and had normal albumin excretion rates ( 77% ) .
table 1 presents socioeconomic and diabetic characteristics at dcct baseline and at the year 10 uro - edic examination by dcct treatment group . at dcct baseline ,
age was the only significant difference between treatment groups ; the intensive group was slightly older ( p = 0.03 ) .
however , at the year 10 examination in the edic study , women randomized to intensive treatment were less likely to have retinopathy , nephropathy , and peripheral neuropathy than those randomized to conventional treatment . clinical characteristics of the female uro - edic cohort ( n = 424 ) data are means sd or n ( % ) . *
determined by etdrs ( early treatment diabetic retinopathy study ) score on a scale of 023 : < 12 = nonproliferative , 12 = proliferative .
hypertension defined as sitting systolic blood pressure 140 mmhg , diastolic blood pressure 90 mmhg , or use of antihypertensive medication .
defined in the dcct by the presence of definite clinically evident distal symmetrical polyneuropathy and an abnormal nerve conduction study or in the edic by the mnsi ( michigan neuropathy screening instrument ) : > 6 positive responses on the questionnaire or a score > 2 on the examination . based on the fsfi - r cutoff score for sexual dysfunction of 22.75 ,
the overall prevalence of fsd among sexually active women in this study was found to be 35.4% .
univariate analyses revealed that women meeting criteria for fsd were on average older than women without fsd ( p = 0.0041 ) , were more likely to be married ( p = 0.0016 ) , be ( post)menopausal ( p = 0.0019 ) , have evidence of microvasculopathy ( composite diabetes complications variable , p = 0.0092 ) , and be depressed ( p = 0.0022 ) than women without fsd ( table 2 ) . among those women who met the criteria for fsd ,
57% reported a problem with decreased desire , 51% had problems with orgasm , 47% had inadequate lubrication , 38% had problems with sexual arousal , and 21% reported pain during intercourse . additionally , 25% of sexually active women reported low overall sexual satisfaction .
for all sexual domains , study participants without fsd scored higher ( i.e. , had better function ) than women with fsd ( p < 0.001 ) .
clinical characteristics of uroedic women according to fsd status at year 10 of the edic ( n = 424 ) * data are means sd and n ( % ) .
hysterectomy defined as a subject 's menstrual period ceasing and it being considered permanent due to surgery .
determined by etdrs ( early treatment diabetic retinopathy study ) score on a scale of 023 : < 12 = nonproliferative , 12 = proliferative .
defined in the dcct by the presence of definite clinically evident distal symmetrical polyneuropathy and an abnormal nerve conduction study or in the edic by the mnsi ( michigan neuropathy screening instrument ) : > 6 positive responses on the questionnaire or a score > 2 on the examination .
variable has a score between ( 0 and 4 ) depending on the total number of yes responses to the question of ever having the following four complications : retinopathy ( defined as scatter laser in both eyes ) , nephropathy ( defined as aer > 300 mg/24 h , serum creatinine > 2 mg / dl , and standard clearance < 60 ml / min per 1.73 m or dialysis and/or kidney transplant or defined by the mnsi : > 6 positive responses on the questionnaire and a score > 2 on the examination ) , and cardiovascular disease ( defined as having any of the following six cardiovascular events : cardiovascular death , acute myocardial infarction , silent myocardial infarction , revascularization , confirmed angina , or cerebrovascular accident ) .
* * depression ascertained by the study coordinator on an annual review of psychiatric events that occurred in the year(s ) since the last evaluation ; if patient indicated yes , then the coordinator completed a documentation form to get more information ( e.g. , where treated , if medication was prescribed , dsm - iii diagnosis ) . additionally , if the patients indicated that they regularly took antidepressants for depression and/or followed psychological counseling for depressive symptoms , they were included in the depression category .
hypertension defined as sitting systolic blood pressure 140 mmhg , diastolic blood pressure 90 mmhg , or use of antihypertensive medication .
antihypertensive medication for any reason including use of ace inhibitors and angiotensin ii receptor blockers .
univariate analyses were conducted to examine which variables predicted the presence or absence of sexual dysfunction in women with type 1 diabetes ( table 2 ) .
those variables that were nominally significant at the p < 0.15 level , with respect to fsd , with no adjustment for multiple comparisons , were selected for further testing in a multivariate model .
( based on a cutoff score of 22.75 on the fsfi - r ) was regressed against the following predictor variables : treatment group ( intensive / conventional ) , cohort ( primary / secondary ) , age ( adolescent vs. adult ) , menopausal status , marital status , a composite variable of diabetes complications , peripheral neuropathy , clinical depression , and the log of the a1c at dcct eligibility . when controlling for the effects of other variables , depression status ( depressed vs. nondepressed ) and marital status ( married vs. not married ) were the only variables in the multivariate model that were significant predictors of fsd .
women with type 1 diabetes in our sample who showed signs of depression were 2.08 times more likely to have fsd than women who were not depressed ( adjusted odds ratio [ or ] 2.08 [ 95% wald ci 1.273.42 ] ) . married women with type 1 diabetes were 2.49 times more likely to have fsd than women who were not married ( 2.49 [ 1.344.65 ] ) .
in addition to the relationship with each of the major predictor variables , the differences between the treatment groups in specific domains of sexual function were both univariately and multivariately analyzed . in the univariate analyses ,
associations were found between menopausal status , marital status , the composite diabetes complications variable , the log of a1c at dcct baseline , and depression and the individual sexual domains .
depression was a statistically significant risk factor for fsd in the arousal ( or for depressed vs. not depressed 2.47 [ 95% ci 1.314.66 ] , p = 0.0062 ) and lubrication domains ( 2.41 [ 1.334.37 ] , p = 0.0041 ) .
the complex composite variable was statistically significant with respect to fsd in the lubrication ( for three vs. none 2.82 [ 0.4218.97 ] , two vs. none 5.332 [ 1.6117.65 ] , and one vs. none 4.17 [ 2.197.95 ] , p < 0.0001 ) and orgasm domains ( for three vs. none 3.20 [ 0.5518.71 ] , two vs. none 3.80 [ 1.1912.18 ] , and one vs. none 2.97 [ 1.625.45 ] , p = 0.0021 ) .
being married was the only significant risk factor for fsd in the desire domain ( for married vs. not married 2.97 [ 1.485.93 ] , p = 0.0008 ) .
menopause was an important risk factor for fsd in the lubrication domain ( for menopausal vs. not menopausal 2.45 [ 1.344.50 ] , p = 0.0041 ) .
based on the fsfi - r cutoff score for sexual dysfunction of 22.75 , the overall prevalence of fsd among sexually active women in this study was found to be 35.4% .
univariate analyses revealed that women meeting criteria for fsd were on average older than women without fsd ( p = 0.0041 ) , were more likely to be married ( p = 0.0016 ) , be ( post)menopausal ( p = 0.0019 ) , have evidence of microvasculopathy ( composite diabetes complications variable , p = 0.0092 ) , and be depressed ( p = 0.0022 ) than women without fsd ( table 2 ) . among those women who met the criteria for fsd ,
57% reported a problem with decreased desire , 51% had problems with orgasm , 47% had inadequate lubrication , 38% had problems with sexual arousal , and 21% reported pain during intercourse . additionally , 25% of sexually active women reported low overall sexual satisfaction .
for all sexual domains , study participants without fsd scored higher ( i.e. , had better function ) than women with fsd ( p < 0.001 ) .
clinical characteristics of uroedic women according to fsd status at year 10 of the edic ( n = 424 ) * data are means sd and n ( % ) .
percentages are based on total sample size minus the number of missing values . * ten subjects
hysterectomy defined as a subject 's menstrual period ceasing and it being considered permanent due to surgery .
menopause defined as a subject 's menstrual period ceasing and it being considered permanent . determined by etdrs ( early treatment diabetic retinopathy study ) score on a scale of 023 : < 12 = nonproliferative , 12 = proliferative .
defined in the dcct by the presence of definite clinically evident distal symmetrical polyneuropathy and an abnormal nerve conduction study or in the edic by the mnsi ( michigan neuropathy screening instrument ) : > 6 positive responses on the questionnaire or a score > 2 on the examination .
variable has a score between ( 0 and 4 ) depending on the total number of yes responses to the question of ever having the following four complications : retinopathy ( defined as scatter laser in both eyes ) , nephropathy ( defined as aer > 300 mg/24 h , serum creatinine > 2 mg / dl , and standard clearance < 60 ml / min per 1.73 m or dialysis and/or kidney transplant or defined by the mnsi : > 6 positive responses on the questionnaire and a score > 2 on the examination ) , and cardiovascular disease ( defined as having any of the following six cardiovascular events : cardiovascular death , acute myocardial infarction , silent myocardial infarction , revascularization , confirmed angina , or cerebrovascular accident ) .
* * depression ascertained by the study coordinator on an annual review of psychiatric events that occurred in the year(s ) since the last evaluation ; if patient indicated yes , then the coordinator completed a documentation form to get more information ( e.g. , where treated , if medication was prescribed , dsm - iii diagnosis ) .
additionally , if the patients indicated that they regularly took antidepressants for depression and/or followed psychological counseling for depressive symptoms , they were included in the depression category .
hypertension defined as sitting systolic blood pressure 140 mmhg , diastolic blood pressure 90 mmhg , or use of antihypertensive medication .
antihypertensive medication for any reason including use of ace inhibitors and angiotensin ii receptor blockers .
univariate analyses were conducted to examine which variables predicted the presence or absence of sexual dysfunction in women with type 1 diabetes ( table 2 ) . those variables that were nominally significant at the p < 0.15 level , with respect to fsd , with no adjustment for multiple comparisons , were selected for further testing in a multivariate model .
( based on a cutoff score of 22.75 on the fsfi - r ) was regressed against the following predictor variables : treatment group ( intensive / conventional ) , cohort ( primary / secondary ) , age ( adolescent vs. adult ) , menopausal status , marital status , a composite variable of diabetes complications , peripheral neuropathy , clinical depression , and the log of the a1c at dcct eligibility . when controlling for the effects of other variables , depression status ( depressed vs. nondepressed ) and marital status ( married vs. not married ) were the only variables in the multivariate model that were significant predictors of fsd .
women with type 1 diabetes in our sample who showed signs of depression were 2.08 times more likely to have fsd than women who were not depressed ( adjusted odds ratio [ or ] 2.08 [ 95% wald ci 1.273.42 ] ) .
married women with type 1 diabetes were 2.49 times more likely to have fsd than women who were not married ( 2.49 [ 1.344.65 ] ) .
in addition to the relationship with each of the major predictor variables , the differences between the treatment groups in specific domains of sexual function were both univariately and multivariately analyzed . in the univariate analyses
, associations were found between menopausal status , marital status , the composite diabetes complications variable , the log of a1c at dcct baseline , and depression and the individual sexual domains .
depression was a statistically significant risk factor for fsd in the arousal ( or for depressed vs. not depressed 2.47 [ 95% ci 1.314.66 ] , p = 0.0062 ) and lubrication domains ( 2.41 [ 1.334.37 ] , p = 0.0041 ) .
the complex composite variable was statistically significant with respect to fsd in the lubrication ( for three vs. none 2.82 [ 0.4218.97 ] , two vs. none 5.332 [ 1.6117.65 ] , and one vs. none 4.17 [ 2.197.95 ] , p < 0.0001 ) and orgasm domains ( for three vs. none 3.20 [ 0.5518.71 ] , two vs. none 3.80 [ 1.1912.18 ] , and one vs. none 2.97 [ 1.625.45 ] , p = 0.0021 ) .
being married was the only significant risk factor for fsd in the desire domain ( for married vs. not married 2.97 [ 1.485.93 ] , p = 0.0008 ) .
menopause was an important risk factor for fsd in the lubrication domain ( for menopausal vs. not menopausal 2.45 [ 1.344.50 ] , p = 0.0041 ) .
this study aimed to investigate the prevalence and risk factors associated with fsd in a large well - characterized prospective cohort sample of women with type 1 diabetes ( uro - edic ) using a validated measure of sexual function ( fsfi - r ) .
these findings are based on the largest well - characterized prospective cohort of women with type 1 diabetes in which sexual function has been evaluated .
considering the relatively young age ( mean 43 years ) of the study cohort , a prevalence rate of 35% for fsd can be regarded as moderately high .
given the decision not to include sexually inactive women in the analyses , this prevalence rate of 35% is rather a conservative estimate .
the fsd prevalence rate in our study is slightly higher than those reported in previous studies of women with type 1 diabetes , which ranged from 27 to 29% ( 12,19 ) .
the fact that in previous studies different questionnaires were used and that participating women were even younger in age might ( partially ) account for the differences observed . although rates of sexual dysfunction in women are not dissimilar to those in men , the pattern of specific effects of diabetes on men and women is markedly different . while ed affects men both with type 1 and with type 2 diabetes ,
the most prevalent sexual dysfunction , lubrication and sexual arousal difficulties , were not the sole or the most prevalent problem in women .
moreover , ed is strongly correlated with a1c and the cardiovascular and neuropathic complications of diabetes ( 3,4,10 ) .
again , in contrast , our study reveals in a multivariate analysis that fsd in women with type 1 diabetes is most strongly and consistently correlated with depression and marital status .
the lack of association between any measurement of a1c and fsd in this study suggests that compared with men , the sexual response in women with diabetes is more likely to be affected by the psychosocial aspects ( e.g. , depression ) than by the metabolic control or complications of the disease .
similar results regarding the association between depression and fsd were observed in a previous study of younger women with type 1 diabetes ( 10 ) .
this finding is also consistent with results of other studies of sexually dysfunctional women , in which associations have been observed between fsd and depression ( 20 ) .
the current study thus provides further evidence for the hypothesis that in diabetic women , sexual dysfunction is more strongly related to psychosocial aspects rather than the typical pattern of cardiovascular- and metabolic - related risk factors observed in studies of men with diabetes ( 3,4,10 ) .
several explanations can be offered to account for the different pattern of effects in men and women .
it is conceivable , for example , that these differences in sex risk factor profiles are due to differences in the underlying physiological mechanisms ( e.g. , differences in neurotransmitter involvement ) of sexual response in men and women ( 21,22 ) .
as early as 1983 , schreiner - engle ( 23 ) hypothesized that diabetes - related vasculopathy or neuropathy might be less readily perceived by women and that women with diabetes might not be aware of a relative decreased lubrication response and therefore not likely to report it , in contrast to men who readily experience and report ed .
alternatively , it has been proposed that , in general , cultural and/or psychosocial factors may play a larger role in female sexuality and that depression is a more prevalent and potentially more impactful factor in women ( 7 ) . because of the multidimensional etiology of fsd in women with diabetes , it will be necessary for future research to use a more comprehensive assessment of sexual function , including a combination of both subjective ( i.e. , standardized questionnaires ) and objective methodology ( i.e. , vaginal plethysmography ) . in this respect
( 24 ) , using vaginal plethysmography as an objective measure of physiological arousal , did find an association between diabetes and decreased vaginal lubrication in women .
further studies in this area would be valuable to test alternative hypotheses and to determine whether treating a mood disorder in women with type 1 diabetes contributes to improved sexual function independent of glycemic control .
although this study is based on a prospective , longitudinal , observational study of treatment effects in patients with type 1 diabetes , the analyses presented are from a cross - sectional analysis of data obtained at 10-year follow - up .
future studies in this field should , therefore , use a true longitudinal design to more directly test sequence effects and order of changes in sexual function and to further elucidate the differences observed between the sexes .
also , since the population of the edic - study is in certain respects limited in its diversity ( age , race , and diabetes type ) , the results of this study only apply to caucasian , relatively young women with type 1 diabetes .
future research should attempt to include more diverse samples in order to examine the risk and risk factor of fsd in other groups .
third , we should reemphasize that the exclusion of sexually inactive women from our analyses most likely biases our overall prevalence findings ( 35% ) in a conservative direction .
however , by restricting our analyses to this group of women , we are able to ascertain specific effects on each of the sexual function domains in relation to specific risk factors or predictors .
a final limitation is that no nondiabetic control women were included in the study , and we therefore relied on norms from previous clinical studies to interpret the prevalence of the sexual dysfunctions observed .
however , this is not a serious limitation in view of the large body of published data on sexual dysfunction in the general population in both men and women . in conclusion ,
the results of this study provide further evidence that women with type 1 diabetes are at risk for several sexual dysfunctions .
in contrast to findings in men , our results showed that in women with type 1 diabetes , depression and marital status are the main predictors of fsd , whereas glycemic control and complications were not associated with fsd .
further studies are needed to elucidate the mechanisms underlying these differences . considering that fsd can have an important negative effect on quality of life and partner relationships , the sexual difficulties of women with diabetes warrant more attention in both research and practice .
similar to the annual evaluation of diabetes complications , women with type 1 diabetes should also be regularly queried about the presence of depressive symptoms , sexual function , and sexual satisfaction .
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### Summary:
: objectivethis study aimed to investigate the prevalence and risk factors associated with sexual dysfunction in a well - characterized cohort of women with type 1 diabetes.research design and methodsthe study was conducted in women enrolled in the long - term epidemiology of diabetes interventions and complications ( edic ) study , a north american study of men and women with type 1 diabetes . at year 10 of the edic study ,
652 female participants were invited to complete a validated self - report measure of sexual function , standardized history and physical examinations , laboratory testing , and mood assessment.resultsof the sexually active women with type 1 diabetes in the edic study , 35% met criteria for female sexual dysfunction ( fsd ) .
women with fsd reported loss of libido ( 57% ) ; problems with orgasm ( 51% ) , lubrication ( 47% ) , and arousal ( 38% ) ; and pain ( 21% ) .
univariate analyses revealed a positive association between fsd and age ( p = 0.0041 ) , marital status ( p = 0.0016 ) , menopausal status ( p = 0.0019 ) , microvasculopathy ( p = 0.0092 ) , and depression ( p = 0.0022 ) .
however , in a multivariate analysis , only depression ( p = 0.004 ) and marital status ( p = 0.003 ) were significant predictors of fsd.conclusionsfsd is common in women with type 1 diabetes and affects all aspects of sexual function and satisfaction .
depression is the major predictor of sexual dysfunction in women with type 1 diabetes .
these findings suggest that women with type 1 diabetes should be routinely queried about the presence of sexual dysfunction and possible co - association with depression .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: in december 2010 , over five million people were on antiretroviral treatment ( art ) in sub - saharan africa . in senegal
, this number reached 18,000 at the end of 2011 , corresponding to a coverage rate of 78% .
the efficacy of art has led to a significant reduction in mortality among people living with hiv [ 36 ] , causing an increase in their life expectancy , which nevertheless remains below that of the general population [ 710 ] .
this excess mortality is partially related to immunodepression but also organic and metabolic disorders that are not classified as aids [ 4 , 1116 ] .
nevertheless , it is recognized that they involve phenomena related to the virus [ 1721 ] , to antiretrovirals ( arvs ) [ 2226 ] , and to the host [ 2731 ] .
these mechanisms contribute to noninfectious diseases including diabetes and hypertension , which are two major risk factors of cardiovascular disease and are associated with increased mortality and morbidity .
available data on prevalence and the factors associated with diabetes and hypertension have dealt with populations of varying ages and whose duration of arv exposure varied greatly .
these studies have rarely addressed sub - saharan africa where most countries have only recently begun art in the 2000s . in 1998 , senegal was one of the first resource - constrained countries to implement a government program providing free access to arvs .
a cohort of the 403 initial patients included in this program received routine followup , thus providing an opportunity to study the long - term impact of art .
therefore , this study was conducted with two objectives : ( 1 ) to measure the prevalence of diabetes and hypertension among patients who have been receiving art for several years in senegal and ( 2 ) identify the factors associated with diabetes and hypertension .
a cross - sectional study was conducted between december , 2009 and march 31 , 2010 .
patients were recruited within the anrs 1215 observational cohort , which initially included 403 hiv-1 patients enrolled in the senegalese antiretroviral drug access initiative between 1998 and 2002 .
a total of 242 patients who were still alive and receiving follow - up on december 1 , 2009 at the fann university hospital in dakar were enrolled in this study .
clinical and biological characteristics , including aids stage according to us centers for disease control and prevention ( cdc ) classification , hepatitis c or b coinfection , date of art initiation , type and duration of all antiretroviral treatments received since initiation , cd4 cell count , and body mass index ( bmi ) at treatment initiation , were extracted from the anrs 1215 cohort database .
bmi , cd4 cell count , viral load , levels of total cholesterol and triglycerides at the time of the study , and diabetes and hypertension diagnostics were collected from medical and laboratory files using standardized forms .
mmol / l at two consecutive measurements or if they were known to be diabetic patients .
patients were considered as hypertensive if their systolic blood pressure was 140 mmhg and/or their diastolic blood pressure 90 mmhg at three consecutive measurements separated by at least two weeks and taken after a 1-hour rest in a sitting position or if they were known to be hypertensive and were treated for it .
frequencies of diabetes and of hypertension were compared according to the main characteristics of the study sample using -tests or fisher 's exact tests when appropriate .
age , sex , current bmi , bmi at treatment initiation , cdc stage , coinfection with hepatitis c virus ( hcb ) or hepatitis b virus ( hbv ) , current cd4 cell count , cd4 count at treatment initiation , viral load , total cholesterol levels , triglyceride levels , treatment duration for each type of arv drug , and total duration of art were included in a bivariate analysis .
all variables with p < 0.20 in the bivariate analysis were entered in a multiple logistic regression .
treatment duration was entered as a continuous variable if the linearity of the association with the outcome variable was verified , and as a categorical variable if not . in the latter situation , the treatment duration ( in months )
was categorized in the following quartiles : [ 8998 [ ; [ 98107 [ ; [ 107119 [ ; [ 119139[. the hosmer - lemeshow test was used to assess the goodness of fit of the logistic regression models .
all statistical tests were two - sided and considered statistically significant at a 5% threshold .
statistical analyses were performed using sas statistical software ( version 9.2 , cary , nc , usa ) .
they had initiated art between 1998 and 2002 . the initial arv regimen was a triple drug combination with two nucleoside reverse transcriptase inhibitors ( nrti ) + a nonnucleoside reverse transcriptase inhibitor ( nnrti ) or a protease inhibitor ( pi ) . at treatment initiation ,
at the time of the study , half of the patients had a cd4 cell count above 500 cells/l , and viral load was undetectable for 83% ( table 1 ) .
the most commonly prescribed nrti combinations were lamivudine ( 3tc ) + zidovudine ( azt ) and stavudine ( d4 t ) + didanosine ( ddi ) .
as for nnrti and pi , the most commonly used molecules were efavirenz ( efv ) and indinavir ( idv ) , respectively ( table 2 ) . among the 242 patients , 39 had diabetes , corresponding to a prevalence of 14.5% ( 95% confidence interval ( ci ) : 10.319.5 )
the frequency of diabetes was higher in patients 45 years of age and in those with long duration of treatment ( 119 months ) ( table 3 ) .
variables associated with diabetes in bivariate analyses were long duration of art , age , bmi at treatment initiation , levels of total cholesterol and triglycerides , and duration of exposure to d4 t , ddi , and idv . in multivariate analysis ,
long duration to art , older age , higher bmi at treatment initiation , and higher level of triglycerides were independently associated with higher risk of diabetes ( table 4 ) .
the prevalence of hypertension in the study population was 28.1% ( ci : 22.534.2 ) .
out of 68 patients who had hypertension ( or were receiving antihypertensive treatment ) , 15 ( 22% ) were aware of their condition before initiating arv therapy .
higher prevalence of hypertension was also observed for male patients , those who were overweight ( bmi 25 kg / m ) at treatment initiation or at time of the study , those who had a cd4 count above 200 cells/l , and those presenting with hypercholesterolemia or hypertriglyceridemia , but differences were not statistically significant ( table 3 ) . in multivariate analysis , older age , higher current bmi , higher cholesterolemia , and longer duration of idv exposure were associated with higher risk of hypertension .
total duration of art was not found to be associated , and longer exposure to lopinavir / ritonavir ( lpv / r ) was associated with a reduced risk of hypertension ( table 4 ) .
the patients in this study were black africans who initiated art in senegal between 1998 and 2002 and who have received regular followup until december 1 , 2009 . at that date
, they had been receiving arvs for a median duration of nearly 9 years ; half of the patients were over 46 years old .
after adjustment , diabetes appeared to be associated with the duration of arv exposure while hypertension did not .
one of this study 's strengths is its investigation of the long - term impact of treatments with arv - exposure durations rarely observed in other developing countries where art was available well after 1998 .
some treatments used at inclusion , such as idv , nelfinavir ( nfv ) , or d4 t ( particularly the 40 mg dosage ) , are no longer in use .
however , most of the patients on arvs in developing countries were also exposed to these molecules for long durations .
our study results may be useful for resource - constrained countries that began with arv triple therapies in the 2000s in populations that generally had the same characteristics as those in our cohort .
these results provide a long - term view for these countries where art started several years after senegal .
another strength is having used definitions for diabetes and hypertension that took into account several successive measurements in accordance with who guidelines or those of specialized american associations .
this is a cross - sectional study and , as such , could only identify associated factors and not risk factors .
family history of diseases under study , the cd4 nadir , and adherence to art were not collected . after a median follow - up duration of 107 months , 14.5% of patients presented with diabetes .
a study in benin reported a prevalence of 8% after a median exposure to arvs of 23.2 months and an average age of 38 years . in south africa , only four cases of diabetes were identified among 304 patients exposed to arvs for more than one year . a recent study involving
4010 patients from seven countries in latin america found an overall prevalence of 3.6% for type 2 diabetes .
the lower prevalence found in these studies when compared to ours can be explained in part by two factors : a younger population and , in some cases , a shorter duration of arv exposure .
more research in the literature has been published from developed countries , and it deals with both the prevalence and incidence of diabetes .
most of these studies report prevalence and/or incidence rates higher than observed in the general population [ 3538 ] , while others report similar , or even lower , figures .
even though conventional risk factors have been confirmed in this population , arv exposure is not unanimously recognized as a factor associated with diabetes [ 36 , 37 , 4046 ] . in france , data from the anrs cohort aproco - copilote report a prevalence of 9% for diabetes after 8 years of art . in a cohort of 1278 males from the united states ( multicenter aids cohort study ( macs ) ) , the prevalence of diabetes , adjusted for age and bmi , was 14% among seropositive patients on arvs , corresponding to 4.6 times greater than among seronegative patients . this same study estimated a 10% risk of developing diabetes after 4 years of treatment .
incidences of 2.50/100 person / years and 2.89/100 person / years , respectively , were reported in the study by tien et al . among patients on pi - based triple therapy and those on triple therapy not containing ip . in the d : a : d study , incidence was 4.42/1000 person / years and 5.72/1000 for a swiss cohort .
the prevalence observed in our study is higher than that reported in the french study and nearly identical to the one found in the macs .
however , differences between the study populations must be taken into account , particularly in terms of age , ethnicity , and treatment duration . in france ,
the prevalence of impaired glucose tolerance rose significantly with age , bmi , and exposure to idv . in the macs , the factor having a high association with the onset of diabetes was art ( hr = 4.11 ; ci : 1.859.16 after adjusting for age and bmi ) , although it was nrti exposure in the female population for the tien pc study . in the swiss cohort ,
the factors associated with the onset of diabetes were male sex , age > 60 years , african or asian ethnicity , stage c of cdc classification , obesity , nrti exposure , and pi exposure .
all of the associated factors found in our study were also found in the d : a : d study to be risk factors for diabetes .
a recent publication from the aproco - copilote cohort also found that advanced age , overweight , and exposure to idv were among the risk factors for incident diabetes .
this involved patients who received arvs for a median duration of 9.6 years with an incidence of 14.1/1000 person / years .
studies on hypertension among people living with hiv report a wide range of prevalence [ 33 , 38 , 5056 ] .
factors associated with this prevalence are the same as those found in the general population .
the role of art remains controversial [ 38 , 48 , 5255 , 5761 ] .
a prevalence of 19.1% was observed among patients infected with hiv , ages 18 to 45 years , and on arvs for over one year . in brazil ,
two studies reported a prevalence of 19.9% and 25.6% , respectively [ 38 , 50 ] .
the study of the south american cohort reported a prevalence of 31.5% but used a different definition ( systolic blood pressure 130 mm hg and/or diastolic blood pressure 85 mm hg ) than that of our study .
in developed countries , prevalence ranges between 20% and 40% among populations exposed to arvs , however , with differences in terms of age ; ethnicity ; duration of arv exposure ; clinical , immunological and virological status [ 5156 ] .
these prevalence figures were reported in norway , spain , italy , and the united states .
the role of conventional risk factors recognized in the general population was unanimously highlighted in all these studies .
, treatment duration appeared to be a predictive factor for hypertension in one study , but it did not investigate the roles of various arv molecules .
another case - control study reported a higher prevalence of hypertension among people on arvs compared to those who were not ( 21% versus 13% , resp . ) , but the difference was not significant .
there was also no difference in prevalence based on whether or not patients were exposed to nnrtis or pis . in spain , a rise in blood pressure was reported after 48 weeks of art .
the authors suggested that treatment had a partial role in raising blood pressure by improving the patient 's health condition .
this study only involved 95 patients with a treatment duration of 48 weeks , making it difficult to draw a precise conclusion on this point .
found no association between art and hypertension , but their study only examined exposure to nrtis and pis and not the duration of treatment exposure nor each arv molecule .
thibaut et al . investigated risk factors of the onset of hypertension in the d : a : d study and exposure to arvs did not appear to be a risk factor for hypertension after adjustment . on the other hand ,
the cumulative duration of exposure to nnrtis was associated with a slight risk of hypertension ( a reduced risk between 22% and 33% was observed among those who were exposed to nnrtis compared to those who never received any nnrtis ) . in the united states , it was found that atazanavir ( atv ) played a protective role in the onset of raised blood pressure compared to efv .
this same study found a slight risk of a raised blood pressure among patients exposed to atv , nfv , and idv compared to patients exposed to lpv / r .
this did not agree with our results , which found that hypertension had a positive association with idv and a negative one with lpv / r .
nevertheless , it should be noted that this last study only took into account art at inclusion in contrast to ours , which investigated exposure duration . on the other hand ,
our patients were exposed to high concentrations of idv ( 2400 mg / day ) without ritonavir .
the association between idv and hypertension , observed in an earlier study , is likely linked to the renal toxicity of this molecule .
our study suggests that prevalence of diabetes and hypertension is higher among people exposed to arvs compared to the general population in senegal [ 64 , 65 ] .
a recent study reported prevalence of 10.4% and 46% for diabetes and hypertension , respectively , but the diagnosis of hypertension was based on one measure and was certainly overestimated .
this observation is consistent with most of the literature that has assessed the association between arvs and diabetes .
however , the association between certain arv molecules and systolic hypertension seems more controversial .
diabetes and hypertension are known risk factors for cardiovascular disease in low- and middle - income countries which represents more than 80% of the global burden of cardiovascular disease worlwide . for patients on arvs
, these factors combine with other comorbidities [ 68 , 69 ] and cause high mortality ; otherwise , they have a potentially negative impact on the quality of life and efficacy of arvs .
treatment for these diseases occurs over the long term , if not for life , thus , posing problems regarding cost and observance in resource - constrained countries .
this highlights the importance of implementing screening , early diagnosis , and prevention measures for these disorders .
screening for diabetes and hypertension must be an integral part of followup for hiv - positive persons , more specifically among those who are on arvs .
the same applies for other prevention measures for cardiovascular disease ( tobacco use , overweight , and hyperlipidemia ) . to do this , models for followup must integrate these parameters . diet and lifestyle advice , including smoking cessation , regular physical activity , and a balanced diet , must be integrated into routine consultations for these populations .
measurements of blood pressure , waist circumference and glycemia , cholesterolemia , and triglyceridemia must also be taken regularly , at least at a certain age and/or specific duration of arv exposure and even for a specified cardiovascular risk level .
our study provides the first data on diabetes and hypertension among people who are living with hiv and on art in senegal .
this contributes to improved assessment and better analysis of this problem in the context of resource - constrained countries where literature on this topic is rare .
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### Summary:
: cardiovascular risk factors in people on antiretroviral treatment ( art ) are poorly documented in resource - constrained settings .
a cross - sectional study was conducted in 2009 to assess prevalence of diabetes and hypertension in a sample of 242 hiv - infected patients who had initiated art between 1998 and 2002 in dakar , senegal ( anrs 1215 observational cohort ) .
world health organization ( who ) criteria were applied to diagnose diabetes and hypertension .
multiple logistic regressions were used to identify factors associated with diabetes and hypertension .
patients had a median age of 46 years and had received art for a median duration of about 9 years .
14.5% had diabetes and 28.1% had hypertension .
long duration of art ( 119 months ) , older age , higher body mass index ( bmi ) , and higher levels of total cholesterol were associated with higher risks of diabetes .
older age , higher bmi at art initiation , and higher levels of triglycerides were associated with higher risk of hypertension .
this study shows that diabetes and hypertension were frequent in these senegalese hiv patients on art .
it confirms the association between duration of art and diabetes and highlights the need to implement programs for prevention of cardiovascular risk factors in hiv patients from resource - constrained settings .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: acute kidney injury ( aki ) is a syndrome with various etiologies , followed by numerous comorbidities , which makes predicting its outcome very complicated .
aki often occurs in the older population of patients with pre - existing chronic kidney disease ( ckd ) , and it is associated with increased risk for dialysis ( 1 ) .
the causes of aki are multi - factorial , but sepsis has consistently been the most common contributing factor , accounting for approximately 50% of all cases , especially in the intensive care units ( icu ) ( 2 ) .
recent evidence suggests that septic aki could be characterized by a distinct pathophysiology ( 3 ) .
regrettably , not many clinical studies have investigated clinical characteristics , profile and renal function outcome of septic in comparison to non - septic aki patients ( 4 , 5 ) .
in addition , other authors have focused only on the clinical outcome of dialysis dependent septic aki patients in the icu , and they defined renal function recovery as independence from dialysis at discharge ( 6 ) . however , a significant proportion of aki patients is not in the icu , nor dialyzed , and may require alternate definitions for assessing renal recovery ( 7 ) .
this encourages us to define renal function outcome according to the values of creatinine clearance at discharge , and to focus on clinical differences between septic and non - septic aki patients and their prognostic significance for renal function outcome .
the objective of this study was to investigate clinical characteristics of septic compared to non - septic aki patients , and to assess predictive value of clinical prognostic factors on renal function outcome of septic and non - septic aki patients .
a prospective , single - center , observational study was conducted from january , 2008 to december , 2012 at nephrology clinic and clinic for infectious diseases , university clinical centre sarajevo .
one hundred patients included in this study were adults ( age 18 years ) with hospital stay 24 hours , and diagnosis of aki .
exclusion criteria were prior kidney transplant , end - stage kidney disease , and initiation of renal replacement therapy ( rrt ) before hospital admission .
clinical data encompassed origin of aki ( septic and non - septic ) , type of aki ( prerenal , intrinsic and postrenal ) , comorbid conditions and different treatment modalities as well as renal function outcome and in - hospital mortality .
aki was defined according to the consensus definition of the rifle criteria with three stages ( risk , injury , failure ) of progressively higher creatinine ( 8) . when pre - admission serum creatinine was unavailable , it was estimated by the modification of diet in renal disease equation , as recommended by the acute dialysis quality initiative working group ( 9 ) .
septic origin of aki was diagnosed in those patients who had recognized source of infection , regardless of whether the blood culture was positive or not , and if they had verified increased serum creatinine .
criteria for the diagnosis of sepsis and septic shock were defined according to consensus american college of chest physicians / society of critical care medicine consensus conference ( 10 ) .
outcome of renal function was defined according to the values of creatinine clearance as recovered ( creatinine clearance > 60 ml / min ) and non - recovered ( creatinine clearance < 60 ml / min ) with impaired renal function .
creatinine clearance was determined from measurement of creatinine in a 24-hour urine specimen and serum specimen .
descriptive statistics , student s t - test ( for variables with normal distribution ) and mann whitney u test ( for variables without normal distribution ) were used to compare mean values between groups .
a multivariate logistic regression was performed to evaluate the impact of the variables on renal function outcome .
considering etiology , patients were divided into two groups : patients with aki of non - septic etiology ( 66 patients ) and patients with aki of septic etiology ( 34 patients ) .
there was no evidence of statistically significant difference in mean values of age and gender between these two groups of patients , while hospital stay was significantly longer in septic aki patients ( p=0.03 ) . in the group of non - septic aki patients ,
prerenal type was recognized in 30.3% of patients , while intrinsic and postrenal type were detected in 51.5% and 18.2% of non - septic aki patients , respectively .
pre - existing chronic kidney disease had 10.6% of non - septic aki patients and 2.3 greater proportion of septic aki patients ( 23.5% ) .
comorbid conditions were present in 70.6% and 60.6% of septic and non - septic patients , respectively . in the group of septic aki patients ,
only 8.8% patients underwent rrt , while 24.4% of non - septic aki patients were treated with rrt .
the mean hospital stay prior to the rrt commencement was significantly longer in septic aki patients when compared to non - septic aki patients ( 10.6 days vs. 2 days , p=0.03 ) .
average values of creatinine clearance at discharge were significantly lower in the group of aki patients with septic etiology ( 46.493.8 ml / min ) than in the group of aki patients with non - septic etiology ( 74.523.82 ml / min , p<0.001 ) .
septic aki patients also had significantly greater proportion of hospital mortality in comparison to non - septic aki patients ( 14.7% vs. 3.03% , p=0.04 ) .
aki acute kidney injury ; n number ; ns non significant ; rifle risk , injury , failure , loss of kidney function and end - stage kidney disease ; ckd chronic kidney disease ; rrt renal replacement therapy figure 1 gives an overview of the most common causes of non - septic aki : lower obstruction of the urinary tract ( 18.18% ) , hantavirus hemorrhagic fever with renal syndrome ( hfrs ) ( 13.64% ) , hypovolemia due to acute enterocolitis ( 13.64% ) and nephrotoxic drug - related acute tubular necrosis ( atn ) ( 10.61% ) .
hepatorenal syndrome ; ain acute interstitial nephritis ; adhf acute decompensated heart failure ; atn acute tubular necrosis ; hfrs hemorrhagic fever with renal syndrome we monitored factors statistically significant in predicting outcome of renal function in all patients with aki , and in the groups of septic and non - septic aki patients , separately .
factors statistically significant in predicting non - recovering of renal function in all aki patients were sepsis ( 95% confidence interval 0.128 to 0.967 , p=0.043 ) and hypertension ( 95% confidence interval 0.114 to 0.788 , p=0.015 ) .
failure was an independent predictor of non - recovered renal function in the group of septic aki patients ( 95% confidence interval 0.026 to 0.868 , p=0.034 ; table 3 ) . in the group of non - septic aki patients , only hypertension was independent predictor of renal function non - recovery ( 95% confidence interval 0.064 to 0.824 , p=0.024 ; table 3 ) .
however , in this , non - septic aki group of patients , postrenal type ari was independently associated with the renal function recovery .
patients with postrenal type of aki had 10 times more probability to achieve renal function recovery ( 95% confidence interval 1.174 to 92.264 , p=0.035 ; table 3 ) .
confidence interval significant independent predictors of renal function outcome in non - septic and septic acute kidney injury patients .
sepsis is a well - known risk factor for the development of aki , but our understanding of the pathophysiology of septic aki is limited .
recent study implies that septic aki may represent unique form of aki : hyperemic aki ( 3 ) . in present study ,
bagshaw and daher with their associates ( 4 , 11 ) estimated that 41.5% and 47.5% of patients had sepsis as a contributing factor to aki , respectively .
accompanied with heart failure , atn and surgical procedures , sepsis was one of the four most common causes of aki development in the best kidney ( 12 ) and picard study ( 13 ) .
our study revealed that the most common causes of non - septic aki were lower urinary tract obstruction ( 18.2% ) , hypovolemia due to enterocolitis ( 13.64% ) , hfrs ( 13.64% ) , nephrotoxic drug - related atn ( 10.61% ) and decompensated heart failure ( 9.09% ) . in comparison to the best kidney ( 12 ) and
picard studies ( 13 ) , present study has shown a higher prevalence of hfrs , which can be explained by endemic occurrence of hfrs in the balkans with epidemic outbreaks and sporadic cases that have been recorded yearly since the disease was first recognized ( 14 ) .
the prevalence of nephrotoxic drug - related atn in our study was lower than in best kidney study and picard study ( 12 , 13 ) , but almost the same as in the study of daher with coworkers ( 11 ) .
both conceptually and diagnostically , the various causes of aki are divided broadly into three anatomic categories : prerenal , intrinsic , and postrenal . since aki of septic origin is more likely intrinsic type , we analyzed prevalence of prerenal , intrinsic and postrenal type of aki only in the group of non - septic aki patients .
prerenal type of aki was present in 30.3% of non - septic aki patients in our study .
similarly , prerenal azotemia was singled out as a separate etiological factor of aki development in the study of other authors ( 15 ) who found prerenal type in 38.9% of aki cases .
more than 80% of patients with severe aki of critical illness have associated respiratory and circulatory failure ( 11 ) .
we analyzed presence of comorbidities in both followed groups of patients . in accordance with previous reports
( 11 , 16 ) , our results have shown that septic aki patients have a higher prevalence of comorbid illnesses compared to non - septic patients .
the main comorbid conditions in non - septic aki patients were hypertension ( 31.8% ) and diabetes mellitus ( 25.8% ) . in septic aki group of patients , almost every second patient had hypertension ( 44.1% ) , and more than a third of patients had diabetes mellitus ( 38.2% ) .
other authors have also confirmed that hypertension and diabetes mellitus were among the five most common comorbid conditions in aki ( 11 ) .
recent data have suggested that rates of rrt utilization in aki are increasing ( 17 ) .
however , only 19% of all aki patients included in our study were treated with rrt , which is similar with prevalence ( 12% ) found in recent survey conducted in 10 italian icu ( 18 ) .
present study detected that need for dialysis was greater in patients with non - septic aki , compared to septic aki patients , but without statistical significance ( 24.2% vs. 8.8% ) , which is consistent with previous reports ( 19 ) .
however , other authors ( 4 ) found no difference in proportion of rrt in septic and non - septic groups of patients .
our patients with septic aki had 5.3 times longer hospital stay before initiation of rrt compared with non - septic aki patients ( 10.6 vs. 2 days , p=0.03 ) .
this significant delay in initiation of rrt was also registered in the study of bagshaw and associates ( 4 ) .
our findings also suggest that septic aki patients have significantly worse outcome of renal function ( measured by creatinine clearance values at the discharge ) and that they have significantly longer hospital stay in comparison to non - septic aki patients , which is consistent with data of other authors ( 18 ) . by multivariate
logistic regression , sepsis was significant predictor of non - recovering of kidney function in aki patients .
this negative prognostic impact of sepsis can be explained by the pathophysiological effect of sepsis on the kidney with significant damage at the level of the tubules ( 3 ) .
using multivariate analysis , failure ( as third , the most difficult class of aki ) , was independently associated with non - recovering of kidney function only in the group of septic aki patients in present study .
although our results confirmed that septic aki patients had significantly greater proportion of mortality when compared with non - septic aki patients ( 14.7% vs. 3.03% , p=0.04 ) , septic etiology was not proved to be predictor of mortality . maybe this can be explained with rather low overall mortality rate in our study ( 7% ) . unlike our results
, sepsis has shown to be strong predictor of death in other studies ( 4 , 5 ) . in accordance with recent findings ( 19 ) , we found that hypertension was independent predictor of adverse renal function outcome in all aki patients and in the group of non - septic aki patients separately .
this is not unexpected since systemic hypertension is potent contributor to the development of arteriosclerosis , tubulointerstitial fibrosis and glomerulosclerosis , all of which may hasten the decline in kidney function .
opposite to hypertension , postrenal type of aki proved to be an independent predictor of renal function recovery in non - septic aki group .
a possible reason for this finding could be the fact that the pathophysiology of lower urinary tract symptoms is the result of bladder outlet obstruction , mainly associated with benign prostatic hyperplasia with no great kidney affection .
are clinically distinct compared to non - septic aki patients with poorer renal function outcome . significant prognostic factor of adverse renal function outcome in septic aki is class failure , while significant predictor of poor renal function outcome in non - septic aki is hypertension .
these findings highlight the importance of identification of clinical risk factors separately in septic and non - septic aki patients , since those patients seem to have not only pathophysiological , but also clinical differences .
close monitoring of aki patients due to sepsis should be recommended in order to improve renal function outcome of these high - risk aki patients .
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### Summary:
: aim : the objective of this study was to evaluate prognostic impact of clinical factors on outcome of renal function in septic and non - septic acute kidney injury ( aki ) patients.methods:the prospective , observational , clinical study was performed at nephrology clinic and clinic for infectious diseases , university clinical centre sarajevo .
one hundred patients with diagnosis of aki were enrolled in the study , and divided into two groups : septic and non - septic aki patients .
clinical parameters included causes and type of aki , pre - existing comorbidities and different treatment modalities .
patients were followed up until discharge or death .
renal function outcome was defined by creatinine clearance values at discharge.results:septic aki patients had significantly longer hospital stay ( p=0.03 ) , significantly worse renal function outcome ( p<0.001 ) , and higher burden of comorbidities ( 70.6% vs. 60.6% ) , compared to non - septic patients .
septic aki patients were almost three times less likely to receive renal replacement therapy ( 8.8% vs. 24.4% ) and they had significant delay in initiation of dialysis ( p=0.03 ) . by multivariate analysis , sepsis ( 95% ci 0.128 - 0.967 , p=0.043 ) and hypertension ( 95% ci 0.114 - 0.788 , p=0.015 ) were independent predictors of adverse renal function outcome in aki patients .
postrenal type of aki was independent predictor of renal function recovery in non - septic aki patients ( 95% ci 1.174 - 92.264 , p=0.035 ) , while failure , as third class of aki , was independent predictor of non - recovered renal function only in septic aki patients ( 95% ci 0.026 to 0.868 , p=0.034).conclusion : septic aki patients are clinically distinct compared to non - septic aki patients with different prognostic factors and poorer renal function outcome .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: a 24-year - old male non - smoker with no prior medical or ocular history presented with 2 days of painless loss of vision in the left eye .
best - corrected visual acuity ( bcva ) was 20/20 in the right eye and 20/80 in the left eye .
motility , pupils , intraocular pressure , and anterior segment exam were unremarkable in both eyes .
left fundus exam revealed retinal hemorrhages in all four quadrants with venous dilation and tortuosity and a small vitreous hemorrhage ( figure 1 ) .
fluorescein angiography revealed delayed venous filling without leakage , vasculitis , or choroidal ischemia ; suggestive of non - ischemic central retinal vein occlusion ( crvo , figure 2 ) .
compressive , autoimmune , and hematologic work - up including complete blood count , a full lipid profile , antinuclear antibody , anti - neutrophil cytoplasmic antibody , ace , homocysteine , syphilis studies , proc and pros levels , anti - cardiolipin and anti - phospholipid antibodies , factor v leiden , atiii , and magnetic resonance imaging ( mri ) of the brain and orbits were negative .
aspirin 81 mg was started as prophylaxis , and the case did not require intravitreal anti - vascular endothelial growth factor therapy.1 at 1 week and 1 month follow - up , bcva was 20/40 in the left eye . by 2 months , bcva returned to 20/20 - 2 .
, the arteries were found to lie directly over the veins with the vessels tightly intertwined in the left eye ( figure 3 ) .
more specifically , an undilated nasal retinal vein was firmly wrapped around the arterial bifurcation .
since the veins that emanated from directly underneath the site of the intertwined vessels were dilated and tortuous , this anatomical relationship was postulated to be the cause of his otherwise idiopathic crvo .
no such vascular intertwining was present in the unaffected right eye ( figure 4 ) .
crvo typically occurs in patients older than 50 years with risk factors including hypertension , diabetes , and open angle glaucoma.2 crvo in a young patient merits work - up for underlying compressive , hematologic , or autoimmune etiology.35 primary pulmonary hypertension has also been reported as the hemodynamic basis of crvo in three patients in whom significant morbidity and mortality followed the vein occlusion.6 crvo has been reported to occur in two young patients with anomalous retinal anatomy at the level of the optic nerve , with proposed mechanism for vein occlusion to include a combination of turbulent flow , increased intravascular volume , and pressure from the arteriolar side of the circulation causing a mechanical mass effect on the venous side.7 these changes , over time , are thought damage the vessel wall of the central retinal vein and lead to thrombosis and occlusion .
these cases highlight the importance of careful inspection of the retinal vascular to aid in assessing the risk of retinal vein occlusion in age group .
thorough work - up and co - management with the patient s primary care physician is recommended .
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### Summary:
: an otherwise healthy 24-year - old man presented with a painless decrease of vision in the left eye for 2 days .
best - corrected visual acuity was 20/20 in the right eye and 20/80 in the left eye .
anterior exam was unremarkable and funduscopic exam in the left eye revealed retinal hemorrhages in all four quadrants with venous dilation and tortuosity consistent with central retinal vein occlusion .
fluorescein angiography revealed delayed venous filling with neither leakage nor vasculitis .
a comprehensive work - up that included infectious , inflammatory , and hypercoagulability studies was unremarkable , and magnetic resonance imaging of the orbits was unrevealing .
after 2 months , best - corrected visual acuity returned to 20/20 - 2 in the left eye . upon closer review of the vascular anatomy in the left eye , a bifurcation of the central retinal artery at the level of the optic disc
was tightly intertwined with an undilated nasal retinal vein in a manner that appeared to compress the underlying central retinal vein , resulting in dilation and tortuosity of the remaining venous branches .
the vessel wall damage , turbulent venous flow , and compressive mass effect resulting from the anomalous retinal vasculature relationship is the proposed mechanism of the central retinal vein occlusion .
careful attention to the retinal vascular anatomy is suggested to aid in assessing the risk of retinal vein occlusion in any age group .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: chemokines are small but potent chemotactic
cytokines ( 814
kda ) . to date , about 50 chemokines have been identified and divided
into four distinct families ( c , cc , cxc , and cx3c ) based
on the arrangement of conserved cysteines in the n - terminus .
these secreted proteins orchestrate homing of cells toward areas
of high chemokine concentration through binding and activation of
their cognate gpcrs ( g - protein coupled receptors ) on the surface of
cells .
processes such as cell trafficking and adhesion greatly depend
on the chemokine receptor signaling axis .
cxcl12
( stromal - cell - derived factor-1 , sdf-1a ) is a cxc - type chemokine
that binds to the cxcr4 and cxcr7 receptors attracting receptor - containing
cells toward areas of elevated cxcl12 levels .
extracellular matrix
glycosaminoglycans ( gags ) also bind cxcl12 and maintain a chemotactic
concentration gradient .
cxcl12 is constitutively
expressed and essential during embryonic development but afterward
functions mainly in inflammatory response , immune surveillance , and
tissue homeostasis .
this is done through trafficking of lymphocytes
to where they are needed such as the lymph nodes , lung , and bone .
metastatic cancer cells exploit the same mechanism as lymphocytes
by upregulating the expression of chemokine receptors .
cxcr4 , for example , is overexpressed
in over 23 human cancers , allowing tumor cells to migrate to organs
that produce cxcl12 , leading to the formation of secondary colonies . because metastasis contributes the most to cancer mortality rates ,
preventing
novel inhibitors of the cxcr4cxcl12
signaling axis have been under active development as potential cancer
therapeutics .
such efforts have mainly focused
on the orthosteric site of cxcr4 , a deep transmembrane pocket suitable
for the binding of small molecule antagonists .
for example , amd3100 ( plerixafor ) , a cxcr4 antagonist ,
has been approved in promoting hematopoietic stem cell mobilization
from the bone marrow to the blood in treating multiple myeloma and
non - hodgkin s lymphoma .
however ,
recent studies also suggest that neutralizing chemokines may prove
to be a successful approach to cancer therapy as well .
nox - a12 , an rna oligonucleotide in l - configuration that
binds cxcl12 and blocks gag binding , is thought to increase the susceptibility
of chronic lymphocytic leukemia cells to chemotherapy by interfering
with chemokine - mediated cell motility .
cxcr4 has been previously described to rest in a constitutuve
dimeric
form , independent of ligand binding . cxcl12
then binds and activates cxcr4 in a two - step / two - site process ( figure 1 ) .
first , cxcl12 is
recognized by the extracellular n - terminal domain of the receptor
( site 1 binding ) ( figure 1b ) .
following recognition , the flexible n - terminus of cxcl12
docks into the receptor ( site 2 binding ) ( figure 1c ) , leading to receptor internalization and downstream signaling
such as calcium influx and chemotaxis .
monomeric representation
of cxcr4 bound by cxcl12 through a two - step / two - site
process .
( b ) in step-1/site-1 , cxcl12 recognizes and binds the n - terminal domain
of cxcr4 aided by sulfotyrosine recognition .
( c ) in step-2/site-2 ,
the flexible n - terminal domain of cxcl12 docks into cxcr4 causing
activation .
multiple lines of evidence suggest that cxcr4 can form
dimers , but there is no evidence to suggest that the site 1 interface
would be altered by a change in oligomeric state of the receptor . as with other chemokine receptors ,
the cxcr4 n - terminus is post - translationally
sulfated at one or more tyrosines , including
y7 , y12 , and y21 , which increases its affinity for cxcl12 .
sulfation
at y21 ( sy21 ) not only contributes the most to enhancing binding affinity
but also has the largest effect on downstream signaling .
structures of locked cxcl12 dimers , in complex with sulfated ( only
at y21 or triply sulfated at y7 , y12 , and y21 ) cxcr4138 , identified discrete binding pockets for each sulfotyrosine , suggesting potential target sites for which
small molecule ligands can be engineered .
thus , as molecular details
of the cxcl12cxcr4 interface emerge , structure - based inhibition
of cxcl12 becomes a practical albeit challenging approach .
previously ,
our in silico screening using dock 3.5.54 and the zinc
small molecule database identified zinc 310454 as a novel small molecule
ligand against the sy21-binding site .
weak binding to the sy21 site and inhibition of cxcl12cxcr4
interactions were confirmed by nmr perturbation studies and by cxcl12-mediated
ca - flux assays using thp-1 cells , respectively .
subsequent
analysis of zinc 310454 , fragment - based design and sar optimization
coupled with a bioisostere approach led to the design and synthesis
of tetrazole derivatives , including compound 1 .
like
the original hits from docking , these compounds bind to cxcl12 with
m affinities .
compound 1 was synthesized by substitution
of the carboxyl group with a tetrazole from the meta- to the para- position and substitution of the
thioureido linker with the urea ( figure 2a ) .
nmr chemical shift mapping suggested that compound 1 also binds to the sy21 site , and molecular docking was used
to estimate the binding pose ( figure 2b ) .
a zinc
310454 derivative binds in the sy21 binding pocket as predicted
by in silico docking .
( a ) fragment - based sar analysis of zinc 310454
led to the design and synthesis of compound 1 .
( b ) significant
chemical shift perturbations in the presence of 1600 m compound 1 map to the predicted binding pocket on cxcl12 ( pdb : 2k05 ) .
the residues most
perturbed are colored in orange . to date , apart from one previous study identifying chalcone-4
as
a neutralizing ligand for cxcl12 , our
virtual screening hits and the tetrazole derivatives are the only
reported cxcl12-specific small molecule inhibitors , yet the structure
of an inhibitor bound to cxcl12 was still lacking . besides the nmr
cxcl12cxcr4138 structure ( pdb i
d : 2k05 ) , the only structure
of a cxcl12ligand complex is the crystal structure of cxcl12
bound by a heparin disaccharide ( pdb i d : 2nwg ) , a fragment
of the natural ligand that binds at the same pocket as sy12 of cxcr4 .
here
we present an x - ray crystallographic complex structure of cxcl12
bound to compound 1 at the sy21-binding site , the first
of cxcl12 with a novel small molecule ligand .
the crystal structure
identifies residues that mediate ligand binding and elucidates unoccupied
hotspots that can be utilized in future optimization efforts .
the complex crystal was obtained by
soaking compound 1 into apo cxcl12 crystals . in previous
experiments
, we noticed that
dmso can nonspecifically bind to the cxcl12 surfaces of interest and
result in a noisy electron density map . as a result
, no dmso was used
in our soaking experiment and the compound was dissolved to saturation
directly in the stabilization buffer .
the resulting complex structure
was solved at 1.9 resolution and has a primitive orthorhombic
space group ( p212121 ) ( table 1 ) with a dimer in each asymmetric
unit ( figure 3 ) .
the overall structure of the
cxcl12 dimer is nearly identical to that of the apo protein ( pdb i d : 2j7z ) with an rmsd of
0.238 aligning 774 atoms .
the only significant backbone movements
between the complex structure and the previously determined apo structure
are observed in the flexible n - terminus of each monomer .
complex crystallographic
structure of cxcl12 dimer ( ribbon and
surface model ) with compound 1 ( yellow ) bound to the
sy21-binding site .
the unbiased fo fc density
unambiguously identifies the binding mode of
compound 1 ( figure 4a ) , residing
in the pocket that normally interacts with sy21 and adjacent residues ,
as seen in the nmr complex structure of cxcl12 bound by a cxcr4 sulfated
n - terminal peptide ( figure 4c ) .
compound 1 was observed only in one of the two monomers in the asymmetric
unit because the corresponding binding pocket in the other monomer
was partially blocked by crystal packing .
( a ) stereo image depiction of the unbiased fofc map
( at 3 ) of compound 1 bound to the sy21-binding
site of cxcl12 .
( b ) complex crystal structure of cxcl12 ( green ) bound
by compound 1 ( yellow ) superimposed to the apo crystal
structure ( pdb i d : 2j7z ) ( cyan ) shows conformational changes induced upon binding .
( c ) nmr
complex structure of cxcl12 bound to the d20-sy21-d22 segment of cxcr4138 ( pdb i d : 2k05 ) outlines the sy21-binding site as well as the possible
hydrogen bond interactions .
a number of protein main chain and side chain functional
groups
are involved in polar and nonpolar interactions with the small molecule
ligand . ala19n and asn22n2 are in close contact ( 3.0
) to the tetrazole group , with the former establishing a favorable
hydrogen bond and the latter an nh interaction ( figure 4b ) .
the urea linker is within hydrogen - bonding distance
to glu15 , asn45 , and arg47 .
interestingly , compared to the apo structure
( pdb i d : 2j7z ) , glu15 side chain swings into the sy21-binding site and forms an
ideal hydrogen - bonding network with compound 1 , with
the two nitrogen atoms of the urea linker serving as hydrogen donors
to the two oxygen atoms of the glutamate side chain ( figure 4b ) .
furthermore , compared to the published apo structure ,
arg47 undergoes conformational changes in order to form a hydrogen
bond with the carbonyl oxygen of the urea linker while partially stacking
against the terminal benzene ring of compound 1 ( figure 4b ) .
the backbone atoms of residues 4345
also move closer into the sy21-binding pocket by 0.50.8 ,
allowing a closer contact between asn45 and the urea linker .
in addition to polar interactions , compound 1 establishes
extensive hydrophobic interactions with val18 , leu42 , and val49 ( figure 4b ) .
the proximal benzene ring nestles in the hydrophobic
pocket formed by val18 and leu42 , making many nonpolar contacts .
the
distal benzene ring is also within van der waals contact distance
with val491 , although the interactions with val49 can be further
optimized .
in fact , most of the terminal benzene ring seems to suspend
in solution past the pocket , suggesting that this part of the ligand
can be further optimized to enhance binding to the chemokine .
it also
highlights the rigidity of the urea linker , which is further immobilized
by the multiple hydrogen bonds as described above .
these observations
suggest additional carbon atoms may be introduced into the linker
to allow adequate flexibility in future lead compounds , which we are
currently investigating .
( a ) cxcl12heparin
sulfate crystal structure ( pdb i d : 2nwg ) positions haparin sulfate ( yellow ) in
the region where sy12 of cxcr4138 normally binds .
( b ) cxcl12compound 1 crystal structure with heparin
sulfate ( yellow ) and sy12 ( purple ) superimposed in sy12 site suggests
that compounds specific to both sites could potentially be linked
together via linkers .
we have previously shown that compound 1 is
a fragment
that binds cxcl12 .
nmr perturbation studies
have placed the compound in the sy21-binding site , but its binding
pose was largely unknown ( figure 2b ) .
molecular
docking successfully predicted the correct orientation of the compound
and assisted us with previous optimization efforts .
docking however
was unable to identify all the possible hydrogen bonds because it
did not predict the protein conformational changes induced upon binding
such as changes in glu15 and arg47 .
the complex crystal structure ,
therefore , has not only confirmed binding but has shed light on crucial
interactions for the first time , previously overlooked through other
complementary methods such as nmr and molecular docking . as
the sy21-binding site also resides close to the crystal - packing
interface
, the binding of compound 1 has caused additional
conformational changes in residues from neighboring molecules in the
crystal lattice .
an alternative conformation is observed for his17
from a symmetry - related molecule in order to relieve a possible steric
clash with the tetrazole group by the original conformation .
we attempted
to investigate whether crystal packing may influence the binding pose
of compound 1 by using crystals of r8a , h17a , and r8a / h17a
mutants for the soaking experiments .
unfortunately , compound 1 was not observed in these crystals , possibly because the
positive charges of these two residues can nonspecifically increase
the chances of incorporating the negatively charged compound 1 into the binding pocket , an unintended but useful effect
considering the challenges faced in crystallizing complexes with weak
ligands .
it should also be noted that his17 in monomer 1 is part of
the sy21-binding site and may directly contribute to ligand binding
through electrostatic interactions .
the
binding of compound 1 and the cxcr4138 peptide to the same sy21-binding site ( pdb i d : 2k05 ) ( figure 4b , c ) share many similarities yet demonstrate key
differences .
both compound 1 and sy21 are negatively
charged at physiological ph and interact with many of the same protein
residues in a series of hydrogen bonds , including glu15 , asn22 , and
arg47 .
these interactions highlight the overall positively charged
and highly polar environment of the binding site . however , the sulfate
group of sy21 and the tetrazole group of compound 1 reside
in different areas of the binding pocket , with the former hydrogen
bonding with asn22 , asn46 , and arg47 and the latter with asn22 and
the backbone n atom of ala19 .
the conformations of glu15 and arg47
also differ in the two complexes . the most significant difference ,
however , lies in the more extensive hydrophobic interactions observed
in the complex with compound 1 .
the aromatic ring of
sy21 is placed perpendicularly and relatively superficially on the
protein surface in a corner of the pocket formed by val18 , leu42 ,
and val49 , while the benzene ring of compound 1 lays
flat on the center of this small hydrophobic cavity .
some
of the differences we have observed between the two complexes
undoubtedly come from the structural ambiguity in nmr structures ,
particularly in terms of side chain conformations , as well as from
the structural biases imposed by crystal packing , especially the lack
of protein flexibility .
however , although cxcl12 exhibits much flexibility
in solution , its core domain including the majority of the sy21-binding
site displays much less variation among different nmr conformations
as well as various crystal structures .
this is particularly true for
the hydrophobic cavity and the peptide segment spanning his17 to asn22 .
asn45 or asn46 each makes one hydrogen bond
with the ligand in the respective complex .
although certain interactions
involving these residues may have been missed in the nmr or crystal
structures due to the limitations of each technique , it is unlikely
that such experimental caveats have drastically distorted the ligand - binding
mode .
cxcl12 was previously
crystallized in complex with an unsaturated heparin disaccharide ,
revealing structural details of the interactions between glycosaminoglycans
and cxcl12 .
only one of them , residing
at the dimer interface , was deemed biologically relevant , whereas
the other one was most likely a crystallization artifact .
the heparin - binding
site at the dimer interface is characterized by a high concentration
of positively charged residues , including his25 , lys27 , and arg41
from both cxcl12 monomers ( figure 5a ) .
it is
not surprising that the disaccharide , with four negatively charged
functional groups , binds to this area .
most of the intermolecular
interactions are mediated through a series of hydrogen bonds involving
the charged moieties exposed to the solvent .
only one nonpolar contact
is observed between the disaccharide and a hydrophobic residue , leu29
( figure 5a ) .
these observations suggest that
the binding surface for the heparin molecule may be less suitable
for engineering small molecule ligands compared with the sy21-binding
site .
the fact that we observed nonspecific binding of dmso to the
sy21-binding site in our control crystals also highlights the features
of that binding surface suitable for small molecule interactions .
the
current complex structure provides important information for structure - based
inhibitor design .
it highlights the urea linker as an optimal anchor
in hydrogen bonding interactions ; the rotation of glu15 , along with
the arrangement of asn45 and arg47 , creates an ideal hydrogen - bonding
network with the urea linker of compound 1 .
this also
suggests that amide linkers are not as efficient as urea linkers because
an amide linker can only form one hydrogen bond with glu15 compared
to the two hydrogen bonds that the urea linker is forming in the crystal
structure .
this difference has been exemplified through our docking
studies that appropriately position amide - linker derivatives in the
sy21-binding site , showing that only one hydrogen bond can form between
the amide and glu15 .
the crystal structure not only identifies
the important interactions between compound 1 and cxcl12
but also elucidates unoccupied potential hot spots for ligand binding .
the terminal benzene extends into a cleft that contains both polar
and nonpolar residues , characteristics that can be exploited in optimization
efforts ( figure 5b ) .
particularly , this cleft
contains several nonpolar residues including pro10 , leu29 , and val39
( figure 5a ) .
it resides on the edge of the
heparin - binding site and interacts with sy12 in the complex structure
with the cxcr4138 peptide ( figure 5b ) . whereas heparin fails to fully utilize the nonpolar binding
surface ,
consequently , in order to leverage these
binding hot spots in our ongoing project of inhibitor design efforts ,
extra carbon atoms were added after the urea linker of the current
inhibitor scaffold for increased flexibility . a docking pose prediction
of compound 2 , which differs from compound 1 through an additional two - carbon linker after the urea , suggests
that a more flexible linker may increase hydrophobic interactions
( figure 6a ) .
this hypothesis is supported by
nmr that shows compound 2 inducing chemical shift perturbation
of val39 , suggesting the terminal benzene may better interact with
the cleft .
additionally , in a chemotaxis assay with thp-1 cells , 25
m of compound 1 causes a 20% decrease
in cell migration , while 25 m of the more flexible compound 2 causes a 40% decrease in cell migration , further
supporting the potential benefits of linker flexibility ( figure 6b ) . docking pose and chemotaxis inhibition .
( a ) compound 2 is based on the compound 1 scaffold but contains
an
additional two - carbon linker past the urea .
docking pose prediction
suggests the flexible linker may help increase hydrophobic interactions
with the cleft above val39 .
( b ) chemotaxis assay in thp-1 cells demontrates
that 25 m compound 1 reduces cell migration by
20% , while 25 m compound 2 reduces cell
migration by 40% .
although the sy12-binding site appears to be a more challenging
target by itself , these observations suggest that small molecule ligands
can be designed to span from the sy21-binding site into the sy12-binding
site or even further into the heparin binding site .
this would further
improve the affinity and specificity of the novel ligand , increasing
its utility in disrupting the cxcl12cxcr4 signaling axis and
establishing a strategy for chemokine targeted therapies across the
entire chemokine family .
the cxcl12cxcr4
signaling axis has been a key target for
drug discovery due to its involvement in various diseases , particularly
cancer .
however , as most drug discovery efforts against
cxcr4 have failed in clinical trials due to toxicity issues , the need
for alternative approaches has become apparent .
we have previously
demonstrated that a structure - based approach can successfully identify
compounds that bind to the sy21-binding site on cxcl12 . even though
binding of inhibitors was confirmed
our new complex structure not only validates the binding
of ligands to the protein but also offers invaluable information to
guide further optimization efforts through a rational design approach .
furthermore , because sulfotyrosine recognition by chemokines is predicted
to contribute to most chemokine receptor interactions , successfully
targeting such sites could potentially extend to targeting other chemokines
as well .
the purity of
the protein and compounds 1 and 2 ( supporting information ) was determined to be
> 95% by sds - page and hplc , respectively .
nmr data was collected on a bruker
avance 600 mhz spectrometer equipped with a tci cryoprobe at 298 k.
lyophilized [ u - n]-cxcl12wt was reconstituted in a 25 mm deuterated mes , 10% ( v / v ) d2o , 0.02% ( w / v ) nan3 buffer , ph 6.8 .
nmr samples of 50
m cxcl12wt and 01600 m compound 1 were made with a leap pal robot , where each sample contained
2.0% deuterated dmso .
a bruker samplejet was used for automated sample
handling and hn heteronuclear multiple
quantum coherence ( hmqc ) spectra were collected for each titration
point .
spectral data was processed with in house scripts , and chemical
shift changes were tracked using cara software .
the qiagen jcsg suites
were screened using the phoenix microdispenser , and hits were optimized
and tested for space group determination .
hits that led to crystals
with a trigonal space group ( e.g. , pdb i d : 3gv3 ) were unsuccessful in binding compound 1 because the sy21-binding site was completely blocked by
crystal packing residues .
hundreds of small crystals appeared in a
condition containing 3.5 amso4 , 1%mpd , and 0.1 m mes sodium
salt , ph 6.5 . these were optimized ( 2 m amso4 , 2% mpd ,
and 0.1 m mes sodium salt , ph 6.5 ) to consistently produce a few and
large single crystals .
one form belonged to the ineffectual trigonal space
group , while the other belonged to an orthorhombic space group ( e.g. ,
pdb i d : 2j7z ) .
because crystals belonging to two different space groups
would form in the same crystallization drop , seeding was used to induce
crystallization of the orthorhombic space group instead of the trigonal
space group form .
crystals belonging to the p212121 space group would grow to their
full size in 34 days , measure up to 400 m in each dimension ,
and diffract up to 1.8 .
attempts to grow complex cxcl12
crystals in the presence of compound 1 were unsuccessful .
we therefore used a soaking method . because
compound 1 was insoluble at high concentrations , we resorted
to introducing it in its solid powder form at various amounts directly
on the crystal drop .
soaking was also performed for only 30 min because
compound 1 would quickly degrade the crystals upon introduction .
crystals were then flash - frozen in 2.2 m amso4 , 25% glycerol ,
2% mpd , and 0.1 m mes sodium salt , ph 6.5 .
data sets were collected
for many crystals in the search for the best candidate because solubility
issues with compound 1 produced inconsistent results
with compound density while damaging a lot of the crystals .
data was collected at
the moffitt cancer center home source with a rigaku raxis detector .
data was processed with xds , and the
structure was solved through molecular replacement ( using pdb i d : 2j7z ) with molrep and refinement with refmac5 and pdb_redo .
the structure has been
deposited into the protein data bank with accession code 4uai .
dock 3.5.54 was used to dock compound 2 into an ensemble of 21
protein conformations ( 20 nmr conformations from pdb i d 2k05 and the current
x - ray structure ) .
compound dilutions were prepared in
100% dmso and added to aliquots of a rpmi 1640 , 25 mm hepes , and 0.2%
( w / v ) bsa buffer and were centrifuged at 15000 rpm for 20 min at 4
c .
a 250 l aliquot of 25 m compound 1 or 2 along with 30 nm cxcl12wt was added
to the lower well of a corning hts transwell 96-well plate . thp-1
cells were washed twice in buffer , and 6 10 cells
were added to the upper well .
plates were incubated for 2 h at 5% co2 and 37 c , and migrated cells in the lower well were counted
on a bd lsr ii flow cytometer .
bar graph is the mean sem of
four replicates on two separate plates ( n = 8) .
significance
was determined by a two - tailed , unpaired student s t test .
|
### Summary:
: cxcl12
binds to cxcr4 , promoting both chemotaxis of lymphocytes
and metastasis of cancer cells .
we previously identified small molecule
ligands that bind cxcl12 and block cxcr4-mediated chemotaxis .
we now
report a 1.9 resolution x - ray structure of cxcl12 bound by
such a molecule at a site normally bound by sy21 of cxcr4 .
the complex
structure reveals binding hot spots for future inhibitor design and
suggests a new approach to targeting cxcl12cxcr4 signaling
in drug discovery .
|
<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: dna damage , such as dna single- or double - strand breaks ( dsbs ) , is known to occur in aging [ 1 , 2 ] as well as in alzheimer 's disease ( ad ) [ 26 ] .
recently dsbs were shown to be produced by a or amyloid- peptides [ 7 , 8 ] through oxidative stress . furthermore , a peptides not only increase neuronal vulnerability ( e.g. , apoptosis ) in dna - dependent protein kinase ( dna - pk ) deficient mice , a key enzyme of the nonhomologous end joining ( nhej ) pathway involved in dsbs repair , but also reduce the activity of this enzyme [ 11 , 12 ] . thus ,
extracellular a peptides trigger dsbs production and impair dsbs repair . however , if numerous factors are contributing to the formation or increased levels of a peptide , such as mainly age , the apoe4 allele , cholesterol rich food , or glucocorticoid stress hormone dexamethasone , others factors , such as the apoe2 allele and the growth factor bdnf , are neuroprotective [ 13 , 14 ] or participate in adaptive cellular responses . among them , some even diminishes dna damage .
this is the case of glutamine that reduces etoposide - induced damage and of nad that attenuates a-induced dna damage . in this study
we were particularly interested in all - trans retinoic acid ( ra ) [ 1720 ] , a derivative of vitamin a .
ra is known to be involved in development , neuronal differentiation , spine formation through the rar receptor , cell growth arrest in anticancer therapy , and memory decline in aging [ 2527 ] .
the neuroprotective role of vitamin a and ra in relation to ad and to the -amyloid cascade not to dna dsbs has intensively been studied , for example , .
firstly , ra was shown to increase , via its rar receptor , the expression of the major -secretase , adam10 ( a disintegrin and metalloproteinase domain - containing protein 10 ) , diminishing the production of a peptides .
this effect is mediated by ra - responsive elements upstream of the adam10 coding region [ 30 , 31 ] .
ra can also inhibit the -secretase activity through activation of the extracellular signal regulated kinase , erk1/2 .
secondly , vitamin a and its derivatives appear to inhibit a oligomerisation in vitro , a deposition , and tau phosphorylation in ad mouse models .
thirdly , rar signaling removes a plaques and induces a oligomers clearance via neprilysin and insulin degrading enzyme . on the contrary
, a is increased in the cerebral vasculature while rar is decreased in the neocortex of rats maintained on a 1-year retinoid - deficient diet . finally , following a ra treatment in app / ps1 double - transgenic mice , a deposits ,
aicds ( the amyloid precursor protein internal c - terminal domains ) , tau phosphorylation , and glial response were decreased , whereas spatial learning was improved .
ra by binding to them allows the formation of rar / rxr heterodimers and the replacement of corepressors , such as hdac ( histone deacetylase ) , by coactivators , such as cbp ( creb - binding protein ) .
the histone acetyltransferase activity of cbp and the down - regulation of dna methyltransferases result in ra - dependent transcription .
indeed , ra hypomethylates promoters , such as the one of rar2 or of methyltransferases , altering gene transcription . according to these data , we wondered if ,
as a consequence of local chromosome relaxation , dna repair proteins , such as the catalytic subunit of dna - pk and ataxia telangiectasia mutated kinase ( atm ) , could be recruited at chromosome sites of ra - dependent gene expression and if dsbs could be repaired at these sites . we have investigated whether ra and its receptor ( rar ) might be involved , not in prevention of a synthesis , a oligomerisation , and plaques removal , as already shown , but in repair of a-induced dsbs .
we showed to our knowledge for the first time that this is indeed the case by studying neuronal and astrocytic cell lines as well as neocortical tissue from young and old mice .
furthermore , we examined the repair mechanisms involved and the consequences on cell viability , in the search for effective early ad therapies .
c57bl/6j male mice ( janvier , le genest - st - isle , france ) were sacrificed at 4 months ( young adults ) and at 16 months ( aged adults ) .
brains were quickly removed and cortices dissected under a binocular microscope , weighted , and homogenized ( about 5 sec with a polytron apparatus , vwr international ) in neurobasal medium ( gibco life technologies ) .
human sh - sy5y cells ( european collection of animal cell culture , uk ) were routinely grown in a 37c incubator containing 5% co2/95% humidified air in rpmi-1640 ( gibco life technologies ) with 10% fcs ( bioconcept , switzerland ) , 2 mm l - glutamine ( gibco life technologies ) , 100 iu / ml penicillin g , and 100 g / ml streptomycin ( invitrogen ) .
the confluent cells were released in dpbs ( 150 mm nacl , 3 mm kcl , 1.5 mm kh2po4 , 7.9 mm na2hpo42h2o , and 0.1 mm edta ; ph 7.4 ) , centrifuged at 1000 rpm during 5 min , and resuspended in rpmi-1640 and 10% fcs at the desired dilution .
the di tnc1 cell line [ 38 , 39 ] was grown in dmem medium ( sigma ) supplemented with 10% fcs in a 37c incubator containing 5% co2/95% humidified air .
confluent cells were released in trypsin solution ( 0.25% ) , centrifuged at 1100 rpm during 5 min , and resuspended in dmem with 10% fcs at the desired dilution .
cells were photographed with an inverted phase contrast microscope ( zeiss telaval 31 ) using a photo camera ( leica dfc 490 ) with the firecam analyst software ( leica ) .
for the cell treatments , two days before experiment , the medium with 10% fcs was replaced by the medium with 1% fcs .
the cultured cells and the homogenized cortical tissue ( see before ) were treated or not with 20 m monomeric a142 peptides ( enzo life sciences ) , during the first 30 min , then with or without 5 m ra ( sigma - aldrich ) for 30 more min , resulting in four combinations of 2 30 min treatments ( - ; a142- ; - ra ; a142-ra ) .
other treatments were carried out with 20 m a421 , 20 m a140 ( enzo life sciences ) , 10 m rar/ agonist am80 ( santa cruz biotechnology ) , 150 m rar// antagonist agn 193109 ( labforce ) , 50 m caspase-3 inhibitor z - vad - fmk ( santa cruz biotechnology ) , 3 m hdac inhibitor trichostatin a ( tsa ; sigma ) , 10 m inhibitor of ataxia telangiectasia mutated kinase or atm ku 55933 ( ku ; labforce ) , and 150 m inhibitor ii of the catalytic subunit of dna - pk nu 7026 ( nu ; calbiochem ) , in combination with ra and/or a142 for 30 min or 24 h. all treatments were carried out in triplicate in a 37c incubator containing 5% co2 and 95% humidified air .
dsbs were measured in sh - sy5y cells , in di tnc1 cells , and in the homogenized cortical tissue using trevigen comet assaytm kit ( ams biotechnology , uk ) with the following modifications . after treatment
, cells were resuspended in ice - cold ca and mg free pbs to a concentration of 1.0 to 1.5 10 cells / ml . the same number of cells from the dissociated cortical tissue was resuspended in the same solution with the addition of 20 mm edta and processed as for the cell cultures .
an aliquot of 50 l cells was added to 500 l of 1% molten low - melting agarose ( seaplaque , fmc bioproduct , usa ) kept at 42c .
fifty microliters was immediately spread on a comet slide ( ams biotechnology ) , which was incubated at 4c in the dark for 10 min to accelerate agarose gelling and then transferred to prechilled lysis solution ( ams biotechnology ) for 60 min at 4c .
subsequently , the slide was incubated in neutral electrophoresis buffer ( 500 mm tris base , 1.5 m sodium acetate , ph 9.0 ) for 30 min at 4c .
then , the slides were immersed in 70% ethanol at room temperature for 30 min and air - dried .
dna was stained 10 min at room temperature with 100 l sybr green i dye ( gibco life technologies ) diluted 1 : 1000 in water and then rinsed with distilled water .
comets of at least 30 cells per treatments were immediately photographed using an olympus digital camera attached to an olympus bx51 epifluorescence microscope ( axio vision rel .
4.6 ) . to visualize the average tail length of a treated cell population , 10 l of sh - sy5y cells ( 1 10 cells / ml ) was mixed with 5 l lysis buffer ( ams biotechnology ) for 5 min at 4c and then 1.5 l tris edta
the whole sample was loaded into a slot of 1% agarose mp gel ( roche life science ) . a 1 kb ladder ( invitrogen )
the agarose gel was stained by ethidium bromide ( 10 mg / ml ) and analyzed with a gs-700 imaging densitometer ( bio - rad ) .
signal intensities were measured with the molecular analyst software program ( bio - rad ) .
cortices of 4- ( n = 3 ) and 16-month - old c57bl/6j male mice ( n = 3 ) were mechanically dissociated and fixed for 30 min at room temperature in 4% paraformaldehyde in pbs on coverslips pretreated with 100% alcohol . after rinsing for 3 5 min with pbs
, cells were incubated for 1 h30 with the primary antibody diluted in pbs . the mouse monoclonal anti - biii - tubulin antibody ( sigma ) ,
diluted 1 : 1000 in pbs , and the mouse monoclonal anti - glial fibrillary acidic protein antibody ( gfap , sigma ) , diluted 1 : 500 , were used .
after rinsing for 5 min with pbs , coverslips were incubated for 1 h at room temperature with the secondary anti - mouse igg antibody coupled to alexafluor 488 ( molecular probes / invitrogen ) , diluted 1 : 1000 , in presence of dapi ( 1.0 g / ml , sigma ) and rinsed for 3 5 min with pbs , and then mounted on glass slides fixed with fluorsave ( calbiochem ) . nine to twelve pictures of immunostained cells , corresponding to 34 to 69 cells , were taken for each mouse using a zeiss axioskop 2 plus microscope ( carl zeiss , feldbach , switzerland ) equipped with epifluorescence and were digitalized with an axiocam camera .
for assessing cell viability of sh - sy5y cells and di tnc1 cells , 20000 cells / well were grown in 1 ml rpmi-1640 with 10% fcs for 68 days and , two days before the experiment , the medium was replaced by rpmi-1640 with 1% fcs . for the cortical tissue , 1 mg freshly homogenized tissue was resuspended in 1 ml of the same medium .
the cells were treated or not during 30 min with 5 m ra and/or 20 m a142 monomers or 3.3 l digitonin ( celltiter - glo luminescent cell viability assay , promega ) used as a positive control to decrease cell viability .
100 l of cell suspension was shaken for 2 min with 100 l of celltiter - glo reagent prepared according to the manufacturer ( celltiter - glo luminescent cell viability assay , promega ) to induce cell lysis and to release the cell atp content , as indicator of metabolic activity .
after 10 min incubation at room temperature , luminescence ( in relative light units ) was recorded with a luminometer ( glomax 20/20 , promega ) .
medium without cells or tissue samples resulted in background luminescence . for assessing caspase-3 and caspase-7 activation , sh - sy5y cells were grown in 1 ml rpmi-1640 with 10% fcs .
two days before the experiment , the medium was replaced by rpmi-1640 with 1% fcs .
cells were treated or not during 30 min or 24 h with 20 m a142 , 50 m z - vad ( in dmso , merk ) , or 100 nm staurosporine ( sigma - aldrich ) .
100 l of cell suspension was mixed for 2 min with 100 l of caspase - glo 3/7 reagent prepared according to the manufacturer ( caspase - glo 3/7 assay , promega ) to induce cell lysis and cleavage of a luminogenic substrate of caspase-3/caspase-7 .
after 1 h30 incubation at room temperature , luminescence was recorded with a luminometer ( glomax 20/20 , promega ) . a control without cells was also used .
for the comet assay , values of mean comet tail length were compared for each condition by a one - way analysis of variance ( anova ) to establish the effects of various treatments .
when overall statistically significant differences in treatments effect were obtained by anova , comparisons of means among subgroups were made after bonferroni corrections . in parallel
, the nonparametric kruskal - wallis test was used to compare the shape of comet tail distribution also with bonferroni corrections to compare subgroups .
the kruskal - wallis analysis is particularly suitable when the number of measures is small ( less than 15 per group ) or when the distribution is not gaussian ( asymmetric box plot ) . level of significance is p < 0.05 .
to demonstrate that ra can repair a-induced dsbs , sh - sy5h cells and astrocytic di tnc1 cells were treated with a142 for half an hour before the addition or not of ra for also 30 min .
the presence of ra resulted in shorter tail lengths comparable to untreated lysed cells ( figures 1(a ) and 1(b ) ) .
the mean comet tail length was significantly higher in a treated sh - sy5y cells as well as di tnc1 cells compared to all other treatments ( figures 1(c ) and 1(d ) ) .
these results were corroborated by an independent experiment showing on an agarose gel comet tails starting from their cell nuclei loaded into the gel 's slots .
short dna fragments between about 0.85 kb and 3.0 kb were generated more frequently when a was present and were reduced in number in presence of ra ( figure 1(e ) ) .
apoptotic fragments of n 180 bp could not be detected , suggesting that apoptosis was not activated under these 30 min treatments .
quantification of signals intensities up to the gel 's slots revealed that dsbs were almost halved when ra was added after a ( figure 1(f ) ) .
we demonstrated that dsbs are induced specifically by the a142 peptide and not by the nonpathological a140 form or a control peptide with the reverse sequence a421 , all treatments being carried out for 30 min with 20 m a peptides ( figure 2(a ) ) .
furthermore , a dose - response curve ( figure 2(b ) ) showed that ra repairs dsbs most efficiently at concentrations between 1 m and 50 m , with a peak of maximal efficiency at 5 m , whereas it had no effect at 0.5 m or 500 m .
using a cell viability assay , we observed that a treatment with 0.5 m ra ( 101.3 15.3% ) and 1 m ra ( 103.8 8.6 ) resulted in a similar viability compared to that of the untreated cells ( 100 10% ) .
however , the viability increased at 5 m ra ( 135.8 30.8% ) , 10 m ra ( 152 12.7% ) , and 50 m ra ( 126 30.2 ) but dropped at 500 m ra ( 27.1 2.1 ) ( n = 3 ) .
furthermore , we demonstrated in sh - sy5y cells that the rar/ agonist am80 used at a concentration of 10 m had the same effect compared to ra ( figure 2(c ) ) .
moreover , no significant difference was observed between am80 and ra suggesting that in sh - sy5y cells the rar/ receptor was sufficient to mediate all dsbs repair activity , thus excluding the involvement of other potential receptors , such as ppar/ . finally , the addition of 1 m rar// antagonist agn 193109 to 5 m ra significantly impaired the diminution of dsbs due to the ra treatment .
this effect was even increased with a higher concentration of agn ( 50 m compared to 1 m ) , clearly demonstrating that the binding of ra to its rar is needed to repair dsbs ( figure 2(d ) ) .
ra added half an hour after the a142 treatment can also repair dsbs in cells originating from the murine cortex of young ( n = 3 ) and aged c57bl/6j mice ( n = 3 ) .
the presence of ra resulted in shorter tail lengths comparable to untreated lysed cells and cells treated with ra alone ( figures 3(a ) and 3(b ) ) .
the mean comet tail length was significantly higher in a treated cortical cells compared to all other conditions in the young as well as in the aged mice ( figures 3(c ) and 3(d ) ) .
however , the difference in mean comet tail lengths between the a treatment and the other conditions was less important in the aged compared to the young mice possibly due to a decreased metabolism . indeed , the difference between the a and the a + ra treatment was statistically different in all 3 young mice , but only in 2 aged mice out of 3 .
we further showed by immunocytochemistry ( figure 3(e ) ) that the cells analyzed in the comet assay consist in neurons ( 68% for pooled age groups ) as well as astrocytes ( 26% ) and that the ratio of astrocytes / neurons ( 0.38 ) was similar to that reported in the literature ( figure 3(f ) ) . to ascertain the mode of action of ra via its receptor rar ,
sh - sy5y cells were treated with histone deacetylase ( hdac ) inhibitor trichostatin a ( tsa ) .
we observed that tsa decreased mean tail length produced by a as efficiently as ra ( figure 4(a ) ) .
moreover , dsbs were significantly decreased in cells treated with tsa + ra compared to ra treated cell , suggesting a possible synergetic effect of both chemicals as they act at different sites of the same receptor complex . moreover ,
the inhibition of the ra repair activity was shown to be mediated both by atm using atm inhibitor ku 55933 and by dna - pk using dna - pk inhibitor nu 7026 ( figure 4(b ) ) .
the atm inhibitor induced as many dsbs as the dna - pk inhibitor or the a treatment . in presence of ra , inhibition of both pathways , but not of only one , produced a similar amount of dsbs as the a treatment .
thus , both atm and dna - pk protein kinases need to be present , so that ra is able to repair dsbs in sh - sy5y cells .
only this last compound resulted in cell death after 24 h , but not after 30 min treatment ( figure 5(a ) ) .
however , in these cells , caspase-3 was already active after 30 min as demonstrated by z - vad treatment ( figure 5(b ) ) .
staurosporine was activating caspase-3 and caspase-7 after 30 min and even more after 24 h compared to the untreated cells .
however , statistical significance was not reached comparing control treatment to staurosporine treatment , even if a tendency towards significance increased at 24 h ( p = 0.08 ) compared to 30 min ( p = 0.92 ) .
after 30 min , caspases were already activated but cell death was not observed , whereas after 24 h cells were dead and caspases could not be activated further .
a comet assay carried out under the same conditions ( figure 5(c ) ) revealed that the mean comet tail length was not diminished by z - vad in presence of a after 30 min compared to the a treatment . in this case , dsbs were not due to activated caspase-3 .
after 24 h , the mean comet tail length was significantly reduced by z - vad in presence of a suggesting the production of dsbs due to activated caspase-3 .
overall , a-induced dsbs appear not to be related to proapoptotic events after 30 min treatment .
furthermore , cell viability was measured by quantification of intracellular atp in comparison to cells lysed by digitonin .
after 30 min a treatment in presence or not of ra , di tnc1 cell viability was neither decreased nor increased , whereas it was the case subsequent to the digitonin treatment ( figure 5(d ) ) .
cells from 4-month - young neocortical tissue showed after 1 h a much higher viability than cells from 16-month - old tissue ( figure 5(e ) ) , suggesting a higher fragility of the latter tissue in the in vitro conditions .
overall viability dropped after 30 min a treatment due to decreased intracellular atp in the young tissue ( p = 0.001 ) .
however , this decrease was less significant when ra was added to a for both young and old cortical tissues ( p = 0.036 ) .
we observed an increase in viability of about 53% for the young tissue and of about 59% for the old tissue , indicating that under the experimental conditions ra enhances viability at a time when dsbs are being repaired .
our main observation is that ra is involved in a-induced dsbs repair in neuronal and astrocytic cell lines as well as in the cortical tissue , likely in cortical neurons as well as astrocytes , and in young and even in aged mice .
this was shown by two independent methods : comet assay and gel electrophoresis with sh - sy5y neuroblastoma cells .
thus , according to these data , ra and its receptor ( rar ) are involved not only in the prevention of a synthesis , a oligomerisation , and plaques removal , as already shown [ 29 , 3234 , 36 ] , but also in the a-induced dsbs repair .
we choose to grow sh - sy5y and di tnc1 cells in presence of fcs 1% instead of fcs 10% . in both cases ,
a induced significantly more dsbs , but in the former condition cells were more differentiated as in the cortical tissue .
l - glutamine was also added as it is already known to protect against dsbs formation and only the effect of ra had to be tested .
l - glutamine was equally added to the homogenized cortical tissue but b27 supplement was avoided as it contains ra .
interesting was the observation that only the most pathological form of a , a142 , was inducing dsbs in both of the sh - sy5y and di tnc1 cells , suggesting that a142-induced dsbs might play a role in alzheimer 's pathology .
noteworthy is also the fact that a142 treatment appeared to be less efficient in inducing dsbs in the aged than in the young murine cortical tissue .
this can not be due to the state of the a that corresponds to a mixture of monomer and oligomers in both cases but rather to the state of the tissue , such as a lower metabolism of the aged cortical tissue .
ra has been shown to reduce dsbs in a concentration - dependent manner in sh - sy5y cells .
5 m ra appears to be optimal for decreasing dsbs and increasing cell viability , that is , atp concentration , compared to the untreated cells .
higher or lower ra concentrations resulted in unchanged dsbs levels compared to the control cells , whereas increased ra concentrations only decreased cell viability .
this variation of ra effect according to its concentration is compatible with the observation that when neuronal activity is low , endogenous ra synthesis is locally activated in order to maintain the structures of neurons ( homeostatic synaptic plasticity ) and that conversely ra synthesis decreases when neuronal activity increases .
it has to be observed that the dsbs levels following the ra treatments were not consistently lower than the background dsbs levels of the untreated samples .
this phenomenon might be due to variations of endogenous ra levels in relation to cell differentiation or division .
furthermore , ra was shown to decrease a-induced dsbs through the rar/ receptors by using the am80 agonist and the agn 193109 antagonist .
the agonist being as effective as ra in reducing dsbs , an effect of ra through another receptor , for example , rxr - ppar/ , appears excluded in sh - sy5y cells .
the observation that the hdac inhibitor tsa , which enables derepression of retinoic acid response element - dependent gene expression , results in a similar decrease of a-induced mean comet tail length as ra strengthens the role of rar in repair of a-induced dsbs .
reparation might occur either through expression of genes involved in dsbs repair or more directly through chromatin decondensation at sites of ra - dependent gene expression allowing access to proteins involved in dsbs repair .
however , its inhibitor nu 7026 , used at a concentration of 150 m , resulted only in a partial repair of a-induced dsbs compared to the ra treatment . a concentration effect of nu was excluded as a dose - response curve demonstrated that mean comet tails lengths reached a maximum size at 150 to 250 m nu and decreased significantly at 50 to 100 m nu ( data not shown ) .
the atm inhibitor , ku 55933 , resulted equally in a partial repair of a-induced dsbs .
we showed in sh - sy5y cells that both of dna - pk and atm , known to be complementary [ 45 , 46 ] , enable the complete counteracting effect of ra on dsbs production . we observed that short - term ( not long - term ) treatment with a is not decreasing cell viability or causing cell death and that caspase-3 was activated at the same level in presence of a or not in sh - sy5y grown with 1% fcs .
indeed , even staurosporine is known to induce neurite outgrowth in the short term before inducing cell death and apoptotic dna fragments in the long term .
we also did not observe apoptotic fragments of n 180 bp after 30 min a treatment , suggesting that apoptosis is not yet activated under these conditions .
however , at that time , dsbs are induced by a , and if not repaired in the longer term , they might be deleterious .
furthermore , in the short time , ra can repair dsbs and appears even to increase viability in the cortex of young and to a lesser extent of aged mice .
the fact that ra is repairing dsbs as am80 and trichostatin a and that both of them alter memorization [ 49 , 50 ] suggests a similar role for ra .
we make the hypothesis that whereas a produces dsbs , ra results in targeted error - prone repair of the subset of dna regions with ra - dependent gene expression , involved in particular in neuronal or synaptic maintenance .
this process of selective dna repair might result in a neuronal state adapted to the metabolic changes occurring with aging .
this phenomenon of dsbs production and repair - dependent adaptive gene expression ( dsb - prae hypothesis ) would remain functional up to a pathological threshold reached by a increase and ra decreased response with aging and might be an explanation for the role of dsbs in memorization . in conclusion , we have found that ra repairs a-induced dsbs in neural cells of the cerebral cortex .
our data are in favor of a role of ra in increasing neural viability and also possibly in providing a neuronal adaptive response .
furthermore , our data suggest that a better knowledge of the mechanisms involved in a-induced dsbs might provide additional means to target pathological a-induced changes , not just by impairing the a-amyloid cascade but by repairing some of its consequences .
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### Summary:
: the amyloid- peptide or a is the key player in the amyloid - cascade hypothesis of alzheimer 's disease .
a appears to trigger cell death but also production of double - strand breaks ( dsbs ) in aging and alzheimer 's disease .
all - trans retinoic acid ( ra ) , a derivative of vitamin a , was already known for its neuroprotective effects against the amyloid cascade .
it diminishes , for instance , the production of a peptides and their oligomerisation . in the present work we investigated the possible implication of ra receptor ( rar ) in repair of a-induced dsbs .
we demonstrated that ra , as well as rar agonist am80 , but not agn 193109 antagonist , repair a-induced dsbs in sh - sy5y cells and an astrocytic cell line as well as in the murine cortical tissue of young and aged mice .
the nonhomologous end joining pathway and the ataxia telangiectasia mutated kinase were shown to be involved in ra - mediated dsbs repair in the sh - sy5y cells .
our data suggest that ra , besides increasing cell viability in the cortex of young and even of aged mice , might also result in targeted dna repair of genes important for cell or synaptic maintenance
. this phenomenon would remain functional up to a point when a increase and ra decrease probably lead to a pathological state .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: alzheimer 's disease ( ad ) is the most common cause of dementia in the general population
. clinical diagnosis of ad is based on a history of progressive and characteristic cognitive decline and the presence of objective cognitive deficits .
exclusion of other diagnoses such as depression , hypothyroidism , other dementias and non - ad brain lesions is an integral part of the diagnostic evaluation.1 since ad is the most common type of dementia and its burden is expected to grow substantially owing to aging of the population , improving the diagnostic accuracy of ad is critical .
these examinations are important not only to identify non - ad pathological processes that can lead to cognitive decline ( e.g. brain tumors or cerebrovascular disease ) but also to search for biological markers that provide supportive features for the diagnosis of ad .
these include medial temporal lobe atrophy as assessed with magnetic resonance imaging ( mri ) and reduced glucose metabolism in temporoparietal regions on functional neuroimaging with f - fluorodeoxyglucose - positron emission tomography ( fdg - pet).2
though there is no test to diagnose ad accurately in vivo , in the past few years advances in neuroimaging technology have changed our understanding of ad .
this review will focus on recent neuroimaging studies of ad that provide relevant information to clinical practice .
amyloid imaging and discuss whether such technique can be combined with innovative methods of data processing and analysis to improve ad diagnostic accuracy . over the past decades , many research investigations have applied neuroimaging techniques to gather information about the anatomical and functional brain changes related to ad .
table 1 summarizes the clinical utility of neuroimaging modalities used in patients with suspected ad .
thanks to major improvements in image acquisition , processing and analysis , these studies have conducted detailed assessments of the human brain in vivo comparing groups of patients with dementia and unaffected elderly volunteers .
a very brief summary of clinically relevant neuroimaging findings in samples of patients with ad is presented in table 2 .
mri has become the most used tool for cerebral imaging in vivo for the assessment of dementia , as it provides detailed information about brain structure , thus allowing the characterization of regional brain atrophy and the identification of causes for the cognitive decline , such as white matter lesions , cerebral infarcts and brain tumors .
conversely , computed tomography ( ct ) investigations are seldom part of the outpatient diagnostic work - up of cognitive complaints owing to its lower spatial resolution .
notwithstanding , ct can be used in cases of contraindications for mri ( e.g. pacemaker ) .
mri is used to evaluate the anatomical features of the brain because it provides a clear distinction between gray matter , white matter and cerebrospinal fluid .
the most consistent findings in mri studies of patients with ad are atrophy in the medial temporal lobe ( hippocampus , amygdala , entorhinal cortex and parahippocampal gyrus ) , ventricular enlargement and smaller total brain volume.3,4 mri data have also been used to compare ad with other neurodegenerative conditions , such as dementia with lewy bodies , frontotemporal lobar degeneration and parkinson 's disease dementia . despite some heterogeneity in the results of these studies , they provide consistent evidence for the presence of a characteristic pattern of gray matter atrophy in ad involving mainly the medial temporal lobe , insula and temporoparietal cortices.3
the dynamics of atrophy in ad has been assessed by cross - sectional and longitudinal mri studies . initially , atrophy is most pronounced in the medial temporal lobe;3 next , the temporal neocortex is involved ; then , the atrophic pattern extends to the parietal and frontal lobes.5,6 these descriptions are in accordance with the results of previous neuropathological studies that examined postmortem brains of patients with different stages of ad.7
since the pathological processes that lead to ad are known to begin years before the clinical syndrome , longitudinal studies have provided valuable information about the preclinical stages of ad , such as mild cognitive impairment ( mci ) , a condition characterized by cognitive decline in the absence of clinical dementia .
recent meta - analyses have shown that gray matter atrophy is a consistent finding in elderly subjects with mci and also that medial temporal lobe atrophy is a neurostructural biomarker of mci conversion to ad.8,9
neurofunctional imaging modalities , such as fdg - pet and regional cerebral blood flow imaging with single photon emission computed tomography ( spect ) provide , respectively , information about regional glucose metabolism and brain perfusion .
several research studies have evaluated samples of patients with ad relative to elderly controls using neurofunctional modalities such as fdg - pet and spect .
the characteristic pattern found in ad is of hypometabolism / hypoperfusion in the temporoparietal cortex.10,11 a recent meta - analysis found that hypometabolism / hypoperfusion of the inferior parietal lobules and precuneus is the most consistent neurofunctional finding in ad in comparison with healthy elderly subjects.9 moreover , longitudinal neurofunctional imaging studies have demonstrated hypometabolism / hypoperfusion in the parietal lobe of mci converters in comparison with those who did not convert to ad.9 these functional imaging techniques can be useful in cases of diagnostic uncertainty despite thorough evaluation12 and have been shown to be valuable to distinguish ad from frontotemporal dementia.13 however , they should not be used as the only imaging modality because they do not allow an adequate evaluation of brain structure.14
a distinct regional finding resulting from neurostructural and neurofunctional imaging studies respectively , medial temporal lobe atrophy and parietal hypoperfusion / hypometabolism has been reported by authors who assessed patients with ad using both mri and neurofunctional methods ( fdg - pet or spect).15,16 the neurofunctional decline in the parietal lobe is thought to be due to a diaschisis ' effect , caused by disruption in the white matter bundles that connect the atrophic temporal lobe structures to the parietal lobe.16
white matter volume can also be measured with mri .
studies comparing groups of patients with ad against elderly controls have found volumetric reduction in the corpus callosum , fornix and the cingulum bundle in ad samples.16,17 more subtle white matter abnormalities can be detected using a novel mri technique called diffusion tensor imaging . by measuring water diffusivity ,
diffusion tensor imaging studies allow researchers to draw inferences about the integrity of white matter.18 in ad , widespread white matter disruption has been demonstrated , involving both limbic pathways ( e.g. fornix ) and cortico - cortical tracts ( e.g. uncinate fasciculus and corpus callosum).19,20
although a very important source of knowledge about the pathophysiology of the disease , the brain imaging modalities cited above have limited diagnostic utility because their findings are not specific to ad and they are not sufficiently sensitive to detect mild or preclinical disease stages .
this is important not only to clinical practice but also to the development of new therapies : researchers seeking disease - modifying agents are aware that an efficient drug should ideally be started before patients present with overt dementia but , in order to choose who will benefit from such therapy , we need accurate diagnostic tools.21,22
in clinical practice , a definite diagnosis of ad is usually not possible owing to the requirement for histopathological examination.1 moreover , owing to the heterogeneity of clinical manifestations and low specificity of the cognitive deficits , the diagnosis of ad can be challenging.23 neuropathological studies that analyzed postmortem brain tissue found that the clinical diagnosis of ad is frequently inaccurate.24,25
accumulation of the -amyloid peptide in the brain is a hallmark of ad.26 -amyloid is the product of sequential proteolytic cleavage of the amyloid precursor protein by - and -secretases.27 senile plaques found in the brain of patients with ad are primarily composed of insoluble deposits of -amyloid.28 until recently , the investigation of amyloid deposition in living humans was limited because it used to rely on brain biopsy or postmortem examinations .
fortunately , in recent years , the development of radiopharmaceutical agents aimed at identifying amyloid deposition has allowed researchers to study in vivo amyloid deposition in humans.29 briefly , amyloid imaging consists of an injection of a radiolabeled ligand targeting amyloid aggregates and use of positron emission tomography ( pet ) technology to acquire images of the brain in order to display foci of abnormal amyloid accumulation.29
despite the recent development of this pet technology , radiolabeled biomarkers for amyloid imaging have already been used in several research studies .
these studies have shown that amyloid deposition : 1 ) occurs years before clinical dementia,30,31 2 ) is related to cortical atrophy and cognitive decline,30 - 32 3 ) is more intense in patients with mci who convert to ad than in nonconverters33,34 and 4 ) plateaus when clinical dementia is established ( while other neurodegenerative processes such as brain atrophy keep progressing).31,35 for the next few years , it is expected that the amount of information provided by amyloid imaging studies will sharply increase .
for instance , this imaging modality is now used in a sub - study of the alzheimer 's disease neuroimaging initiative , a large longitudinal ( 6-year ) multicentric project in the usa involving cohorts of elderly controls and subjects with mci and ad , aimed at validating neuroimaging and cerebrospinal fluid / blood biomarkers for use in clinical trials of ad treatments . in this project ,
subjects are investigated with mri and fdg - pet and then followed , thus allowing measurements of change in these biomarkers at different disease stages.36
amyloid deposition is not pathognomonic of ad and , in fact , it is rather unspecific .
for instance , it can be found in dementia with lewy bodies and in cognitively intact elderly subjects.36,37 therefore , a positive amyloid biomarker scan may have limited diagnostic value ; on the other hand , a negative result from such a sensitive imaging test can be informative because amyloid deposition is a defining feature of ad.37,38 thus , the immediate clinical usefulness of sensitive imaging biomarkers for brain amyloid deposition would be to rule out the presence of significant levels of -amyloid in the brain .
in other words , a negative result would mean that ad is an unlikely diagnosis .
as an example , researchers showed that amyloid biomarkers could be useful to differentiate between ad and frontotemporal dementia.37,39,40
amyloid imaging could also be useful as a non - invasive biomarker allowing a more adequate selection of subjects without overt dementia but with a high likelihood of progressing to ad in clinical trials of disease - modifying agents.21,41 perhaps this imaging tool could even become useful to measure the efficacy of new drugs,42 as suggested by the results of a recent study that used amyloid imaging to quantify the reduction of -amyloid load in patients treated with anti - amyloid antibody.43
one logistic concern is the short physical half - life of carbon-11 , which prevents the applicability of pittsburgh compound b - pet imaging to wider populations in clinical settings .
this has raised interest in the development of amyloid imaging agents that can be labeled with fluorine-18 ( f ) , which has a longer decay half - life .
florbetapir ( amyvid ) is one of the most promising of such agents , not only owing to the longer radioactive half - life of f , but also because of the rapid kinetics and stable plateau of uptake of florbetapir in the brain following intravenous administration.44 these properties increase its potential availability and allow short post - dose waiting periods and flexibility in timing of image acquisition.44 recent investigations have shown that f - florbetapir pet imaging performed during life in a sample of elderly patients from hospice , long - term care and community healthcare facilities accurately predicted the presence of -amyloid in the brain as verified at autopsy of the same subjects.45
in spite of the above advances , there are still important difficulties to be overcome before amyloid imaging with pet can be seen as a useful resource in clinical practice for the diagnostic work - up for dementia .
indeed , florbetapir has been rejected by a recent preliminary document of the united states food and drugs administration ( fda ) , which highlighted the problem of inconsistent reader - to - reader image interpretation.46 this represents a set - back that will force the neuroimaging community to improve the reliability of amyloid imaging interpretations .
the fda document is based on the first phase 3 study focused on the relationship between florbetapir imaging and postmortem -amyloid pathology.45 results based on the binary classification ( positive negative ) of the mean rating given by three trained nuclear medicine physicians resulted in an impressive 93% sensitivity.45 however , the detailed fda report pointed out that there was too much variation in the individual reader performance ; for instance , one reader demonstrated an unacceptably low sensitivity of 55% .
furthermore , in over one - third of the subjects , at least one reader would have had a different binary interpretation of amyloid status from the other two readers.46 based on the reader inconsistency , this document concluded that
the data did not produce evidence of clinical usefulness.46
so , what would be the next step ? one of the most relevant messages from the fda document is the following : the available data suggest that the variability in f - florbetapir pet test results more likely stems from variability in image interpretation rather than image acquisition.46 in other words , if this imaging modality is one day to be widely used in clinical practice , then efforts should be focused on how to improve the reliability of imaging interpretation
. one way would be to improve the physicians ' training , with lengthier and/or more sophisticated learning protocols . in real world clinical settings , this would not only be expensive but also limit the availability of this method to a few physicians and patients . an alternative would be to develop automated methods of image analysis that could help physicians make more accurate interpretations .
numerous results from recent years have provided evidence that automated techniques have a great potential to advance the diagnostic accuracy of neuroimaging methods for dementia and other neurological and psychiatric disorders .
neuropsychiatric researchers commonly perform between - group comparisons using neuroimaging data to obtain valuable insights into the neuropathological processes that underlie the diseases .
the statistical methods of most of the studies cited in the sections above are based on this principle .
nevertheless , such an approach can not be used in clinical practice because neuroimaging techniques must provide reliable information of individual scans in order to be diagnostically useful .
for this reason , researchers have recently developed computer - based , automated classification methods that analyze substantial amounts of information looking for a pattern that characterizes the disease .
methods for automated classification of brain imaging data can provide high accuracy in the evaluation of individual cases and for this reason , it has been recently suggested that such techniques could become established as useful diagnostic tools for clinical applications.47
for instance , these methods also known as pattern classification approaches have already been applied in mri studies to differentiate : -patients with ad from controls , with 8795% accuracy48 - 51
-ad and frontotemporal lobar degeneration with 89% accuracy49
-mci from healthy controls , with 90% accuracy52
-subjects with mci who convert to ad and nonconverters ( 81% accuracy)53
-children with and without autism ( 81% accuracy)54
-patients with schizophrenia from controls ( 90% accuracy).55
pattern classification approaches have also been used in neurofunctional imaging studies designed to differentiate between patients with ad and controls,56 ad and frontotemporal dementia,57 patients with schizophrenia and healthy subjects,58 schizophrenia and bipolar disorder59 and depression and controls.60 moreover , these automated classifiers can be designed to combine multiple biomarkers ( e.g. demographic data , structural and functional neuroimaging , genotyping information and laboratory results , such as cerebrospinal fluid biomarkers ) in order to improve successful classification.61
despite these recent findings , we are not aware of any study using pattern classification approaches to classify amyloid imaging data on an individual basis . given the insufficient consistency in reader - to - reader interpretation of individual amyloid imaging data as pointed out by the recent fda document discussed above,46 testing the accuracy of pattern classification methods in this neuroimaging modality seems a sensible next step .
over the past decades , many research investigations have applied neuroimaging techniques to gather information about the anatomical and functional brain changes related to ad .
table 1 summarizes the clinical utility of neuroimaging modalities used in patients with suspected ad .
thanks to major improvements in image acquisition , processing and analysis , these studies have conducted detailed assessments of the human brain in vivo comparing groups of patients with dementia and unaffected elderly volunteers .
a very brief summary of clinically relevant neuroimaging findings in samples of patients with ad is presented in table 2 .
mri has become the most used tool for cerebral imaging in vivo for the assessment of dementia , as it provides detailed information about brain structure , thus allowing the characterization of regional brain atrophy and the identification of causes for the cognitive decline , such as white matter lesions , cerebral infarcts and brain tumors .
conversely , computed tomography ( ct ) investigations are seldom part of the outpatient diagnostic work - up of cognitive complaints owing to its lower spatial resolution .
notwithstanding , ct can be used in cases of contraindications for mri ( e.g. pacemaker ) .
mri is used to evaluate the anatomical features of the brain because it provides a clear distinction between gray matter , white matter and cerebrospinal fluid .
the most consistent findings in mri studies of patients with ad are atrophy in the medial temporal lobe ( hippocampus , amygdala , entorhinal cortex and parahippocampal gyrus ) , ventricular enlargement and smaller total brain volume.3,4 mri data have also been used to compare ad with other neurodegenerative conditions , such as dementia with lewy bodies , frontotemporal lobar degeneration and parkinson 's disease dementia . despite some heterogeneity in the results of these studies , they provide consistent evidence for the presence of a characteristic pattern of gray matter atrophy in ad involving mainly the medial temporal lobe , insula and temporoparietal cortices.3
the dynamics of atrophy in ad has been assessed by cross - sectional and longitudinal mri studies . initially , atrophy is most pronounced in the medial temporal lobe;3 next , the temporal neocortex is involved ; then , the atrophic pattern extends to the parietal and frontal lobes.5,6 these descriptions are in accordance with the results of previous neuropathological studies that examined postmortem brains of patients with different stages of ad.7
since the pathological processes that lead to ad are known to begin years before the clinical syndrome , longitudinal studies have provided valuable information about the preclinical stages of ad , such as mild cognitive impairment ( mci ) , a condition characterized by cognitive decline in the absence of clinical dementia .
recent meta - analyses have shown that gray matter atrophy is a consistent finding in elderly subjects with mci and also that medial temporal lobe atrophy is a neurostructural biomarker of mci conversion to ad.8,9
neurofunctional imaging modalities , such as fdg - pet and regional cerebral blood flow imaging with single photon emission computed tomography ( spect ) provide , respectively , information about regional glucose metabolism and brain perfusion .
several research studies have evaluated samples of patients with ad relative to elderly controls using neurofunctional modalities such as fdg - pet and spect .
the characteristic pattern found in ad is of hypometabolism / hypoperfusion in the temporoparietal cortex.10,11 a recent meta - analysis found that hypometabolism / hypoperfusion of the inferior parietal lobules and precuneus is the most consistent neurofunctional finding in ad in comparison with healthy elderly subjects.9 moreover , longitudinal neurofunctional imaging studies have demonstrated hypometabolism / hypoperfusion in the parietal lobe of mci converters in comparison with those who did not convert to ad.9 these functional imaging techniques can be useful in cases of diagnostic uncertainty despite thorough evaluation12 and have been shown to be valuable to distinguish ad from frontotemporal dementia.13 however , they should not be used as the only imaging modality because they do not allow an adequate evaluation of brain structure.14
a distinct regional finding resulting from neurostructural and neurofunctional imaging studies respectively , medial temporal lobe atrophy and parietal hypoperfusion / hypometabolism has been reported by authors who assessed patients with ad using both mri and neurofunctional methods ( fdg - pet or spect).15,16 the neurofunctional decline in the parietal lobe is thought to be due to a diaschisis ' effect , caused by disruption in the white matter bundles that connect the atrophic temporal lobe structures to the parietal lobe.16
white matter volume can also be measured with mri .
studies comparing groups of patients with ad against elderly controls have found volumetric reduction in the corpus callosum , fornix and the cingulum bundle in ad samples.16,17 more subtle white matter abnormalities can be detected using a novel mri technique called diffusion tensor imaging . by measuring water diffusivity ,
diffusion tensor imaging studies allow researchers to draw inferences about the integrity of white matter.18 in ad , widespread white matter disruption has been demonstrated , involving both limbic pathways ( e.g. fornix ) and cortico - cortical tracts ( e.g. uncinate fasciculus and corpus callosum).19,20
although a very important source of knowledge about the pathophysiology of the disease , the brain imaging modalities cited above have limited diagnostic utility because their findings are not specific to ad and they are not sufficiently sensitive to detect mild or preclinical disease stages .
this is important not only to clinical practice but also to the development of new therapies : researchers seeking disease - modifying agents are aware that an efficient drug should ideally be started before patients present with overt dementia but , in order to choose who will benefit from such therapy , we need accurate diagnostic tools.21,22
in clinical practice , a definite diagnosis of ad is usually not possible owing to the requirement for histopathological examination.1 moreover , owing to the heterogeneity of clinical manifestations and low specificity of the cognitive deficits , the diagnosis of ad can be challenging.23 neuropathological studies that analyzed postmortem brain tissue found that the clinical diagnosis of ad is frequently inaccurate.24,25
accumulation of the -amyloid peptide in the brain is a hallmark of ad.26 -amyloid is the product of sequential proteolytic cleavage of the amyloid precursor protein by - and -secretases.27 senile plaques found in the brain of patients with ad are primarily composed of insoluble deposits of -amyloid.28 until recently , the investigation of amyloid deposition in living humans was limited because it used to rely on brain biopsy or postmortem examinations .
fortunately , in recent years , the development of radiopharmaceutical agents aimed at identifying amyloid deposition has allowed researchers to study in vivo amyloid deposition in humans.29 briefly , amyloid imaging consists of an injection of a radiolabeled ligand targeting amyloid aggregates and use of positron emission tomography ( pet ) technology to acquire images of the brain in order to display foci of abnormal amyloid accumulation.29
despite the recent development of this pet technology , radiolabeled biomarkers for amyloid imaging have already been used in several research studies .
these studies have shown that amyloid deposition : 1 ) occurs years before clinical dementia,30,31 2 ) is related to cortical atrophy and cognitive decline,30 - 32 3 ) is more intense in patients with mci who convert to ad than in nonconverters33,34 and 4 ) plateaus when clinical dementia is established ( while other neurodegenerative processes such as brain atrophy keep progressing).31,35 for the next few years , it is expected that the amount of information provided by amyloid imaging studies will sharply increase . for instance , this imaging modality is now used in a sub - study of the alzheimer 's disease neuroimaging initiative , a large longitudinal ( 6-year ) multicentric project in the usa involving cohorts of elderly controls and subjects with mci and ad , aimed at validating neuroimaging and cerebrospinal fluid / blood biomarkers for use in clinical trials of ad treatments . in this project ,
subjects are investigated with mri and fdg - pet and then followed , thus allowing measurements of change in these biomarkers at different disease stages.36
amyloid deposition is not pathognomonic of ad and , in fact , it is rather unspecific .
for instance , it can be found in dementia with lewy bodies and in cognitively intact elderly subjects.36,37 therefore , a positive amyloid biomarker scan may have limited diagnostic value ; on the other hand , a negative result from such a sensitive imaging test can be informative because amyloid deposition is a defining feature of ad.37,38 thus , the immediate clinical usefulness of sensitive imaging biomarkers for brain amyloid deposition would be to rule out the presence of significant levels of -amyloid in the brain .
in other words , a negative result would mean that ad is an unlikely diagnosis .
as an example , researchers showed that amyloid biomarkers could be useful to differentiate between ad and frontotemporal dementia.37,39,40
amyloid imaging could also be useful as a non - invasive biomarker allowing a more adequate selection of subjects without overt dementia but with a high likelihood of progressing to ad in clinical trials of disease - modifying agents.21,41 perhaps this imaging tool could even become useful to measure the efficacy of new drugs,42 as suggested by the results of a recent study that used amyloid imaging to quantify the reduction of -amyloid load in patients treated with anti - amyloid antibody.43
one logistic concern is the short physical half - life of carbon-11 , which prevents the applicability of pittsburgh compound b - pet imaging to wider populations in clinical settings .
this has raised interest in the development of amyloid imaging agents that can be labeled with fluorine-18 ( f ) , which has a longer decay half - life .
florbetapir ( amyvid ) is one of the most promising of such agents , not only owing to the longer radioactive half - life of f , but also because of the rapid kinetics and stable plateau of uptake of florbetapir in the brain following intravenous administration.44 these properties increase its potential availability and allow short post - dose waiting periods and flexibility in timing of image acquisition.44 recent investigations have shown that f - florbetapir pet imaging performed during life in a sample of elderly patients from hospice , long - term care and community healthcare facilities accurately predicted the presence of -amyloid in the brain as verified at autopsy of the same subjects.45
in spite of the above advances , there are still important difficulties to be overcome before amyloid imaging with pet can be seen as a useful resource in clinical practice for the diagnostic work - up for dementia . indeed , florbetapir has been rejected by a recent preliminary document of the united states food and drugs administration ( fda ) , which highlighted the problem of inconsistent reader - to - reader image interpretation.46 this represents a set - back that will force the neuroimaging community to improve the reliability of amyloid imaging interpretations .
the fda document is based on the first phase 3 study focused on the relationship between florbetapir imaging and postmortem -amyloid pathology.45 results based on the binary classification ( positive negative ) of the mean rating given by three trained nuclear medicine physicians resulted in an impressive 93% sensitivity.45 however , the detailed fda report pointed out that there was too much variation in the individual reader performance ; for instance , one reader demonstrated an unacceptably low sensitivity of 55% . furthermore , in over one - third of the subjects , at least one reader would have had a different binary interpretation of amyloid status from the other two readers.46 based on the reader inconsistency , this document concluded that
the data did not produce evidence of clinical usefulness.46
so , what would be the next step ? one of the most relevant messages from the fda document is the following : the available data suggest that the variability in f - florbetapir pet test results more likely stems from variability in image interpretation rather than image acquisition.46 in other words , if this imaging modality is one day to be widely used in clinical practice , then efforts should be focused on how to improve the reliability of imaging interpretation
. one way would be to improve the physicians ' training , with lengthier and/or more sophisticated learning protocols .
in real world clinical settings , this would not only be expensive but also limit the availability of this method to a few physicians and patients .
an alternative would be to develop automated methods of image analysis that could help physicians make more accurate interpretations .
numerous results from recent years have provided evidence that automated techniques have a great potential to advance the diagnostic accuracy of neuroimaging methods for dementia and other neurological and psychiatric disorders .
neuropsychiatric researchers commonly perform between - group comparisons using neuroimaging data to obtain valuable insights into the neuropathological processes that underlie the diseases .
the statistical methods of most of the studies cited in the sections above are based on this principle .
nevertheless , such an approach can not be used in clinical practice because neuroimaging techniques must provide reliable information of individual scans in order to be diagnostically useful .
for this reason , researchers have recently developed computer - based , automated classification methods that analyze substantial amounts of information looking for a pattern that characterizes the disease .
methods for automated classification of brain imaging data can provide high accuracy in the evaluation of individual cases and for this reason , it has been recently suggested that such techniques could become established as useful diagnostic tools for clinical applications.47
for instance , these methods also known as pattern classification approaches have already been applied in mri studies to differentiate : -patients with ad from controls , with 8795% accuracy48 - 51
-ad and frontotemporal lobar degeneration with 89% accuracy49
-mci from healthy controls , with 90% accuracy52
-subjects with mci who convert to ad and nonconverters ( 81% accuracy)53
-children with and without autism ( 81% accuracy)54
-patients with schizophrenia from controls ( 90% accuracy).55
pattern classification approaches have also been used in neurofunctional imaging studies designed to differentiate between patients with ad and controls,56 ad and frontotemporal dementia,57 patients with schizophrenia and healthy subjects,58 schizophrenia and bipolar disorder59 and depression and controls.60 moreover , these automated classifiers can be designed to combine multiple biomarkers ( e.g. demographic data , structural and functional neuroimaging , genotyping information and laboratory results , such as cerebrospinal fluid biomarkers ) in order to improve successful classification.61
despite these recent findings , we are not aware of any study using pattern classification approaches to classify amyloid imaging data on an individual basis . given the insufficient consistency in reader - to - reader interpretation of individual amyloid imaging data as pointed out by the recent fda document discussed above,46 testing the accuracy of pattern classification methods in this neuroimaging modality seems a sensible next step .
neuroimaging techniques have led to an increasingly large body of knowledge about ad by allowing the study of the brain in living subjects .
these imaging methods are not only highly important research tools , but they are also commonly used in the evaluation of patients presenting with dementia in order to improve the accuracy of clinical diagnosis and identify brain lesions contributing to the cognitive decline .
a recent major advance is the development of amyloid imaging techniques that allow in vivo identification of amyloid deposition in the brain .
this imaging modality has already yielded important results and will likely determine an increase in the diagnostic accuracy of ad in the near future .
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### Summary:
: alzheimer 's disease is the most common cause of dementia and its prevalence is expected to increase in the coming years . therefore , accurate diagnosis is crucial for patients , clinicians and researchers .
neuroimaging techniques have provided invaluable information about alzheimer 's disease and , owing to recent advances , these methods will have an increasingly important role in research and clinical practice .
the purpose of this article is to review recent neuroimaging studies of alzheimer 's disease that provide relevant information to clinical practice , including a new modality : in vivo amyloid imaging .
magnetic resonance imaging , single photon emission computed tomography and 18f - fluorodeoxyglucose - positron emission tomography are currently available for clinical use .
patients with suspected alzheimer 's disease are commonly investigated with magnetic resonance imaging because it provides detailed images of brain structure and allows the identification of supportive features for the diagnosis .
neurofunctional techniques such as single photon emission computed tomography and 18f - fluorodeoxyglucose - positron emission tomography can also be used to complement the diagnostic investigation in cases of uncertainty .
amyloid imaging is a non - invasive technique that uses positron emission tomography technology to investigate the accumulation of the -amyloid peptide in the brain , which is a hallmark of alzheimer 's disease .
this is a promising test but currently its use is restricted to very few specialized research centers in the world .
technological innovations will probably increase its availability and reliability , which are the necessary steps to achieve robust clinical applicability .
thus , in the future it is likely that amyloid imaging techniques will be used in the clinical evaluation of patients with alzheimer 's disease .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: as most discussions of physician he rely on a single episode in the commentary , our analysis begins by returning to the episode in question . as we will see below , the description of physician he is less than straightforward
certainly , the diagnosis of lord ping would seem to eschew spiritual or demonic explanations of illness .
yet the conversation between the physician and another member of the jin court suggests that illness or death could result from heavenly punishment . in other words ,
physician he begins to look like a medical pluralist . given the importance of the account to my story , a few introductory remarks about the episode are in order .
the account can be divided into roughly three parts , each of which is progressively shorter than the last .
the first and longest part opens with physician he s consultation with his noble patient , lord ping .
there is nothing that can be done, he tells the lord , for this is what is referred to as a case of being close to women , a sickness generated in the same way as gu [ ] .
it is at this point that physician he issues his mysterious prophecy about the imminent death of the jin minister
i say mysterious only because it is initially unclear how physician he arrived at this conclusion .
the prophecy , however , is ignored by the lord , who is evidently worried about the prospect of having to abandon his riotous lifestyle .
is it really true, he asks physician he , that women are not to be approached? the question gives the physician an opening to expound on the virtues of moderation and embark on a lengthy digression about music before turning to what scholars usually see as his main point : the role of the six qi in generating illness . according to the physician , lord ping was suffering from an imbalance of yang and dark qi , the consequence of excessive sexual relations . in the second part , the narrative moves away from the consultation between the patient and healer to a conversation between physician he and minister zhao wu [ ] ( d. 541 bc ) , who was then the most powerful minister of jin .
good minister. evidently intrigued , or perhaps worried , the minister asks physician he to identify the minister in question . without batting an eyelid , physician
the conversation has taken an awkward turn , and so minister zhao changes the subject and asks about the illness called gu , which the physician mentioned in his initial remarks . in response ,
physician he furnishes an explanation based on the book of zhou changes [ ] .
it is that which is produced from being excessively besotted and dissolute [ in relations with women ] .
if we look at the graph , we see that utensil and worms make gu . that which flies out of the grain is gu . in the zhou book of changes ,
it is that which is produced from being excessively besotted and dissolute [ in relations with women ] . if we look at the graph , we see that utensil and worms make gu . that which flies out of the grain is gu . in the zhou book of changes , a woman deluding a man or the wind toppling a mountain is gu
.
, the narrative closes with minister zhao s words of praise for physician he , who is extolled as a
with such an introduction , we turn to the main problem at hand : what evidence exists to suggest that physician he eschewed spiritual conceptions of illness ?
the evidence would seem to be cut and dried ; nowhere in his diagnosis does physician he mention the spirits .
this is obvious enough from the text of the physician s celebrated diagnosis :
in heaven there are six kinds of qi , which come down and produce the five flavours , emitted as the five hues , and result in the five tones .
the six qi are referred to as the yin , yang , wind , rain , dark , and light , each of which are separated into four periods and arranged into five pitches .
when the yin is excessive , there will be a cold illness , when the yang is excessive , there will be a heat illness ; when wind is excessive , there will be an illness in the extremities ; when rain is excessive , there will be an illness of the abdomen ; when darkness is excessive , there will be avolition , and when light is excessive , there will be an illness in the heart .
the bright or hard ] in things during the hours of darkness ( ? ) .
when there is excess in this , an internal heat , avolition , and gu will be produced . in the present case , i knew that his lordship had been immoderate and untimely in his sexual relations ; thus how could this calamity not have befallen him ?
in heaven there are six kinds of qi , which come down and produce the five flavours , emitted as the five hues , and result in the five tones .
the six qi are referred to as the yin , yang , wind , rain , dark , and light , each of which are separated into four periods and arranged into five pitches .
when the yin is excessive , there will be a cold illness , when the yang is excessive , there will be a heat illness ; when wind is excessive , there will be an illness in the extremities ; when rain is excessive , there will be an illness of the abdomen ; when darkness is excessive , there will be avolition , and when light is excessive , there will be an illness in the heart .
the bright or hard ] in things during the hours of darkness ( ? ) .
when there is excess in this , an internal heat , avolition , and gu will be produced . in the present case , i knew that his lordship had been immoderate and untimely in his sexual relations ; thus how could this calamity not have befallen him ?
the passage presents several points of interest . to begin with , not only are references to gods and spirits absent from the diagnosis , but the emphasis here is on the cosmological underpinnings of human illness : the excesses of yin and yang , as well as uneven proportions of dark and light , moisture and heat , which cause the body to lose its natural equilibrium
notice , for example , that the physician brings up symptoms that the patient does not experience suggests that physician he saw the theory of the six qi as a framework for understanding not only the illness of lord ping , but all cases of human sickness .
perhaps more importantly , physician he denies that the lord s illness was the result of spiritual involvement : this illness is not the work of ghosts .
such a denial is all the more surprising in light of fourth - century sources .
if divinatory records recovered from various tombs are to be trusted , illness was largely seen by the ruling elite as the result of spiritual displeasure : heaven sending down its punishments , an ancestor or spirit miffed about having received less than his or her due of the offerings , a demon seeking vengeance upon the murderer or his descendants , and the war dead incensed by the lack of sacrifices .
the case of one nobleman , who died a few decades after the compilation of the commentary , leaves clues as to the strength of such beliefs .
his illnesses occasioned the coordinated efforts of twelve diviners , who sacrificed no fewer than thirty - six pigs , six dogs , twenty - three sheep , nine oxen , and a horse .
given such a background , the physician s denial that spirits and ghosts were responsible for the lord s illness seems all the more like an expression of defiance , a protest lodged against the dominant views of the age .
the attention given to symptoms , it may be further argued , is incompatible with older conceptions of illness .
the fact that physician he could work backwards from symptoms to the source presumes a one - to - one relationship between symptom and cause a stance at odds with older views that emphasised the capriciousness of spirits . while they ascribed a rationality to illness
the gods and spirits usually had a reason for sending down the scourge of sickness older views nevertheless did not posit a necessary connection between specific symptoms and causes .
as divination records hint , the expression of spiritual displeasure varied widely ; the same illness could have any number of potential sources .
when investigating the shortness of breath and loss of appetite suffered by the aforementioned nobleman , for example , diviners considered a long list of candidates : royal ancestors , various nature spirits such as the god of the grand river and wei mountain , and the angry war dead .
given the lack of correspondence between symptom and cause , diviners understandably paid little attention to the symptoms themselves , instead scrutinising the patterns found in the shells and stalks for clues about the causes of illness .
other elements in the episode militate against the view that the physician opposed spiritual or demonic explanations of illness . although he does not assign any role to the spirits in his diagnosis of lord ping , physician he fails to issue a categorical denial
. a closer look at the text , in fact , reveals that the physician not only ruled out spiritual causes , but also the effects of bad food in this particular case
this is not the work of ghosts , nor the result of what was eaten. to be sure , too much can be made of an absence .
it is one thing to claim that the physician stopped short of ruling out spiritual causes in all cases , and quite another to say that the compilers attributed to him the belief that ghosts or gods were only sometimes behind human sickness . for the latter
, we will have to search for positive signs that he attributed sickness or dying to spiritual forces .
the prognosis regarding minister zhao provides positive evidence that links physician he to older views that highlighted spiritual causes of illness .
granted , the physician does not say in so many words that the spirits can punish men or women by making them sick .
as we saw above , physician he claimed that minister zhao would die because heaven had withdrawn its protection .
sure enough , the commentary tells us that the aforementioned minister died suddenly in the twelfth month of the same year without a hint of violence ; physician he s prophecy turned out to be on the mark .
at the end of the episode ,
physician he goes on to explain his prophecy , an explanation that indicates that an early death could be the result of divine sanction :
i , he , have also heard it said that if honoured by titles and having assumed responsibility for the gravest of state matters , the great minister does not change course when a disaster arises , he too will suffer the consequences of the spiritual fault . at present
the lord has been licentious to the point where he is comatose and thus unable to focus on the altars of earth and grain ( ie .
you , sir , have been unable to intervene in this matter , and so i was speaking of you .
i , he , have also heard it said that if honoured by titles and having assumed responsibility for the gravest of state matters , the great minister does not change course when a disaster arises , he too will suffer the consequences of the spiritual fault . at present
the lord has been licentious to the point where he is comatose and thus unable to focus on the altars of earth and grain ( ie .
you , sir , have been unable to intervene in this matter , and so i was speaking of you .
physician he s speech presents two relevant points . to begin with
, he uses the term jiu [ ] , which i have translated as spiritual fault. in ancient texts , the term could refer generally to blameworthy conduct .
but jiu was often used to describe offences that merited divine retribution ; hence the common rendering of curse. not surprisingly , in divinatory texts jiu was paired with sui [ ] , the sickness , misfortune , or even death meted out by baleful spirits .
and indeed , the use of jiu makes sense given the larger context of the passage .
physician he goes on to explain that minister zhao was richly deserving of heavenly punishment . in permitting lord ping to pursue a life of pleasure
the minister was thus remiss in carrying out his duties to the state and so would be punished by heaven . with the exclusive focus on qi in his diagnosis of lord ping , physician
but the prophecy reveals that it was far from a foregone conclusion that the physician was an opponent of older , spiritual conceptions of illness .
had this been the case , we would not expect physician he to speak of heaven sending down premature death as punishment , for such a position implies the power of spirits to deliver lesser punishments , including the scourge of sickness . on the contrary , such a position linked the physician to demonic views of illness .
through an examination of the description of physician he , we have arrived at a more complex view of the figure .
our analysis of physician he , however , would be incomplete without a consideration of the formal structure of the narrative .
embedded within a larger story of the illness of lord ping , the visit of physician he represents less than one half of the episode , of which the rest is devoted to the visit by the famous statesman from zheng , zichan [ ] ( d. 522 bc ) .
events are recounted selectively , and the speeches and episodes have been crafted so as to illustrate the historical and moral vision of its compilers . in this regard ,
as historian jin shiqi points out in a brilliant article , the purpose of the episode is not so much to expound on the finer points of medical theory as to explain the underlying causes behind the decline and eventual fall of the jin state in the fifth century bc .
for all of these reasons ,
we situate physician he s visit to jin within the context of the larger narrative . along the way
, we arrive at an additional reason to question whether physician he represents a challenger of spiritual or demonic conceptions of illness : the persona of the commentary looks increasingly less like an actual historical person as much as a rhetorical device . when read in context , physician he resembles the textual double to zichan , a renowned expert on spiritual matters and an important minister .
it is worth starting by providing a brief outline of zichan s visit , which can be analysed in three parts .
the first opens with the arrival of zichan in jin , where a divination was performed to determine the aetiology of the illness .
as no one in the jin court was familiar with the identity of the spirits , zichan was asked about them .
although he had heard of them , zichan was nevertheless sceptical that the spirits were involved .
the pair , zichan explained , were nature spirits and did not even have dominion over the lord s body .
what do the gods of the hills and rivers , or of the stars and planets , he asks , have to do with the health of the prince?
the real cause , zichan adds , lay with the lord s riotous lifestyle , a lifestyle characterised by slack discipline and violations of sexual taboos . in the second part , which is considerably shorter , the narrative moves away from zichan to a conversation between a jin noble and another member of the zheng delegation .
the jin nobleman inquires about the chief minister of zheng , to which the delegate replies that the days of the zheng minister in question are numbered . in the third and shortest part , the narrative returns to the lord of jin , who hears of the diagnosis before bestowing words of praise and tokens of appreciation upon zichan .
before showing how physician he represents an alter ego to a well - regarded expert on the spirits , it is worth considering first a potential objection . even if we assume that the visit of physician he is merely one half of the larger narrative about the sickness of lord zhao , this does not mean that physician he s views about illness were necessarily comparable to those of zichan . for the story to be plausible ,
the expertise ascribed to physician he arguably reflected fourth - century medical wisdom . and insofar as noble ministers and physicians heralded from different backgrounds ,
, it assumes that the positions ascribed to physician he in the commentary reflected specialised knowledge .
but recent work suggests that such an assumption is unwarranted . through a comparison of the episode with other passages in the commentary ,
jin shiqi argues that we have no reason to believe that the views ascribed to physician he were unique to healers .
the conceptual vocabulary associated with the physician , jin furthermore points out , was in fact indistinguishable from those of other noble figures in the commentary , including zichan .
in addition , this line of reasoning underestimates the level of creative licence exercised by the compilers of the commentary ; the other physicians featured in the text also functioned as rhetorical devices .
the famous encounter between physician huan and an earlier ruler of jin provides one such example .
the episode opens with lord ping s predecessor dreaming of a vengeful ghost who explains that the lord will be punished for having murdered the descendants of the ghost .
concerned , the lord consults a witch , who confirms the dream , adding that the lord would not live to eat the new grain , and so when the lord falls ill , physician huan is summoned from qin .
before the physician arrives , however , the lord has a second dream , where the illness takes the form of two lads residing inside of his body and discussing the physician s imminent arrival .
huan is a fine physician , and i fear that he will harm us and so how can we escape? in response , the other proposes to evade the physician , moving to the area between the heart and diaphragm .
if we do this, the second lad replies , what can he do to us? and indeed , when he finally arrives , physician huan declares the illness to be incurable . the illness , he tells the lord , resides in the space between the heart and diaphragm , and so the physician s arsenal of remedies was of no use .
fine physician and sends him back to his home state in pomp and ceremony . at first
, the lord s condition does not worsen , leading him to believe that he has outwitted fate .
the lord then recalls the witch and shows him the new grain before killing him .
but just as the lord is about to taste the grain , he collapses , dying shortly thereafter .
here
, the parallels between physician huan s visit and the encounter with the unfortunate witch suggest a doubling effect . as li wai - yee notes ,
structurally , physician and witch stand in the same relation to the lord ; both converse with him after his dream and confirm its message .
the witch describes a future that corresponds to the first dream about ghostly retribution , and the physician s prediction is consistent with the conversation overheard in the second .
such doubling introduces an element of narrative intensification , as the repetition reinforces the inevitability of the lord s end .
if we return to the illness of lord zhao , it becomes clear that physician he and zichan represent textual doubles or twins .
the doubling effect becomes clear if we consider the narrative as a whole , where the two figures not only occupy parallel positions within symmetrical narratives , but also exhibit the same logic . as figure 1 reveals , the two halves of the narrative are almost identical , with minor variation . whereas zichan s explanation of the oracle appears early in the narrative , physician he defers discussion of the hexagrams until the end of his speech .
the variation is to be expected ; other instances of doubling in the commentary contain small variations that minimise the monotony of repetition .
discrepancies aside , the two halves proceed in parallel . both open with the main figure disputing the message of the oracle and providing two alternative explanations of the lord s sickness .
zichan blames the illness on the lord s use of time and concubines who share the lord s surname , while physician he traces the causes to the lord s over - indulgence in loud musical performances and sexual excess .
a narrative turn , or what poets call a svolta ,
is then introduced , as the discussion shifts away from the subject of the lord s health to the conduct of the chief ministers in the states of zheng and jin .
the narrative then closes with words of praise ; zichan is described by lord ping as a gentleman of broad learning ( ) and given a rich gift , whereas physician he is extolled as a fine physician ( ) by minister zhao and escorted back to his home state with ceremony .
the illness of lord ping at a glance . aside from such structural parallels , the doubling of zichan and physician he can be seen at the level of thematic content and style .
physician he s message closely resembles that of zichan ; both figures reject the conclusion of the oracle and stress the importance of restraint .
in addition , zichan s emphasis on timing resonates with physician he s injunctions for men to know when to stop a musical performance .
zichan rules out the gods by exploring likely expressions of spiritual displeasure and clarifying the lack of connection between the power of the spirits and the lord s sickness .
as he puts it , if the gods of the mountains and rivers were angry , they would bring disasters of floods , droughts and pestilence. and if it were the gods of the sun , moon , stars and planets , we would expect to see untimely snow , frost , wind and rain. physician he similarly arrives at his final diagnosis by entertaining other scenarios before arriving at the description that provides the best match : when the yin is excessive , there will be a cold illness , and when the yang is excessive , there will be a heat illness ; when wind is excessive , there will be an illness in the extremities ; when rain is excessive , there will be an illness of the abdomen
. we have argued that physician he and zichan represent textual doubles , but was the physician actually the counterpart to an expert on the spirits ?
pointing to zichan s invocation of qi , one historian argues that zichan challenges older beliefs regarding the divine or demonic origins of illness .
in cosmology and political culture , aihe wang similarly characterises the episode as evincing a break with bronze age cosmology , whereby the sicknesses of princes were no longer signs of ancestral displeasure so much as the expression of a cosmic pattern that regulated both natural and social orders.
in fairness , zichan ( like physician he ) does not deny the role of the spirits in producing lord ping s illness . instead , zichan points to the effects of habits that destroy the body s integrity :
i , qiao [ ie .
zichan ] , have heard it said that there are four periods of time for the gentleman : the morning is when one listens to the business of governance , daytime is when one pays visits , the dusk is for deciding upon commands , and the evening for resting the body . in this way , one is able to temper the qi , thereby preventing blockages and accumulations that weaken the body , dull the heart , and bring disorder to the hundred affairs from developing .
now , because all of these different times have been treated as one and the same ,
an illness was produced .
i have also heard it said that the inner palace should not have those of the same surname ; otherwise no offspring will be produced .
once the initial attraction has worn off , the two will produce illnesses in each other ; this is something that the gentleman detests .
thus the record says , if one buys a concubine and does not know her surname , one must divine it. the departure from these two principles was something of which the ancients were cautious . with respect to men and women ,
now , four women of the surname ji actually reside in the prince s household .
zichan ] , have heard it said that there are four periods of time for the gentleman : the morning is when one listens to the business of governance , daytime is when one pays visits , the dusk is for deciding upon commands , and the evening for resting the body . in this way , one is able to temper the qi , thereby preventing blockages and accumulations that weaken the body , dull the heart , and bring disorder to the hundred affairs from developing .
now , because all of these different times have been treated as one and the same ,
an illness was produced .
i have also heard it said that the inner palace should not have those of the same surname ; otherwise no offspring will be produced .
once the initial attraction has worn off , the two will produce illnesses in each other ; this is something that the gentleman detests .
thus the record says , if one buys a concubine and does not know her surname , one must divine it. the departure from these two principles was something of which the ancients were cautious . with respect to men and women ,
it is necessary to distinguish their surnames so as to avoid marriage this is the great order of ritual .
now , four women of the surname ji actually reside in the prince s household .
thus , how could there not have been a calamity ?
as with physician he s diagnosis , zichan s explanation of the illness is rooted in the physiological : the flow of the qi and the fruits of the womb .
timeliness are explained as providing a check against the dangers of sexual excess and the pursuit of amusement , which result in blockages and accumulations of qi. the taboos against endogamy are similarly justified in terms of preventing barren unions and illnesses resulting from sexual contact with relatives .
questions aside , considerable evidence exists to suggest that physician he s textual double , zichan , was a noble expert on spiritual matters .
as a point of fact , zichan is not called upon to weigh in on the causes of the illness , but rather to explain the oracle .
in contrast to the confucius of the analects , who is famously reticent about spiritual matters ,
zichan accepts the challenge readily ; he recounts the identity of the spirits their origins , the background behind their respective domains , and the states under their control , and so forth .
the description , which continues at length , represents no minor point in zichan s presentation ; such background occupies more than one third of zichan s entire speech it is longer , in fact , than his actual diagnosis .
given such an emphasis , zichan s knowledge of the numinous realm seems hardly incidental . to put it differently , zichan appears less as a naturalist or
other episodes in the commentary further support the view that physician he s double ( zichan ) was an expert on spiritual matters .
as li wai - yee points out , zichan serves as a consultant on spiritual matters in several different episodes . for example
, he is summoned after the people of zheng experience nightmares in the wake of the murder of a nobleman who lost a power struggle at court .
taking his cues from the dreams , zichan realises that the spirit of the murdered man is restless and would continue to haunt the living unless placated .
accordingly , zichan reinstates the son of the murdered man who had been stripped of rank and fortune in the aftermath of the murder .
more importantly , zichan allows the son to offer sacrifices to the spirit of the murdered father , and so the nightmares cease .
a second episode involving the same lord ping provides a final example of zichan s prowess at interpreting signs from the numinous realm .
several years after the visits of zichan and physician he , lord ping becomes deranged and is confined to bed . at this time , minister zhao wu is dead , and a new minister has assumed a leading role in the governance of the state .
this new minister dreams about a golden bear entering the door of the lord s bedchamber . suspecting that the bear was responsible for the illness
what demon might this be? this time zichan does not deny that spiritual forces are at work .
the bear , zichan tells the minister , is a spirit who had been offered sacrifices by previous dynasties .
so , zichan inquires whether the jin ruler might have neglected the cult of the spirit .
being a man of superior judgement , the minister recognises the value of zichan s advice and restores the sacrifices to the spirit .
our analysis of the narrative structure of the larger account in the commentary discloses that physician he represented the textual double of zichan . though sometimes treated by modern historians as a proponent of a new naturalist philosophy , the figure of zichan was associated in the commentary with deep knowledge of the spiritual realm .
the symmetry between the two episodes , moreover , points to a high level of artistic licence exercised by the editors , who must have reworked existing archival materials if not fabricated entire speeches . as a result , physician
he begins to look more like a literary device in a didactic story than the historical figure behind a scientific revolution .
we have seen that the compilers of the commentary associated physician he not only with prophecies , but also with famous experts on the spirits .
was there something inconsistent about the fact that the physician would contradict the oracle and then issue a prophecy in the same breath ? in order to answer this question ,
our investigation must be broadened to encompass the larger corpus of early narratives about medical divination , to determine whether physician he s speeches fit a pattern . to put it somewhat differently
, we look at the rhetorical resources marshalled by the compilers of the commentary in their construction of a patterned past .
as we will see , a third and final reason exists to question the received view of the physician as initiating a shift in medical thinking . in warring states narratives about divination ,
the noble expert of the spirits often disputed the oracle and questioned the necessity of sacrifices of appeasement ; physician he s denial of spiritual involvement thus fits with an established archetype . before going further
, it is worth noting that experts on the numinous realm were hardly created equal in works from the warring states period . as marc kalinowski points out , there was a world of difference in the commentary between the diviners or invocators at court , on the one hand , and noblemen known for their understanding of spirits , on the other .
of comparatively low status , diviners occupied hereditary posts , rarely associated with any special discernment or knowledge of the numinous realm .
counting ministers and rulers among their ranks , noble experts were linked , in contrast , with more unconventional interpretations of the numinous realm . when called upon to interpret dreams or omens and to determine which sacrifices were required , it was these figures , kalinowski points out , who took a critical stance about oracles , going so far as to contest the interpretations of diviners and to question sacrifices of appeasement .
the incident of 562 bc , which involves the father of lord ping , reveals that physician he s denial of spiritual involvement has precedents .
according to the commentary , the elder jin lord is being entertained by the ruler of song , who proposes to use the ceremonial music of the spirit sanglin [ ] .
the proposal meets with favour from members of the jin lord s entourage , but one nobleman protests on the grounds that the ceremony is improper . over the objections of the nobleman ,
the lord of jin agrees to the ceremony but has second thoughts not long after it starts and decides to leave early .
en route back to jin , the lord falls ill , and so the shells are consulted and the spirit of sanglin is reportedly seen in the oracle .
but when members of the jin entourage urge their lord to rush home to sacrifice to the spirit , the nobleman protests once more .
we declined the ceremony, he tells the lord , it was the song delegation that used it , and so if the illness is indeed caused by a ghost or god , it is the song delegates who should be all the worse for it.
the analysis of the nobleman turns out to be on the mark , for the lord of jin recovers from his illness without offering a single sacrifice .
the oracle is revealed to be a red herring , but it is only the nobleman who knows better .
however , as with physician he and his twin , the critical stance of the nobleman can not be chalked up to agnosticism . on the contrary ,
the nobleman s wariness of the ceremony reveals his attentiveness to spiritual matters and , above all , his concern about ritual missteps that might incur divine wrath .
indeed , his comment about the song delegation hints that the lord would have been subject to divine retribution had the ceremony continued .
490 bc ) provides an additional example of an expert on the numinous realm , who challenges the message of the oracle .
according to the commentary , when the king falls ill , the tortoise is consulted and the yellow river is named as the source .
interestingly , the king does not act on the information provided by the oracle , which prompts his nobles to request permission to offer sacrifices on the king s behalf .
the king nevertheless resists the pressure and explains his reasoning as such :
according to the sacrificial mandates of the three dynasties , [ the ruler ] should not make offerings that extend beyond the hills and mountains that can be seen from within the distance of the state .
the jiang , han , ju , and zhang rivers represent [ the limits ] of such sacrificial [ obligations ] for chu . since blessings and calamities have nothing to do with [ what resides ] beyond these rivers , the [ god of the ] yellow river could not have been offended by me , however deficient in virtue that i may be .
according to the sacrificial mandates of the three dynasties , [ the ruler ] should not make offerings that extend beyond the hills and mountains that can be seen from within the distance of the state .
the jiang , han , ju , and zhang rivers represent [ the limits ] of such sacrificial [ obligations ] for chu . since blessings and calamities have nothing to do with [ what resides ] beyond these rivers , the [ god of the ] yellow river could not have been offended by me , however deficient in virtue that i may be .
, we find a familiar contest between the oracle and the noble expert . as with physician he and his double
while the king does not reveal the actual source of his illness , he is nevertheless clear that the oracle is a red herring .
in addition , the rejection of the oracle does not amount to scepticism regarding the existence or power of the numinous realm . on the contrary ,
the king s comment affirms the power of the gods and sacrificial obligations of human princes .
it is only that the king knows that the jurisdiction of the god does not extend to chu territory , which lies south of the yellow river .
our discussion has been confined to accounts preserved in the commentary , but it is worth emphasising that similar themes can be found in other warring states texts .
as table 1 should reveal , narratives of medical divination which are to be distinguished from divination records are found in a handful of historical chronicles and excavated manuscripts , including the spring and autumn annals of master yan [ ] . in many cases ,
the narratives feature the interpretations of a nobleman who either contests the message of the oracle or argues against the necessity of performing sacrifices of appeasement .
let us look at one of the accounts found in the annals of master yan , which shows that there was nothing unusual about physician he both disregarding the message of the oracle and discussing heavenly retribution .
the most famous of such episodes revolves around a bout of fever that plagued the lord of the powerful state of qi , which is interpreted by the famous minister yan ying [ ] ( d. 500 bc ) .
by one account ,
confident that the illness will improve by doubling the number of sacrifices , the lord dispatches his diviners to make rich offerings to the ancestral spirits above and beyond what had been offered by his predecessors .
suspecting his diviners of foul play , the sick lord convenes a meeting with several nobles including yan ying , announcing his plan to kill the diviners in order to move the gods and to end the scourge .
predictably , the plan meets with approval from the sycophants , but yan ying remains silent .
sensing opposition , the lord presses yan for an answer , thus giving the minister an opening to express his disapproval :
master yan said , does your lordship believe that offering prayers will bring benefits?the lord replied ,
if this is indeed the case , then cursing will also bring harm to your lordship .
your lordship keeps at a distance the ministers who would assist him and alienates those who would help him .
thus , the loyal ministers have been blocked [ in their efforts ] and their admonishments are silenced
. your servant has heard it said that when the favourites are blind to the truth and those distant are dumb , the sound of the angry clamours of the masses will be great indeed ! at present , the state of qi reaches to the west from the cities of liao and she , and in the east , its borders reach to gu and you . among the different inhabitants of qi , the hundred surnames are full of resentment and dissatisfaction , and many of them curse your lordship to heaven
. if the whole state curses you , then your lordship s two invocators even if they are good will be unable to counteract the effects of the curse .
master yan said , does your lordship believe that offering prayers will bring benefits? the lord replied ,
if this is indeed the case , then cursing will also bring harm to your lordship .
your lordship keeps at a distance the ministers who would assist him and alienates those who would help him .
thus , the loyal ministers have been blocked [ in their efforts ] and their admonishments are silenced .
your servant has heard it said that when the favourites are blind to the truth and those distant are dumb , the sound of the angry clamours of the masses will be great indeed ! at present
, the state of qi reaches to the west from the cities of liao and she , and in the east , its borders reach to gu and you . among the different inhabitants of qi , the hundred surnames are full of resentment and dissatisfaction , and many of them curse your lordship to heaven .
if the whole state curses you , then your lordship s two invocators even if they are good will be unable to counteract the effects of the curse .
in contrast to physician he , yan ying does not find himself questioning whether the illness had a spiritual cause ; instead , yan is sceptical that the deities were disgruntled in this case because of their lack of sacrifices .
still , the narrative is similar enough to the illness of lord ping . to begin with
physician he s rejection of spiritual causes can be seen as a challenge to the view that illnesses could always be handled through sacrifices of appeasement .
yan ying s position similarly overturns the simple arithmetic of sacrifice ( ie . the more sacrifices and prayers , the less vulnerable the prince to illness ) . all the same , neither of these figures questions the existence of gods and spirits .
much like the physician , yan affirms the power of gods to make humans sick , and indeed , his stance on sacrifice reveals his belief in heavenly justice . just as physician
he stresses the power of heaven to strike down negligent ministers , yan ying highlights the connection between the conduct of the prince and his health . as he explains it to the lord , the only way to reverse the effects of the curse is to address the root problem : the quality of the lord s governance .
if the lord rules in a benevolent fashion and leads an austere life , the collective curses will come to an end and the illness will improve .
the illness of a king of the fifth - century bc comes still closer to articulating the positions found in the visit of physician he .
this account is preserved in a manuscript dating to the third or fourth century bc that was looted from a tomb before being bought by the shanghai museum from an auction in hong kong .
possessing no known parallels in sources transmitted through the ages ,
this manuscript recounts a series of divinations performed in the chu court in the mid - fifth century . according to this manuscript
, the king falls ill after observing a divination performed to determine the cause of a long drought .
the king subsequently dreams of hills and streams and suspects that the nature spirits of a state recently annexed by chu were responsible .
consequently , the tortoise is consulted , but the nobles at court debate about what to do .
one noble interprets the oracle as confirmation of the king s dream ; the culprits were indeed the nature spirits of the new acquisition and so a sacrifice should be made to appease them .
another noble , however , disagrees on the grounds of precedent ; the earlier chu kings , this noble reminded the other , had not offered sacrifices to the spirits in question , and so it would be improper for the king to do so . at a loss about what to do , the pair consults a third nobleman , the wise taizai jinhou [ ] , who is described , no less , as a sage and descendant of a sage. taizai sides with the second nobleman , arguing that the king would be rewarded for putting ancestral traditions above his own wellbeing . the ghosts , spirits , and the lord - on - high [ ie .
a god] , taizai explains , are the most exalted and clear - sighted and so they invariably will know [ about the king s choice]. the king s illness , he furthermore promises , will come to an end starting today.
by now , all this should be familiar , as the shanghai manuscript contains echoes of themes seen in the narrative about lord ping .
much like physician he ( and zichan ) , taizai challenges the message of the oracle , which is understood by other members of the court to mean that a sacrifice of appeasement was necessary . as with physician
he and zichan , taizai s challenge to the oracle should not be read as a sign of scepticism about the numinous realm .
( in a later episode recounted in the same manuscript , taizai in fact calls for a sacrifice to be carried out by the king in order to end the drought . ) on the contrary , taizai s comments betray confidence in the power of the spirits . as with physician
he , taizai explains that the spirits not only monitor the conduct of men , but they will also reward and punish them . in this respect , taizai s position is very similar to that of physician he , who emphasises that minister zhao would be punished for failing to shepherd the ruler . by situating the figure of physician he within the larger corpus of divination narratives ,
we find a third reason to question whether the episode in the commentary by zuo portended changes in medical theory .
judging from other episodes in the commentary and accounts about divination , the compilers used existing tropes and templates to cobble together the image of the healer .
what is more , there was nothing strange about the denial of spiritual involvement , nor incoherent about the fact that physician he would reject the message of the oracle in one case and issue a prophecy about divine retribution in another . on the contrary ,
such a position makes sense within the context of the larger warring states corpus , where contested oracles and disputed sacrifices represented a leitmotif .
an examination of the narrative structure and larger historiographical context of the episode long seen as
china s first medical case history provides a new perspective on physician he . when examined with care , it becomes clear that the figure of physician he did not occupy an important role in the medical tradition because of any challenges to conceptions of the demonic causes of illness .
the contributions of the original physician he , if he ever existed , are lost to us .
instead , the figure found in the commentary should be understood as a persona , one that functioned as a rhetorical device .
what is more , within this narrative , the persona of physician he not only affirmed the power of the spirits to visit death on the wicked , but was also patterned after noble experts of the numinous realm .
such experts moreover were not only apt at detecting when the hand of the spirits was at work , but also capable of determining when illness or death was the result of bodily imbalance and immoderate lifestyles . for all of these reasons , the views ascribed to physician he can only be understood in relation to the rhetorical conventions of warring states narratives about divination .
what is more , an understanding of the significance of physician he requires that we move beyond the earlier , decontextualised readings of the commentary to appreciate the role that historiographical conventions played in creating the medical persona and shaping the self - fashioning of later healers . indeed ,
our contention that physician he was originally the creation of chroniclers receives support from a later account found in the discourses of the states ( third century bc ) . for the most part , the later description overlaps with the earlier presentation in the commentary .
yet it is worth pointing out that the later account provides a few new details , which further suggest that the physician was a rhetorical device .
the discourses altogether drops the theory of the six qi and instead focuses on master zhao s impending death . as a result
, the association between physician he and older views of sickness and death as divine punishment is still more pronounced .
moreover , the later text provides us with a remark not found in the earlier commentary . at one point
, minister zhao asks physician he whether healers have a role to play in state affairs , to which the physician remarks , the superior physician rescues the state , whereas the inferior one merely attends to the sick.
the physician s comment underscores the rhetorical interchangeability of the good minister and the exemplary physician in early chinese chronicles . and
indeed , in many other texts from early china , the physician stands in a metonymical relationship to the sagely minister , just as the body exists in parallel to the body politic .
our foregoing discussion begs the question how physician he became a medical ancestor , particularly one credited with the naturalistic turn in chinese medicine .
for this to happen , the rhetorical account in the commentary by zuo had to be first remade into a literal piece of medical history , and physician he had to be transformed from a rhetorical device to an actual historical personage .
the physician s name is noticeably missing from the great compendiums of the han medical tradition : the yellow emperor s inner classic [ ] , the pharmacopeia of the divine husbandman [ ] , and the classic of difficult issues [ ] .
moreover , the name of the physician can not be found in any of the formula books or manuals for vessel diagnosis recovered from qin ( 221206 bc ) and han - dynasty ( 206 bc
the first presentation of physician he as a historical personage and medical ancestor occurs in the seven summaries [ ] . written by liu xin [ ] ( ca .
ad 23 ) , son of the imperial bibliographer liu xiang [ ] ( 776 bce ) , the text was based on an earlier catalogue that contained a bibliography of all surviving medical texts , compiled with the assistance of court physician li zhuguo [ ] .
here
, liu xin provides the first reference to physician he after centuries of silence :
in high antiquity , there was qibo and yufu ; in middle antiquity , there was bian que and physician he , whose analyses of illnesses had implications for the state and who examined the body to learn of the circumstances of governance . since the founding of han , there was the lord of the granaries [ ie .
at present , the technical arts have fallen into obscurity , and so for this reason , i have analysed the documents , ordering such arts into four kinds .
in high antiquity , there was qibo and yufu ; in middle antiquity , there was bian que and physician he , whose analyses of illnesses had implications for the state and who examined the body to learn of the circumstances of governance . since the founding of han , there was the lord of the granaries [ ie .
at present , the technical arts have fallen into obscurity , and so for this reason , i have analysed the documents , ordering such arts into four kinds .
the passage is worth marking , for we must first bear in mind that the genealogical account that contains physician he was not only associated with healing , but with the technical arts ( fangji [ ] ) more generally . by some han - dynasty accounts , such arts encompassed astrology , hemerology , and diviners .
in other words ,
the new role awarded to physician he moreover deserves comment . here , physician he figures in a genealogical account that treats medicine and other related arts as a subject of independent enquiry rather than as a metaphor for statecraft .
along with bian que , who also played a large role in political allegories from the warring states , physician he is now presented as an exemplary practitioner of the middle ages , a halfway point between a golden antiquity and recent times . to put it differently ,
physician he is no longer a rhetorical construct or literary prop , but rather a historical person that anchored the craft in space and time .
the sudden interest in physician he after so many centuries of silence and in a discussion concerned primarily with medical matters is striking .
granted , liu xin is never explicit as to why physician he acquires so much importance both as an ancestor and a historical personage .
we may attribute the interest in part to logistical factors ; in contrast to his contemporaries , liu had access to the commentary , which made it possible for him to hear of physician he in the first place .
in addition , the personal agendas of liu xin and his father undoubtedly played a role . to see this , we must not only bear in mind that the lius associated physician he with all forms of technical knowledge , but also that they saw the early physician as epitomising the connections between technical learning and statecraft . to paraphrase liu , physician he examined the body to learn of state matters .
in other words , the expertise of masters of the technical arts extended to the health of the body politic .
the importance of such a message was not lost on the lius . though blood relatives of the emperor , father and son were relegated to minor posts within the han court .
in order to raise their fortunes ,
the two busily applied their knowledge of astrology to matters of state .
for them
, figures such as physician he illustrated the critical importance of giving men with mastery of the technical arts a leading voice at court . while commentaries produced in the centuries after the seven summaries disclose that physician he s position as an ancestor was secure , interestingly he did not acquire a reputation as the forefather of chinese medical naturalism until the twentieth century .
in fact , premodern works on medicine often mention he s theory of the six qi alongside his prophecy about the minister , which suggests that the interchangeability of divinatory and medical forms of knowledge remained unchanged
.
one sixteenth - century work , the history of medicine [ ] , provides a case in point .
its author even discussed the puzzle with which we began namely , how physician he came to the conclusion that the chief minister would die while examining the lord of jin . in the margins , this author noted that some were sceptical about the episode . by way of rebuttal , the same author alluded to the controversy surrounding a buddhist monk of the song dynasty ( 9601279 ) .
the monk was famous for his ability to determine the station , luck , and virtues of a person based on an examination of the pulse. and like a
divine being ( shen [ ] ) the same monk was also capable of discerning the fortune of a son based on the condition of the father .
this physician s penchant for divining apparently had created a stir , with at least one famous man objecting that the monk s feats had no precedent in antiquity and were either impossible or unorthodox .
the famous minister wang anshi [ ] ( 10211086 ) , however , disagreed , citing the example of physician he . in ancient times, wang said with approval ,
physician he examined the pulse of the lord of jin and determined that his great minister was about to die. this led him to conclude , if the fate of a minister can be seen in the pulse of the lord , what is so strange about a physician seeing the father and knowing the [ fate ] of the son?
wang does not explain his reasoning at length . presumably , he thought that since physician he knew of minister zhao s impending death , the monk could also divine a son s fate based on an examination of the father .
the comments of wang which are quoted with admiration in the ming history of medicine are illuminating .
such comments reveal that in the minds of premodern physicians and their literate patrons , there was nothing strange about a physician acquiring the qualities of a seer and being able to divine the future .
what was at stake was whether it was possible to infer someone s fate based on an examination of a close associate . for wang anshi as well as the author of the history of medicine , the answer to this question was to be found in the commentary by zuo . and given what we have learned about the original account , healers through the centuries naturally would have found the figure of physician he to their liking .
after all , physician he was as shrewd at detecting imbalances in the qi as he was at predicting the turns in the wheels of fortune .
we have seen the process by which physician he became a medical ancestor , but this raises the question of how he specifically acquired the reputation as a naturalist , particularly when he had been extolled for his ability to discern the will of heaven for two millennia . to answer this question , it would be instructive to close by reflecting on the account of physician he in chen s aforementioned history of chinese medicine . by the time this work was revised in 1937 ,
admittedly , chen s treatment of physician he does not appear to have been very different from those of his premodern forebears . much like earlier commentators , chen was something of a bricoleur , for he was in the habit of cutting out passages from ancient sources and stitching them into a new genealogical narrative .
still , there is one subtle difference worth marking , one that foreshadowed the strong associations of physician he with naturalism in the 1960s .
in recapping the story about physician he s visit to jin
, chen omits mention altogether of the prophecy both in his history of medicine and his later record of chinese medical personalities ( 1957 ) .
what is more , chen goes so far as to argue that physician he s diagnosis discloses medicine s momentous split with superstitious healers.
to understand why chen chose to downplay physician he s associations with religious experts , we must set the writing of modern accounts within a broader context of the ascendancy of biomedicine .
as sean lei shows us , not content merely to compete with practitioners of chinese medicine , western - style doctors went so far as to demand in 1929 a ban on traditional chinese drugs and acupuncture .
while ultimately unsuccessful , the call prompted a thorough re - evaluation of the indigenous medical tradition .
some of the defenders of traditional chinese medicine argued that the tradition had value because it was empirical and was thus worth retaining in spite of its metaphysical failings .
others took a different tack , however , asserting that the metaphysical framework of chinese medicine represented a symbolic system for conveying naturalistic concepts .
the decades the follow the history of chinese medicine saw intensified efforts to reconcile the indigenous medical tradition with the universal values of modern , western science .
the communist victory in 1949 brought with it state support for chinese herbs and acupuncture , as mao declared that chinese medicine represented our motherland s treasure house. such support not only spurred efforts to defend the dignity of chinese medicine , but also to reconcile it with a materialistic science so as to create what mao envisioned as the unified medicine of china .
figures such as chen bangxian and fan xingzhun , the early leaders of the institute of chinese medicine in beijing , worked towards such ends . in their writings , they upheld the universal validity of biomedicine , more specifically , and evolutionist narratives of the progress of science , more generally .
at the same time , such historians rejected the proposition that there was nothing of scientific value to the chinese medical tradition . over thousands of years of accumulated experience , such historians asserted , the chinese had made discoveries that could contribute to the progress of medicine .
and
amid the darkness of feudal society , there were forward - thinking secularists , who challenged the dominant superstitions of the day .
given such circumstances , we can see how physician he acquired his modern reputation . by omitting mention of the physician s prophecy and overlooking centuries of commentary ,
chen bangxian and later fan xingzhun were able to attribute a materialist outlook to the physician . in this way
, they could find new uses for the physician from qin , one better suited for the story of chinese medicine developing in parallel to that in the west .
rather than exemplifying the backward tendencies of traditional society , he now exemplified the genius of chinese civilisation , for in the account of the visit to jin , we find the first stirrings of a scientific mentality that also took root in greece . and indeed , roughly about the time that hippocrates purportedly broke with older views about the divine sources of illness , he s
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### Summary:
: this paper examines the reasons why physician he ( yi he , sixth century bce ) was regarded as a founder in the classical medical tradition of china . by most accounts , physician he s importance owes much to his theoretical innovations .
in contrast to earlier healers , physician he purportedly framed the aetiology of illnesses solely in terms of natural causes , as opposed to attributing sickness to gods or demons . in this paper , i reread a famous episode in the commentary by zuo , which is often cited as evidence of the physician s naturalism . by paying close attention to the formal elements of the narrative as well as its larger discursive context , i argue that the standard reading of physician he falls short .
the episode provides little evidence of any secular challenge to religious conceptions of illness , and physician he was , in fact , patterned after occult experts .
a careful look moreover at the reception of physician he in premodern histories of medicine reveals that the physician was extolled for his attunement to the will of the spirits as well as his powers of examination .
physician he s reputation as a naturalist furthermore represents a modern interpretation , one that reflects efforts to defend the indigenous medical tradition against its biomedical detractors .
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: multiple sclerosis ( ms ) is a chronic disease of the central nervous system ( cns ) characterized by unpredictable clinical relapses and remissions and/or by progression of disability over time .
relapses are considered to be the clinical expression of acute inflammation in the cns , whereas progression reflects chronic demyelination , gliosis , and axonal loss . although axonal / neuronal damage has been recognized in ms for more than a century , a refocused interest on the role of axonal pathology and neurodegeneration as the cause of permanent neurological disability in ms patients appeared since the 1990s [ 49 ] .
the development of new immunostaining protocols and new magnetic resonance imaging ( mri ) techniques has enabled earlier detection of more subtle changes in diffuse neuroaxonal pathology not only within focal white matter [ 6 , 10 ] and gray matter lesions [ 1113 ] , but also within normal appearing white matter ( nawm ) [ 1416 ] and normal appearing gray matter in ms [ 14 , 15 ] .
current evidence suggests that axonal loss occurs at an early stage of ms [ 6 , 17 ] , but because of cns compensatory mechanisms it remains clinically silent until a threshold level of axonal loss is achieved and the functional reserve capacity is exhausted [ 9 , 18 ] .
subsequent progressive axonal loss underlies a continuous and irreversible neurological decline , causing a transition from initially relapsing remitting ( rr ) to the secondary - progressive ( sp ) ms [ 7 , 9 ] .
since inflammation correlates only poorly with disability and the loss of neurons and axons may be subject to biochemical monitoring , biochemical markers of neuroaxonal degeneration gain increasing importance .
such biomarkers could provide tools for development and evaluation of new therapeutic strategies and might serve as prescreening tools and/or cross - sectional surrogate endpoints in ms clinical trials [ 22 , 23 ] , more importantly in those testing potentially axon - protective compounds . additionally , the assessment of neuroaxonal biomarkers could help in better understanding of ms pathogenesis and identification of disease subtypes , as well as in routine patient management for ( 1 ) prediction of conversion to ms after a first clinical episode , ( 2 ) early prediction of disease course and future disability , ( 3 ) selection of patients for individually tailored treatments , and ( 4 ) monitoring of disease activity and individual treatment response [ 23 , 2527 ] .
however , it is unlikely that a single biomarker could serve for any of these aims due to the extreme complexity of the pathogenetic processes which cause tissue damage and neuroaxonal loss in ms .
recent research has introduced new candidate biomarkers but also elucidated pathogenetic and clinical relevance of the well - known ones .
this paper reviews the existing data on blood and cerebrospinal fluid ( csf ) biomarkers of neuroaxonal damage in ms in the light of their clinical relevance and suggests strategies for future research in this field .
the mechanisms leading to axonal damage in ms are essentially not well elucidated . however , challenging some clinical [ 2830 ] , neuroradiological , and neuropathological [ 11 , 32 ] observations that neurodegeneration in ms might progress independently from or even precede the inflammation , recent neuropathological reports confirmed the positive correlation between axonal pathology and the degree of inflammation even in cases with progressive ms [ 33 , 34 ] .
this further supports the scenario in which a variety of effectors from the inflammatory microenvironment could injure axons , such as direct attack by autoreactive antibodies [ 3537 ] or cytotoxic cd8t - cells [ 36 , 38 , 39 ] , invading macrophages , proteolytic enzymes , cytokines , nitric oxide [ 3941 ] and free radicals [ 42 , 43 ] , defects in calcium homeostasis , glutamate - mediated excitotoxicity [ 43 , 44 ] , an increased axonal energy demand , and mitochondrial injury and failure [ 45 , 46 ] ( figure 1 ) .
axonal damage could also be secondary to acute or chronic demyelination [ 6 , 47 ] , damaging changes in sodium channel distribution [ 2 , 48 ] , and disruption of axonal / glial interactions [ 49 , 50 ] as well as related to the lack of myelin - derived trophic deprivation and/or impaired axonal regeneration by axon growth inhibitory molecules including those from myelin debris recently called myelin - associated inhibitory factors ( maifs ) such as myelin - associated glycoprotein , oligodendrocyte myelin glycoprotein , nogo - a , semaphorin 4d / cd100 , and ephrin b3 [ 51 , 52 ] ( figure 1 ) .
following damaging processes , molecules released from neuronal cytoplasm , membrane , or nucleus are released into the extracellular cns compartment ( figure 2 ) and their further metabolic , transport , and reuptake mechanisms , drainage pathways or other interactions with the cns tissue , as well as the degree of tissue destruction would determine the level of these substances in csf and blood .
csf analysis is more pathology specific as it provides information from the body fluid that is most closely associated to the disease process , but sometimes substances measured in lumbar - sac - csf are not necessarily completely representative of brain pathology .
however , there is a need for new biomarkers in more easily accessible body fluids such as peripheral blood , since substances produced within the cns and found in the blood could also be representative of the ongoing cns pathology .
csf and/or blood levels of biomarkers associated with neuroaxonal injury in patients with ms and clinically isolated syndrome suggestive of ms ( cis ) are summarized in tables 1 , 3 , 4 and 5 and their relation to clinical parameters in table 2 .
neurofilaments ( nfs ) are cytoskeletal proteins which play a role in stabilizing axons , determining axon diameter and participate in axonal transport [ 54 , 55 ] . as nfs are found exclusively within neurons , their detection in blood or csf therefore reflects neuronal and axonal damage .
mammalian nfs consist of different subunits : nf - light chain ( nf - l ) , which serves as a backbone for nf- intermediate chain ( nf - m ) and a heavy chain ( nf - h ) to copolymerise .
the most abundant , the smallest and most soluble nf subunit is nf - l but is susceptible to proteases . on the other hand ,
phosphorylated parts of nf molecules are mostly abundant within hf - m and nf - h subunits , and the state of phosphorylation influences axonal diameter .
the highly phosphorylated nf - h are normally found only in axonal nfs and this marker is thought to indicate axonal injury and/or degeneration , whereas nf - l constitutes only a minor part of the neuronal cell body and dendrites relative to axons .
nf - h phosphorylation may increase during the progressive phase of ms . due to the lower molecular weight of nf - l and/or its lower phosphorylation rate
, nf - l could diffuse earlier from the parenchyma into csf than nf - h , but also could be degraded quicker . although changes in the blood - brain barrier ( bbb ) might influence the csf nf - l concentration , the degree of such influence was considered to be negligible .
healthy individuals have no nf - l in their csf , whereas most people with neurological disorders , such as amyotrophic lateral sclerosis , stroke , ms and alzheimer 's disease , can have elevated levels .
several studies have shown the increase of the csf nf - l levels in ms or cis patients ( table 1 ) , in the latter more so in those who converted to ms within 3 years .
on the other hand , csf nf - l was detectable at low concentrations , or even undetectable in some other studies albeit the assay was similar to that used by others .
csf nf - l levels were reported to be increased during acute relapses [ 54 , 64 ] , in patients with enhancing mri lesions , as well as in patients with higher relapse rate ( table 2 ) and were also shown to have a peak during the first two months after the start of the previous exacerbation and to gradually decrease thereafter to a low level . a correlation between nf - l with expanded disability status scale ( edss ) score as a disability measure
norgren et al . reported a significant correlation between csf nf - l levels and progression index over 10 years whereas in a recent study the risk for high multiple sclerosis severity score ( msss ) at long - term follow - up after 14 years was increased threefold for cases with high nf - l levels .
conversion from rrms to spms was more likely in cases with high csf nf - l levels when compared with those with undetectable or intermediate nf - l levels ( table 2 ) .
other authors could not demonstrate any correlation with disability measures [ 64 , 66 ] . in some studies csf
nf - l concentration did not correlate with gender or age [ 61 , 64 , 66 , 67 ] or disease duration [ 64 , 65 ] , but in some reports csf nf - l levels were found to increase with age .
blood nf - l levels have not been reported to date ( table 1 ) .
nf - m subunit has not been analysed so far in body fluids of ms patients . in patients with optic neuritis ( on ) , the levels of nf - h phosphorylated form ( nf - h ) in plasma , or its hyperphosphorylated form in csf ( nf - h ) , as well as csf nf - h levels in cis patients , were found to be significantly higher compared to controls ( table 1 ) .
significantly higher csf nf - h levels in ms patients than in control subjects ( table 1 ) were also reported in several recent studies ( table 1 ) [ 23 , 54 , 72 ] , with higher , or significantly higher [ 54 , 62 ] levels in patients with a progressive course .
opposite to these findings , no difference in csf levels of this biomarker was found between rr , sp and primary progressive ( pp ) ms patients by eikelenboom et al . .
in some studies , csf nf - h levels correlated significantly with edss score both in cis and ms patients [ 54 , 62 ] .
csf nf - h levels also significantly correlated with the ambulation index and the nine - hole - peg test scores , as well as with the msss . in the latter study the degree of nf phosphorylation ( ratio , hyperphosphorylated versus phosphorylated nf - h ) was 8-fold higher in severely versus mildly disabled patients , whereas no correlation of nf - h levels with edss was found in some other studies in csf or plasma .
the highest csf nf - h levels were found during relapses [ 25 , 54 ] or correlated with mri lesion enhancement , but petzold et al . found no correlation of plasma hf - h with the relapse rate . in the study of brettschneider
et al . , the sensitivity for predicting conversion to clinically definite ( cd ) ms after cis was generally low , but could be increased by combining mri with csf nf - h criteria . additionally , a tendency towards a higher rrms to spms conversion rate over 3 years in patients with high csf nf - h levels was also shown . moreover , petzold et al .
found significantly higher plasma nf - h levels in on patients with poor recovery of visual acuity than in those with good recovery . in the study of lim et al . ,
in which 8/18 patients in the on trial and 15/32 subjects in the ms attack trial were treated with oral methylprednisolone , in the ms attack trial group , csf nf - h and nf - h measured at week 3 and csf nf - hlevels from baseline to week 3 were predictive of clinical outcome at week 8 and 52 . in the study of rejdak et al . ,
csf nf - h levels inversely correlated with the edss recovery grade over a short - term follow - up of 68 weeks .
moreover , in 30 rrms patients , plasma nf - h levels were higher , albeit nonsignificantly , in nonresponders than in responders to ifn beta1-a or 1-b over 1 year of treatment .
a correlation of csf nf - h levels with age was found in cis or ms patients in some studies , but in the others no age influence [ 62 , 66 ] or a correlation with disease duration was found [ 66 , 72 ] .
axonal damage and subsequent exposure of nfs could lead to antibody generation in a t - cell - dependent secondary immune response to a foreign antigen .
cytoskeletal and myelin debris , released by neurons , are removed by macrophages which may be able to reach the peripheral lymph nodes .
additionally , anti - nf - antibodies could be induced from exposure to exogenous agents , possibly virus - derived peptides and subseqently may cross - react with neuronal antigens .
autoimmune responses to neuronal antigens might contribute to axonal damage and irreversible disability in ms , but could also be an epiphenomenon . in the latter study , intrathecal immunoglobulin ( ig ) g and
igm anti - nf - l synthesis did not differ between ms subgroups ( rr , sp , or pp ) or between cis , ms patients , or healthy controls ( table 3 ) .
on the other hand , the intrathecal anti - nf - l igg was shown to correlate with mri parameters of cerebral atrophy and nf - l - autoimmunity has been also recently reported to be pathogenic in mice .
additionally , anti - nf - l - igg levels in serum were found to be significantly increased in ppms patients compared to other neurological diseases or healthy controls and in some studies a specific csf / serum anti - nf - l igg index correlated with edss or msss scores [ 74 , 81 ] ( table 2 ) . in some reports
, anti - nf - l levels did not correlate with age or disease duration or edss score [ 66 , 80 ] , although some other authors showed a correlation between both anti - nf - l igg index and csf anti - nf - l igg and duration of symptoms before lumbar puncture .
anti - nf - m antibody response was analyzed in ms in a few studies . in a study of barto
, the extent of anti - nf - m antibody levels did not correspond to any individualized clinical profiles of ms patients although the intrathecal production of igm and igg anti - nf - m was significantly increased in all ms subgroups compared to patients with other diseases or healthy controls ( table 3 ) . in the latter study ,
the intrathecal igg and igm anti - nf - m synthesis in ms patients was unrelated to gender , age , disease duration , and edss score , but fialov et al
. found a correlation between anti - nf - m igg intrathecal synthesis and disability .
anti - nf - h igg in csf / serum was found to be similar in ms patients and controls and between rr , sp , and ppms patients ( table 3 ) .
the intrathecal production of anti - nf - h igg correlated with some parameters of brain atrophy such as the parenchymal fraction .
the csf anti - nf - h levels correlated with the duration of disease before lumbar puncture and edss score in the study of silber et al . , but no correlation with edss was shown by others .
in addition to nfs , the other major component of the axonal cytoskeleton is the microtubule , which mainly consists of and tubulin subunits , but also of microtubule - associated proteins ( maps ) such as map2 and tau .
tubulin comprises as much as 20% of the cellular protein in brain and is mainly responsible for axonal migration and longitudinal growth as well as for providing the conduit for fast axonal transport .
csf tubulin levels were found to be increased in progressive ms ( sp+pp ) patients as compared to rrms or controls ( table 4 ) .
antitubulin antibodies were also investigated and in some studies csf levels of these antibodies were shown to be increased in ms patients , a finding which was not shown by others .
csf tubulin levels , but also csf antibodies to tubulin and the csf / serum antitubulin index correlated significantly with edss in one study , whereas no similar correlations with disability were found in two other studies [ 81 , 83 ] ( table 2 ) . no correlations of antitubulin antibodies
csf actin levels were found to be significantly elevated in ms patients than in the control group , with higher levels in progressive ms cases and correlated with the edss scores ( table 4 ) .
anti - actin antibodies were not separately investigated in ms patients to date and could also be detected in normal sera .
gelsolin is an actin - binding protein that regulates actin organization and is expressed in neurons in addition to the other cells .
additionally , its secreted isoform could be found in the circulation and belongs to the extracellular actin scavenger system . following some preliminary results showing low blood and csf gelsolin concentration in 4 ms patients , kulakowska et al .
recently reported significantly lower plasma gelsolin levels in ms samples than in controls , whereas there was no difference in its csf levels between the two groups ( table 4 ) .
tau is an axonal cytoskeletal protein that is involved in microtubule assembly and stabilisation and therefore is essential for the efficient axonal transport .
abnormal phosphorylation of tau can lead to the formation of potentially neurotoxic insoluble tau aggregates that have been shown to be characteristic features of common neurodegenerative diseases [ 97 , 99 , 100 ] .
pathological studies demonstrated the association of abnormally phosphorylated tau ( p - tau ) protein with spms and ppms [ 101 , 102 ] but also the absence of insoluble tau fraction in early ms , thus indicating the possibility that insoluble tau accumulates with disease progression [ 100 , 102 ] .
total - tau ( t - tau ) protein and/or p - tau have been investigated in a respectable number of studies performed in cis [ 25 , 54 , 103106 ] and ms patients ( table 4 ) and the reported results are quite contradictory .
tau protein could be detectable in serum , but in concentrations that are ten times lower than in csf .
csf t - tau levels in cis have been reported to be higher than in controls , but other authors found no difference in t - tau or p - tau compared to controls [ 104106 ] ( table 4 ) . in some ms studies , csf levels of t - tau [ 103 , 107110 ] and p - tau were reported to be significantly higher in ms patients than in controls , whereas some other authors could not confirm these differences [ 54 , 104 , 111 ] .
t - tau and p - tau were also investigated in childhood rrms cases in which their csf levels were similar to controls .
a positive correlation of csf t - tau levels was shown with edss in rrms and cis patients and with the progression index over 3 years in early rrms , but in some other studies no correlation with disability in cis or ms was demonstrated for the csf [ 103 , 104 , 110 ] or serum and csf levels ( table 2 ) .
two studies have indicated an increased csf - tau release in clinically active disease states [ 109 , 114 ] , in one study there was a significant elevation of csf t - tau among patients with gadolinium - enhancing brain mri lesions , but the latter finding was not confirmed afterwards .
however , the relation of csf tau levels with the extent of intrathecal inflammation in ms was also supported by findings of bartosik - psujek and archelos who showed a significant positive correlation between csf t - tau levels and igg index . as shown by brettschneider et al . , the sensitivity and specificity of csf tau levels for predicting cis conversion to cdms was generally low , but could be increased by combining with mri parameters or with nf - h levels .
could not show a significant predictive value of csf t - tau in patients with acute myelitis either for conversion to ms or for disability after a median followup of 6.2 years , but in the study of martnez - ylamos et al .
, csf - t - tau was the only independent variable to predict time to the next relapse ( table 2 ) .
interestingly , phosphorylation of tau and axonal pathology were significantly reduced when eae rats were treated with prednisolone , but similar findings in ms were not reported .
although csf t - tau levels were found associated with age in the control group in the study of bartosik - psujek and archelos , no correlation of csf t - tau / p - tau levels with age or disease duration was found in the majority of other studies [ 104 , 106 , 107 , 110 , 111 , 117 ] .
amyloid precursor protein ( app ) probably works as a cargo receptor for binding proteins during axonal transport , but could have some other important neural functions including those in memory processes .
app is transported by a fast anterograde axonal transport and subtle changes in axonal transport or axonal transection could lead to app deposits in the axon that are easily detectable by immunocytochemistry . based on immunopathological findings
, it was suggested that app accumulation could be a sensitive marker of ms disease progression , but also a potential marker of acute or active ms .
app is cleaved by an integral membrane aspartyl protease ( -site app - cleaving enzyme 1 , bace1 ) , which results in the release of n - terminal -cleaved soluble app ( -sapp ) .
the c - terminal fragment is further processed by -secretase to yield the amyloid beta ( a42 ) and the app intracellular domain .
app can also undergo -secretase - mediated cleavage , which results in the release of the solubile -sapp . in the recent study of mattsson et al .
, csf levels of -sapp , -sapp , and a42 were significantly lower in ms patients than in controls and patients with ongoing or recent ms exacerbation had lower -sapp levels than stable ms patients .
csf bace1 activity was slightly reduced in patients with ms compared to controls and patients with spms tended to have lower bace1 activity than patients with rrms .
baseline bace1 activity did not predict change in edss score after 10 years ( table 2 ) but low bace1 activity was associated with prolonged ms disease duration and disease severity .
in contrast to controls , a reduction in bace1 activity over 10 years was seen only in rrms , whereas patients with spms displayed constantly low bace1 activity levels .
additionally , two molecules , bri2 and bri2 - 23 have been shown to interact with app and regulate a42 cleavage and aggregation in vivo [ 124 , 125 ] .
recent findings revealed that csf levels of bri2 - 23 , a peptide cleaved from bri2 , may be a biomarker of cerebellar / cognition dysfunction in progressive ms patients in which csf bri2 - 23 levels have been recently shown to be decreased . in a recent study of mori et al .
, csf a42 levels were significantly lower in cognitively impaired ms patients and were inversely correlated with mri parameters of disease activity . on the contrary , vali et al
. found a significantly higher csf a42 levels in ms patients compared to the control group ( table 4 ) .
no study has followed the effect of treatment on csf - app - derived proteins although some preliminary results in 16 nondemented , non - ms patients indicated a significant decrease in csf a42 levels following corticosteroid treatment .
csf a42 levels were not shown to correlate with age or disease duration [ 122 , 126 ] .
n - acetylaspartate ( naa ) is the amino acid synthesized and almost exclusively localized in neurons and is one of the most abundant molecules in the cns .
postmortem studies of spinal cords from ms patients related lower tissue concentrations of naa to the lower axonal volume .
several functions of naa molecule in the cns have been hypothesized , such as ( a ) an osmolite to remove water from neurons , ( b ) an acetate contributor in myelin sheath synthesis , ( c ) a mitochondrial energy source , ( d ) a precursor for n - acetylaspartyl glutamate , and ( e ) a ligand for certain metabotropic glutamate receptors .
brain proton mr spectroscopy ( mrs ) allows in vivo examination of axonal integrity by quantifying the resonance intensity of naa .
previous proton mrs studies have found the reduced naa levels in ms lesions , the surrounding nawm and cortical grey matter , and a decline in global mrs - naa levels was also demonstrated in benign ms . a decrease in relative naa levels by proton
mrs was found in patients with cis in cns gray matter and wm lesions .
other studies have shown that naa decrease in lesions and nawm is related to clinical disability and progressive brain atrophy [ 136138 ] and was indicated to be a feature of progression .
moreover , some preliminary mrs findings have shown a beneficial effect of glatiramer acetate on increase of relative naa peaks in ms lesions and nawm over 2 years , whereas relative naa peaks had become significantly higher in the interferon beta - lb -treated ms patients following 1 year of treatment . in the study of jasperse
, csf concentrations of naa correlated with edss and ms functional composite ( msfc ) ( table 2 ) , although these levels were similar to controls both in ms and early ms patients .
csf naa levels were shown to be lower in spms patients compared to rr and ppms cases [ 54 , 141 ] ( table 4 ) .
reported a decrease in csf naa levels as the disease progressed , therefore possibly reflecting the accumulation of axonal degeneration in a later ms stage .
apolipoprotein e ( apo - e ) is mostly produced by astrocytes in the cns , but it is also found in neurons .
there are three different alleles of the human apo - e gene coding for the three isoforms : 2 , 3 , and 4 .
however , its functions within the cns are not so clear and might include immunomodulation , a protective role against oxidative stress , a role in maintaining the bbb integrity , a role in myelin lipid metabolism , and a potential role in neurorepair . as there is a limited permeability of apo- e across the bbb , apo- e changes in csf might dominantly result from a reduction of its local synthesis and secretion by brain tissue [ 146 , 149 ] .
several studies have indicated that apo - e 4 allele might be associated with ms , although evidence is still not sufficient enough [ 146 , 150 ] .
although plausible , the association between apo - e and ms course and disease severity remains controversial .
apo - e genotypes seem not to influence the development of ms , but apo - e 4 allele might predispose carriers with ms to a faster disease progression [ 153 , 154 ] . in line with this ,
lower levels of naa in ms patients with the apo - e 4 allele have been demonstrated by mrs .
it has been recently suggested that apo - e polymorphism may interact with cigarette smoking in promoting ms progression .
although some authors have shown an association between apo - e 4 and cognitive impairment in ms patients , the others could not confirm this finding .
however , it was suggested that the decreased csf apo - e concentration in ms patients occurs independent of the apo - e genotype . in one study
the plasma concentration of apo - e was significantly lower in ms patients than in healthy controls although its csf concentrations were similar in these two groups .
have shown higher csf / serum apo - e index in rrms in remission compared to controls , chiasserini et al . demonstrated an increased csf expression of an apo - e isoform in rrms compared to cis patients or controls , whereas gaillard et al
. found lower concentrations of both csf apo - e and intrathecal apo - e in ms patients than in controls ( table 5 ) .
no correlation of apo - e in serum or csf with age or clinical course was found .
enolase is a glycolytic enzyme ( 2-phospho - d - glycerate hydrolase ) , which exists in three isoforms : -enolase , which is ubiquitous , -enolase , which is predominant in muscle , and -enolase ( neuron - specific enolase , nse ) , which is found in neurons , glial , and neuroendocrine cells .
nse was shown to be an indicator of the acute neuro - destructive disorders , but its levels are usually normal in ms patients and no clear difference in the nse levels has been observed between ms patients and controls in csf or serum , or between patients with rr and spms in csf ( table 4 ) .
nse concentration in csf and serum was shown to be decreased in cis patients when compared to the control group , potentially indicating a reduced neuronal metabolic activity at the early stage of the disease .
interestingly , forooghian et al . demonstrated a higher t - cell responses against nse in the peripheral blood mononuclear cells of ms patients than in controls .
one study which followed csf nse levels in ms patients treated with intrathecal triamcinolone administration did not show any changes in its levels following treatment .
a recent study examined plasma nse levels in ms patients over a five - year period and found a strong inverse relationship between serum nse levels and disease progression as expressed through edss and msss score changes , thus potentially reflecting a reduced metabolic activity secondary to axonal loss . in two other studies
no correlation of csf [ 64 , 105 ] or serum nse levels were found with edss ( table 2 ) .
age - related changes of nse in csf with an increase of 1% per year have been reported , but in some other studies csf nse levels were independent of gender , age [ 64 , 165 ] , and disease duration .
growth - associated protein 43 ( gap-43 ) , also known as b-50 or neuromodulin , is a marker associated with growth cones , synaptic plasticity , and synaptic regeneration .
it is a calmodulin - binding protein being attached to the cytoplasmic site of the axonal membrane , involved in neurotransmitter release which also stimulates neurite outgrowth .
a decreased gap-43 expression was found in postmortem white matter ms lesions , independent of the lesion stage , whereas increased or unaltered expression was detected in remyelinated lesions and was found unchanged in grey matter lesions . in a recent study ,
csf gap-43 levels were comparable among rr / sp and ppms subtypes and controls and gap-43 was not detected in serum ( table 5 ) .
a tendency towards a negative correlation between csf gap-43 levels and edss was found , but csf gap 43 levels positively correlated with mri measures of atrophy ( table 2 ) .
no significant correlation was reported between csf gap-43 levels and age , gender , and disease duration .
cholesterol plays a crucial structural role in the brain being the main lipid of neuronal membranes . for maintenance of brain cholesterol homeostasis
, cholesterol is converted into its more polar metabolite cerebrosterol ( 24s - hydroxycholesterol , 24s - oh - chol ) by the cns - specific cytochrome p450 enzyme cyp46 .
virtually all of the cerebrosterol in the peripheral circulation is cns derived and its blood levels are assumed to reflect the relation between cholesterol cns production caused by demyelination or neurodegeneration and hepatic clearance [ 170 , 177 , 178 ] .
the level of 24s - oh - chol highly correlated with total cholesterol and the ratio between 24s - oh - chol and cholesterol is assumed to be a better marker for the cerebral production than the absolute cerebrosterol concentration .
the majority of daily efflux of this oxysterol from the brain to the circulation apparently occurs as a direct transport across the bbb and less than 1% of the total flux of 24s - oh - chol from the brain occurs via csf , which might cause the lack of correlation between csf and plasma levels of this metabolite .
the higher csf levels of 24s - oh - chol were shown in patients with gadolinium - enhancing mri lesions , indicating the pronounced release of the 24s - oh - chol from damaged cells during cns inflammation [ 171 , 173 ] ( table 2 ) .
moreover , patients with a defective bbb were found to have markedly increased absolute levels of 24-oh - chol in csf .
. demonstrated a negative correlation between the cerebrosterol / cholesterol ratio in plasma and volume of t2-weighted mri lesions , whereas a significant inverse relation between the edss score and plasma cholesterol - related levels of 24s - oh - chol was found in the other study .
showed the reduction in serum 24s - oh - chol concentrations to be most pronounced in the pp clinical subtype ( table 5 ) .
found a tendency to increased plasma levels of 24s - oh - chol in younger patients with high levels in the 3rd and 4th decades of life , and significantly lower levels in older ms patients aged 5170 years than in healthy age - matched controls .
there seems to be no gender influence on plasma levels of 24s - oh - chol or the ratio between cerebrosterol / cholesterol and no correlation of the latter with disease duration was reported to date .
14 - 3 - 3 family proteins are ubiquitous , highly conserved proteins with the highest concentrations in brain [ 162 , 180 ] and within cns are constitutively expressed in neurons and glia both in cytoplasmic and nuclear regions with small amounts bound to synaptic membranes .
a growing body of evidence indicates that it might act as a novel type of molecular chaperone which interacts with key molecules involved in cell differentiation , proliferation , and transformation , and recent data suggested its antiapoptotic effects [ 183 , 184 ] .
the detection of 14 - 3 - 3 protein in the csf is highly sensitive for in vivo diagnosis of creutzfeldt - jakob disease , but this protein , in the csf , could be also detected in some other prion - unrelated conditions associated with cns tissue damage [ 175 , 181 , 186 ] .
the 14 - 3 - 3 protein is more frequently detectable in the csf of ms or cis patients than in controls although in such cases it is present in a small subgroup of patients [ 108 , 174 ] .
the detection of the 14 - 3 - 3 protein in the csf of cis patients was shown to be an independent predictor of short - term conversion to cdms [ 175 , 176 ] ( table 2 ) . moreover ,
the 14 - 3 - 3 positive group had a significantly higher relapse rate and a higher frequency of patients with edss 2.0 after a median followup of 33.4 months , which confirmed previous results by the same authors . in some studies , 14 - 3 - 3 protein positivity in ms patients
was associated with a more severe disability [ 140 , 187 ] and the rate of disease progression during a mean of 10-month clinical followup , but was also shown to be a potential predictor of permanent neurological disability after an episode of the acute transverse myelitis .
however , the latter was not shown in two other studies [ 115 , 174 ] .
the presence of 14 - 3 - 3 reactivity was not shown to prevail in ms clinical subgroups and seems not to correlate with age or disease duration .
recently , a rapid development of proteomic approaches refocused biomarker research interest to the use of novel methods in the discovery of potential ms - specific biomarkers in biological fluids and especially in the csf [ 189 , 190 ] . among the wide range of proteins that have been found to be exclusively present in the csf of ms patients [ 125 , 189 , 191194 ] ,
only some of them are expressed on neurons ( contactin-1 , neurofascin , neurotrimin , and chromogranins / secretogranins ) [ 193195 ] .
it was recently shown that contactin-2 was recognised by both autoantibodies and th1/th17 t - cells in ms patients [ 36 , 37 ] and neurofascin - specific autoantibodies were identified in ms patients
. however , there is a range of neuroaxonal proteins which still need to be studied in cis / ms patients although some of them have been investigated in animal models .
based on the majority of available results , the increased levels of the csf nf - l or nf - h seem to be present even at early ms phases , a scenario which continues during the entire course of the disease and correlates with different measures of disability ; the increased levels of these markers seem to be more pronounced in active disease states and have a potential value in an effort to predict conversion to cdms after a first cis episode , estimate future progression and disability , but their value for the prediction of treatment response still has to be investigated , most importantly in early ms patients . although the presence of anti - nf antibodies could , in part , be an epiphenomenon of the disease , the elevated levels of these antibodies in progressive disease and correlations with disease duration and disability indicate a rise in antibodies induced by axonal destruction , but also a possible pathogenic role of these antibodies in promoting axonal damage and disease progression .
this indicates that serum and/or csf anti - nf - l , nf - m , and nf - h antibodies might be a potential a marker of cns tissue damage in ms , but their potential predictive value for the future disease course , disability , disease progression , and treatment response needs to be investigated .
csf levels of actin and tubulin seem to be elevated in progressive ms and correlate with disability , but their levels in early ms patients , as well as the potential predictive value have been underreported to date . it is possible that elevated csf t - tau levels are present from early ms phases and increase in clinically / mri active disease phases ; although its potential correlation with ongoing disease progression has been indicated , the reports related to this molecule so far have been quite contradictory and its validity as a biomarker needs to be further studied both in blood and csf .
csf and blood levels of app - derived proteins seem not to be reliable markers of disease activity or progression since their levels are largely dependent on complex regulatory metabolic processes which could be highly variable in a complex and heterogenous disease such as ms .
a correlation of csf naa levels with disability measures even in cis patients suggests the potential clinical relevance of this molecule as a biomarker that should be further investigated .
nse and apo - e levels in csf / blood are not consistently abnormal in ms patients and their relation to neuroaxonal damage is complicated since the expression of both molecules is not limited to neurons .
csf / blood levels of gap-43 were investigated to date in a paucity of studies and some preliminary results might indicate the need for further investigations of this molecule as of the potential biomarker of disease progression and disability .
24s - oh - chol levels seem to be as reliable as levels in csf to estimate neuronal membrane status .
some reports indicated its correlation with disability and ms disease activity and thus the validity of this molecule as a biomarker should be further investigated .
the 14 - 3 - 3 family proteins could be potentially related to cis conversion to ms , disability , and its progression , but this still has to be further confirmed .
astrocyte - derived 14 - 3 - 3 protein could complicate the relation of csf / blood levels of 14 - 3 - 3 protein only to neuroaxonal status in ms .
additionally , it would be desirable to systematically compare the proteome profiles of ms subgroups at a defined disease stages and in large cohorts in order to identify proteins which are consistently present in the csf at a certain disease phase in a given subgroup , a task which is still facing a lot of obstacles .
so far , the abovementioned markers have been investigated in the light of their significance to reflect the presence and the extent of neuroaxonal damage in cis / ms patients .
since each of them could be related to different structural levels of neuroaxonal loss of integrity , the combined evaluation of these markers could be more informative on the ongoing neurodegenerative process .
moreover , the relevance of the single biomarker has to be judged in the light of disease stage and/or disease activity since biomarker levels could show temporal dynamics that correlates with the dynamics of the ms natural course [ 54 , 198 ] .
the results of the biomarker studies could have been influenced by small study sizes , cross - sectional designs , and insufficient followup to allow meaningful conclusions .
biomarker studies in ms neurodegeneration have been conducted in a variable patient population , varying from a few to over a hundred patients included [ 108 , 171 ] . moreover , followup in most of these studies was up to three years [ 54 , 62 , 113 , 140 , 175 , 176 ] which could allow only tentative conclusions on biomarker 's long - term prognostic significance .
the differences in preanalytical processes and different assay sensitivities could also cause contradictory results in biomarker studies .
the comparable results were shown in several studies that used the same nf - h enzyme - linked immunosorbent assay ( elisa ) method [ 62 , 7072 ] .
however , a poor interlaboratory coefficient of variation in a recent multicenter nf - l elisa validation study has been shown , mainly due to the lack of preparation of accurate and consistent protein standards .
therefore , a standardization of body fluid sampling and storage , as well as the use of the standardized and validated assay procedures [ 23 , 200 ] , are needed . since none of the potential csf / blood biomarkers studied so far fulfils all necessary criteria for a surrogate biomarker there is an ongoing need for further biomarker studies , especially those aiming to predict future disease course , disability , and/or treatment response at the early ms stage .
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### Summary:
: following emerging evidence that neurodegenerative processes in multiple sclerosis ( ms ) are present from its early stages , an intensive scientific interest has been directed to biomarkers of neuro - axonal damage in body fluids of ms patients .
recent research has introduced new candidate biomarkers but also elucidated pathogenetic and clinical relevance of the well - known ones .
this paper reviews the existing data on blood and cerebrospinal fluid biomarkers of neuroaxonal damage in ms and highlights their relation to clinical parameters , as well as their potential predictive value to estimate future disease course , disability , and treatment response .
strategies for future research in this field are suggested .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: a more complete and detailed research design and methods has been provided in the supplementary appendix .
the procedures used in the study protocol were in accordance with the helsinki declaration on human experimentation guidelines .
the study was approved by the ethical committee of the department of obstetrics and gynecology of the magna graecia university of catanzaro .
the purpose of the protocol was carefully explained to all women , and their written consent was obtained before entering the study . between february 2003 and october 2009
, 243 pregnant patients were screened for gdm and pcos from a large population of women who were suffering from hyperandrogenism and/or ovulatory disorders and seeking pregnancy , and 42 subjects were included in this study protocol as cases .
in addition , other 84 non - pcos , pregnant patients with gdm were screened in our gdm ambulatory and enrolled , after matching procedure for age and bmi with cases , as controls . a clinical evaluation , a complete hormonal and metabolic pattern assessment , and a 2-h , 75-g oral glucose tolerance test ( ogtt ) were preliminarily evaluated in each subject before pregnancy to confirm or exclude the diagnosis of pcos ( for cases and controls , respectively ) and of pre - existing dm .
pcos was diagnosed before pregnancy according to the international criteria ( 1 ) , whereas pregnant patients were included as controls if they had regular menstrual cycles before pregnancy , no signs of clinical hyperandrogenism , normal ranges of serum androgen levels , and no pco morphologies on transvaginal ultrasonography . in each subject
, gdm was defined as any degree of glucose intolerance with onset or first recognition during pregnancy using well - recognized criteria ( 9 ) . in particular ,
glucose concentrations were measured at basal and after a 2-h , 75-g ogtt in women who were not previously diagnosed with overt dm between the 24th and 28th weeks of gestation ( 9 ) . for all patients ,
the exclusion criteria consisted of the following : age > 35 years , severe obesity , multiple pregnancies , a gestational age at the gdm diagnosis that was > 28 or < 24 weeks , medical conditions or other concurrent medical illnesses , a previous diagnosis of dm , cigarette smoking , drug / alcohol abuse , noncompliance with our study protocol , and a previous use of any antidiabetic drugs . at baseline and throughout the study period , each subject was monitored with clinical , biochemical , and ultrasonographic assessments according to a specific schedule . upon entering the study ,
the socio / economic , work , and educational statuses and associated medical conditions were carefully assessed for each subject .
in addition , the women were asked to complete a questionnaire on their family history of dm or complicated pregnancies .
clinical and ultrasonographic assessments were performed at study entry and every 4 weeks until delivery . the clinical evaluation consisted of an obstetric examination , anthropometric measurements , and heart rate and blood pressure assessments . during the same visits ,
the daily diet and physical activity were monitored in all patients using two well - validated questionnaires .
biochemical assessments were performed for each subject monthly . at study entry , a 2-h , 75-g ogtt ( see above ) , a1c levels , insulin resistance , and -cell function were evaluated . in particular ,
insulin resistance was assessed with the use of two surrogate indexes , i.e. , the insulin sensitivity index ( isiogtt ) and the homeostasis model assessment of insulin resistance ( homa - ir ) , whereas insulin secretion
the monitoring and ongoing care were given by the attending obstetrical team with a physician s support .
interventions included individualized medical nutrition therapy ( mnt ) , self - monitoring of blood glucose ( smbg ) , and insulin therapy , with the dose adjusted on the basis of glucose levels .
the goals of gdm therapy were to maintain the maternal capillary glucose concentrations at < 96 mg / dl ( 5.3 mmol / l ) in the fasting state and < 140 mg / dl ( 7.8 mmol / l ) at 1 h and < 120 mg / dl ( 6.7 mmol / l ) 2 h after initiation of a meal .
treatment compliance was evaluated by an examination of the self - reported daily diary that was performed at each follow - up visit .
the adherence to the interventions ( mnt , smbg , and insulin therapy ) was defined as high , moderate , or low according to multidisciplinary parameters . during the study ,
all subjects underwent trans - abdominal ultrasonographic evaluations , which consisted of measurements of fetal growth and abdominal circumference , the placenta s location and grade , and an amniotic fluid index .
each subject was advised to monitor fetal movements during the last 810 weeks of pregnancy and to immediately report any reduction in their perception . at hospital discharge ,
persistent hyperglycemia was evaluated by measuring fasting glucose levels and mnt , whenever it was confirmed .
each patient underwent three follow - up visits at 6 weeks , 12 weeks , and 18 months after delivery .
in particular , each patient underwent anthropometric measurements and biochemical assessments , which consisted of a complete blood count , serum glucose , insulin , and a1c levels at baseline , and glucose concentrations during a 2-h , 75-g ogtt .
in particular , dm was diagnosed when the fasting plasma glucose levels were 126 mg / dl ( 7.0 mmol / l ) and/or the 2-h plasma glucose levels were 200 mg / dl ( 11.1 mmol / l ) during a 75-g ogtt .
conversely , hyperglycemia , which was not sufficient to meet the diagnostic criteria for dm , was defined as prediabetes and categorized as either ifg or igt depending on whether it was identified through the fasting plasma glucose levels or the ogtt . at each follow - up visit ,
the normal distribution of the continuous variables data was evaluated with the use of a kolmogorov - smirnov test , and a log transformation was used for the nonnormal data .
continuous variables were analyzed with a one - way anova and an anova for repeated measures with a bonferroni test for the post hoc analysis .
the relative risk ( rr ) was calculated with a 95% ci for composite outcomes and for each alteration of glucose homeostasis .
forward , stepwise , multivariate , logistic regression analysis was performed to identify independent predictors of a persistent glucose metabolism impairment .
the procedures used in the study protocol were in accordance with the helsinki declaration on human experimentation guidelines .
the study was approved by the ethical committee of the department of obstetrics and gynecology of the magna graecia university of catanzaro .
the purpose of the protocol was carefully explained to all women , and their written consent was obtained before entering the study .
between february 2003 and october 2009 , 243 pregnant patients were screened for gdm and pcos from a large population of women who were suffering from hyperandrogenism and/or ovulatory disorders and seeking pregnancy , and 42 subjects were included in this study protocol as cases .
in addition , other 84 non - pcos , pregnant patients with gdm were screened in our gdm ambulatory and enrolled , after matching procedure for age and bmi with cases , as controls . a clinical evaluation , a complete hormonal and metabolic pattern assessment , and a 2-h , 75-g oral glucose tolerance test ( ogtt ) were preliminarily evaluated in each subject before pregnancy to confirm or exclude the diagnosis of pcos ( for cases and controls , respectively ) and of pre - existing dm .
pcos was diagnosed before pregnancy according to the international criteria ( 1 ) , whereas pregnant patients were included as controls if they had regular menstrual cycles before pregnancy , no signs of clinical hyperandrogenism , normal ranges of serum androgen levels , and no pco morphologies on transvaginal ultrasonography . in each subject
, gdm was defined as any degree of glucose intolerance with onset or first recognition during pregnancy using well - recognized criteria ( 9 ) .
in particular , glucose concentrations were measured at basal and after a 2-h , 75-g ogtt in women who were not previously diagnosed with overt dm between the 24th and 28th weeks of gestation ( 9 ) . for all patients , the exclusion criteria consisted of the following : age > 35 years , severe obesity , multiple pregnancies , a gestational age at the gdm diagnosis that was > 28 or < 24 weeks , medical conditions or other concurrent medical illnesses , a previous diagnosis of dm , cigarette smoking , drug / alcohol abuse , noncompliance with our study protocol , and a previous use of any antidiabetic drugs .
at baseline and throughout the study period , each subject was monitored with clinical , biochemical , and ultrasonographic assessments according to a specific schedule . upon entering the study ,
the socio / economic , work , and educational statuses and associated medical conditions were carefully assessed for each subject .
in addition , the women were asked to complete a questionnaire on their family history of dm or complicated pregnancies .
clinical and ultrasonographic assessments were performed at study entry and every 4 weeks until delivery . the clinical evaluation consisted of an obstetric examination , anthropometric measurements , and heart rate and blood pressure assessments . during the same visits ,
the daily diet and physical activity were monitored in all patients using two well - validated questionnaires .
biochemical assessments were performed for each subject monthly . at study entry , a 2-h , 75-g ogtt ( see above ) , a1c levels , insulin resistance , and -cell function were evaluated . in particular ,
insulin resistance was assessed with the use of two surrogate indexes , i.e. , the insulin sensitivity index ( isiogtt ) and the homeostasis model assessment of insulin resistance ( homa - ir ) , whereas insulin secretion
the monitoring and ongoing care were given by the attending obstetrical team with a physician s support .
interventions included individualized medical nutrition therapy ( mnt ) , self - monitoring of blood glucose ( smbg ) , and insulin therapy , with the dose adjusted on the basis of glucose levels .
the goals of gdm therapy were to maintain the maternal capillary glucose concentrations at < 96 mg / dl ( 5.3 mmol / l ) in the fasting state and < 140 mg / dl ( 7.8 mmol / l ) at 1 h and < 120 mg / dl ( 6.7 mmol / l ) 2 h after initiation of a meal .
treatment compliance was evaluated by an examination of the self - reported daily diary that was performed at each follow - up visit .
the adherence to the interventions ( mnt , smbg , and insulin therapy ) was defined as high , moderate , or low according to multidisciplinary parameters . during the study ,
all subjects underwent trans - abdominal ultrasonographic evaluations , which consisted of measurements of fetal growth and abdominal circumference , the placenta s location and grade , and an amniotic fluid index .
each subject was advised to monitor fetal movements during the last 810 weeks of pregnancy and to immediately report any reduction in their perception . at hospital discharge ,
persistent hyperglycemia was evaluated by measuring fasting glucose levels and mnt , whenever it was confirmed . if necessary
each patient underwent three follow - up visits at 6 weeks , 12 weeks , and 18 months after delivery .
in particular , each patient underwent anthropometric measurements and biochemical assessments , which consisted of a complete blood count , serum glucose , insulin , and a1c levels at baseline , and glucose concentrations during a 2-h , 75-g ogtt .
in particular , dm was diagnosed when the fasting plasma glucose levels were 126 mg / dl ( 7.0 mmol / l ) and/or the 2-h plasma glucose levels were 200 mg / dl ( 11.1 mmol / l ) during a 75-g ogtt .
conversely , hyperglycemia , which was not sufficient to meet the diagnostic criteria for dm , was defined as prediabetes and categorized as either ifg or igt depending on whether it was identified through the fasting plasma glucose levels or the ogtt . at each follow - up visit , the rate of breast - feeding and its frequency and duration were also evaluated .
the normal distribution of the continuous variables data was evaluated with the use of a kolmogorov - smirnov test , and a log transformation was used for the nonnormal data .
continuous variables were analyzed with a one - way anova and an anova for repeated measures with a bonferroni test for the post hoc analysis .
the relative risk ( rr ) was calculated with a 95% ci for composite outcomes and for each alteration of glucose homeostasis . forward , stepwise , multivariate , logistic regression analysis was performed to identify independent predictors of a persistent glucose metabolism impairment .
before pregnancy , the cases and controls were significantly ( p < 0.05 ) different by the ferriman - gallwey score and for testosterone , androstenedione , dehydroepiandrostenedione , sex - hormone binding globulin , free androgen index , and fasting insulin levels and homa - ir ( data not shown ) .
no other significant differences in any clinical and biochemical data were detected between the cases and controls ( data not shown ) . at the same time , the distribution between cases and controls of obese ( 15 [ 35.7% ] vs. 33 [ 39.3% ] , respectively ) , overweight ( 19 [ 45.2% ] vs. 38 [ 45.2% ] , respectively ) , normal weight ( 6 [ 14.3% ] vs. 9 [ 10.7% ] , respectively ) , and lean ( 2 [ 4.8% ] vs. 4 [ 4.8% ] , respectively ) subjects was not significantly ( p = 0.865 ) different .
similarly , no significant ( p = 0.776 ) difference between the cases and controls was detected in the incidence of patients with igt ( 6 [ 14.3% ] vs. 14 [ 16.7% ] , respectively ) and ifg ( 5 [ 11.9% ] vs. 15 [ 17.9% ] , respectively ) .
spontaneous conception occurred in 22 out of 42 ( 52.4% ) cases and 71 out of 84 ( 84.5% ) controls ( p = 0.0002 ) , whereas the others had conceived under ovulation inductors , such as clomiphene citrate ( 11 [ 26.2% ] cases and 4 [ 4.8% ] controls ) , aromatase inhibitors ( 2 [ 4.8% ] cases and 0 [ 0.0% ] controls ) , or gonadotropins ( 7 [ 16.7% ] cases and 9 [ 10.7% ] controls ) .
no difference between cases and controls was observed in the proportion of pregnancies achieved with the use of in vitro fertilization techniques ( 5 [ 11.9% ] vs. 7 [ 8.3% ] , respectively ; p = 0.532 ) .
patients had full - blown , non - pco , nonhyperandrogenic , and ovulatory phenotypes in 19 ( 45.2% ) , 8 ( 19.0% ) , 5 ( 11.9% ) , and 10 ( 23.8% ) out of the 42 pcos women , respectively .
clinical data in cases and controls at baseline no differences between groups were observed in socio / economic status , daily diet , and physical activity ( data not shown ) .
all case and control subjects underwent mnt and smbg , whereas the rate of patients who needed insulin therapy was higher for the cases than the controls ( 20 out of 42 cases [ 47.6% ] and 22 out of 84 controls [ 26.2% ] ; p = 0.027 ) .
no significant ( p = 0.234 ) difference between cases and controls was detected for adherence to the treatment assigned , and , specifically , it was high in 20 out of 42 ( 47.6% ) and 39 out of 84 ( 46.4% ) , moderate in 16 out of 42 ( 38.1% ) and 35 out of 84 ( 41.7% ) , and low in 6 out of 42 ( 14.3% ) and 10 out of 84 ( 11.9% ) cases and controls , respectively .
the main maternal , perinatal , and neonatal outcomes recorded in the cases and controls are detailed in table 2 .
a total of 16 out of 42 cases ( 38.1% ) and 15 out of 84 controls ( 17.9% ) had adverse maternal / perinatal / neonatal outcomes ( p = 0.017 ) .
no differences between groups were recorded in the placental location and grade distribution , amniotic fluid index , and mean umbilical artery pulsatility index ( data not shown ) .
maternal , perinatal , and neonatal outcomes in cases and controls in table 3 , the bmi measurements and glucose metabolism parameters that were recorded at 6 weeks , 12 weeks , and 18 months after delivery for the cases and controls are reported . at each follow - up after delivery , a trend ( 0.05 < p < 0.07 ) toward a significantly higher bmi was observed in the cases compared with controls ( table 3 ) .
a significant ( p < 0.05 ) difference between the cases and controls was detected in the homa - ir and isiogtt at each follow - up evaluation ( table 3 ) .
the ogtt parameters ( including issi-2 ) were significantly ( p < 0.05 ) different between cases and controls only after 18 months .
bmi measurements and glucose metabolism parameters recorded after 6 and 12 weeks and 18 months from delivery in pcos ( cases ) and non - pcos ( controls ) patients at the 18-month follow - up , a significant ( p < 0.05 ) improvement in the ogtt parameters and in the igt and ifg - igr incidence were observed in the control group ( table 3 ) . at the same follow - up visit ,
a significant ( p < 0.05 ) difference in the igt , ifg , ifg - igr , and dm incidence was detected between the cases and controls ( table 3 ) .
the rate of patients who breast - fed was significantly ( p = 0.019 ) lower in cases than in controls ( 27 of 42 [ 64.3% ] vs. 71 of 84 [ 84.5% ] , respectively ) .
additionally , the duration ( months ) of breast - feeding was significantly lower in cases than in controls ( 2.1 1.1 vs. 5.3 2.6 ; p = 0.007 ) , whereas its daily frequency was not different between groups ( 3.6 1.2 vs. 4.8 2.1 , respectively ; p = 0.122 ) .
the rrs for igt , ifg , igt - ifg , and dm after gdm in pcos women were 4.0 ( 95% ci 1.0515.02 ; p = 0.042 ) , 2.80 ( 95% ci 0.948.3 ; p = 0.063 ) , 4.0 ( 95% ci 0.7620.96 ; p = 0.101 ) , and 4.0 ( 95% ci 0.3742.86 ; p = 0.252 ) , respectively .
the rr for the composite outcome of glucose metabolism impairment after gdm in pcos women was 3.45 ( 95% ci 1.826.58 ; p = 0.0002 ) .
the composite outcome was significantly influenced by bmi ( p = 0.010 ) and the presence of hyperandrogenism ( p = 0.032 ) , oligo - anovulation ( p = 0.044 ) , igt ( p = 0.011 ) , and ifg ( p = 0.007 ) before pregnancy .
the need for insulin therapy during pregnancy ( p = 0.036 ) and the breast - feeding ( p = 0.024 ) also significantly influenced the composite outcome .
gdm is present in 0.615% of pregnancies , and it is associated with a potential recurrence of gdm ( 10 ) and an increased risk for the development of type 1 ( 11 ) or type 2 ( 12 ) dm or igt , with a relevant impact on the later onset of cardiovascular disease ( 3,12 ) . in particular , the incidence of developing dm after gdm may vary between 20 and 60% within 5 years of pregnancy ( 13 ) .
this wide variability depends on the characteristics of the population studied ( 14 ) . in the current study
, we wanted to evaluate the hypothesis that pcos is a pathologic condition with an increased risk for the persistence / development of an impairment in glucose metabolism after gdm .
our study hypothesis was based on recognition of the syndrome as a condition related to several risk factors for igt and cardiovascular diseases ( 3 ) , to an increased risk for gdm ( 7 ) , and to an increased conversion rate form normal glucose tolerance to igt and from igt to dm ( 15,16 ) . to this aim
, we prospectively enrolled 42 consecutive subjects who satisfied standardized criteria for both pcos ( 1 ) and gdm ( 9 ) , and who were representative of the pcos population because the distributions of phenotypes , such as of igt / ifg and bmi , reflected those described in the literature ( 3 ) .
a well - selected sample of non - pcos women with gdm , who had similar characteristics and risk factors , were selected as controls .
in addition , cases and controls were also similar in prepregnancy conditions , such as parity and incidence of igt or ifg .
all these points strengthen the findings obtained in the current study . at 6 weeks , 12 weeks , and 18 months after delivery , the incidences of dm and prediabetes , i.e. , igt , ifg , and ifg - igt , as single events or a composite outcome , were evaluated in the current analysis . in the non - pcos controls with gdm
, we demonstrated a sharp improvement in the glycemic pattern and metabolic condition after delivery , with an incidence of dm and prediabetes of 1.2 and 12.0% , respectively , at the 18-month follow - up .
alternatively , a persistence of a glucose alteration was observed in 45.2% patients with pcos at the same follow - up visit .
specifically , dm , ifg - igt , ifg , and igt were found in 4.8 , 9.5 , 16.7 , and 14.3% of pcos women , respectively , which reached statistical significance compared with the controls for all end points except dm , which was likely due to the small sample studied .
our findings demonstrated that women with pcos and gdm had a 3.5-fold higher risk for impaired glucose metabolism after delivery than the non - pcos controls .
in addition , although the cases and controls had a comparable adherence to the treatment and were similarly treated with mnt and smbg at diagnosis of gdm , the subjects affected by pcos had a lower glycemic control and more frequently were in need of insulin therapy than controls . at present , no specific data that could explain our findings are available in the literature .
the multivariate logistic regression analysis , which was performed for this purpose , showed that the composite outcome was influenced by several factors occurring before pregnancy ( such as bmi , hyperandrogenism , oligo - anovulation , glucose abnormalities , and insulin resistance ) , during pregnancy ( such as the need for insulin therapy ) , and after pregnancy ( such as the breast - feeding ) , suggesting that , probably , various factors interact , increasing the risk of glucose metabolism impairment after gdm in pcos women .
pcos patients have a higher risk of conversion from normal glycemia to igt or dm , irrespective of pregnant state ( 1416 ) .
this higher risk for glucose metabolism impairment seemed strongly related to insulin resistance and influenced by bmi ( 15 ) .
in fact , pcos is a condition that is characterized by a chronic insulin - resistant state present before pregnancy , as was observed in the current study , and is exacerbated by the physiological changes that lead to insulin resistance during pregnancy ( 4 ) . in this
regard , adverse maternal / perinatal / neonatal outcomes , which are related to the insulin resistance state ( such as pregnancy - induced hypertension , preeclampsia , the type of delivery , and the gestational age at delivery ) ( 17 ) , occurred more frequently in pcos patients than in the controls .
after delivery , the insulin resistance remained worse in pcos women than in non - pcos controls .
this abnormality , already described for pcos , resulted from a combination of increased insulin resistance with defective pancreatic -cell function ( 18 ) .
it has recently been demonstrated that in women with igt during pregnancy , hepatic insulin resistance is an early determinant of declining -cell function after gestational dysglycemia in the first postpartum year ( 13 ) .
the current analysis confirmed the impaired insulin resistance state in pcos women during the early postpartum follow - ups .
moreover , at the same time , a -cell dysfunction , assessed by means - appropriate test , was also observed more frequently in pcos women .
it would be interesting to identify pcos - related factors that influence the insulin resistance state and the -cell function , with subsequent persistence of glucose alterations . in this regard
, a subanalysis of our results based on the pcos phenotypes would be clinically useful for evaluating major factors associated with abnormal glucose tolerance in pcos .
unfortunately , this analysis was not done because our sample was too small for that aim .
in addition , the roles of the different phenotypes of pcos on the metabolic pattern are still debated ( 1923 ) .
our data confirmed ( 24 ) that women with pcos have a reduced breast - feeding rate and duration , losing the beneficial effect of lactation on glucose metabolism and insulin sensitivity that may reduce dm risk after gdm pregnancy ( 25 ) .
thus , the reduced breast - feeding could be a further factor that interacts with others playing a role in the persistent impaired glucose metabolism after gdm in high - risk patients , such as pcos subjects .
on the basis of these considerations , pcos should be considered a high - risk condition for glucose impairment after gdm .
thus , two main points of debate should be discussed : 1 ) the need for an accurate follow - up in order to recognize early glucose impairments and 2 ) strategies to prevent the decline in glucose metabolism . with regard to the first point ,
the american diabetes association has included pcos among the criteria for dm testing of asymptomatic adult individuals at the first prenatal visit ( evidence level b ) ( 26 ) .
moreover , a recent prospective study ( 27 ) provided insights into the relative accuracy of the various clinical methods used to detect prediabetes and dm in women with pcos and demonstrated the accuracy of both ogtt and a1c for dm screening . alternatively , a lower level of evidence has been demonstrated regarding postpartum surveillance , which suggests screening women with gdm for persistent dm 612 weeks postpartum and lifelong screening for the development of dm or prediabetes at least every 3 years ( 26 ) . at present , no data on specific indications for postpartum screening in pcos women are available , but screening these women more frequently has been advised because most will have additional risk factors for developing dm , including obesity , glucose intolerance , and insulin resistance ( 27 ) .
the same authors ( 27 ) suggested that pcos women with prediabetes or dm should be considered as having insulin resistance and the remaining women should undergo homa - ir and insulin level assays to identify insulin resistance . with regard to preventative strategies , all interventions that are able to affect the risk factors for gdm and the persistence of glucose alterations , i.e. , obesity , hyperandrogenism , oligo - anovulation , glucose abnormalities , and insulin resistance ,
the prevention of dm , and translationally of gdm , was defined as a long and winding road without a shortcut , and a persistent and prolonged intensive lifestyle intervention seems to be the most effective treatment ( 28 ) . in pcos women , lifestyle modification improves body composition , hyperandrogenism , and insulin resistance ( 29 ) .
in addition , for women with gdm , a lifestyle intervention that starts during pregnancy and continues postpartum is feasible and may prevent pregnancy weight retention and also may help overweight women lose weight ( 30 ) .
however , the main challenge of real life behavioral changes is the adherence to the program ; therefore , pharmacological therapies alone or in combination with lifestyle programs have been proposed to reduce development of dm in high - risk subjects ( 31 ) . in pcos women , insulin - sensitizing drugs , such as metformin ,
have been proven to be effective on hormonal and metabolic features of the syndrome ( 32 ) . however , the effect of metformin on gdm prevention in pregnant pcos subjects is still controversial ( 3337 ) .
additional well - designed studies on an adequate sample population to evaluate the effect of metformin administration before and during pregnancy on gdm development in pcos are needed . in conclusion , patients with pcos are at an increased risk for persistent impaired glucose metabolism after gdm . in this population ,
accurate follow - ups and preventative strategies should be adopted to avoid long - term consequences .
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### Summary:
: objectiveto test the hypothesis that the risk of persistent glucose impairment after gestational diabetes mellitus ( gdm ) is increased in patients with polycystic ovary syndrome ( pcos).research design and methodsthe prospective case - control study included 42 pregnant patients with pcos and gdm and 84 pregnant control patients with gdm but without clinical and biochemical hyperandrogenism , polycystic ovaries , and oligo - anovulation .
the case and control subjects were matched one to two for age and bmi .
the glycemic profiles were studied in all subjects 6 weeks , 12 weeks , and 18 months after delivery .
the incidence and the relative risk ( rr ) were calculated for overall persistence of an abnormal glycemic pattern and for each specific alteration , i.e. , impaired glucose tolerance ( igt ) , impaired fasting glucose ( ifg ) , and diabetes mellitus ( dm).resultsat 18 months after delivery , the incidences of ifg , igt , and ifg - igt were significantly ( p < 0.05 ) higher in the cases than in the controls . at the 18-month follow - up ,
the rr for the composite outcome of glucose metabolism impairment in pcos women was 3.45 ( 95% ci 1.826.58).conclusionspatients with pcos are at increased risk for a persistent impaired glucose metabolism after gdm .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: child sexual abuse ( csa ) is generally defined as child exploitation that leads to achievement of sexual satisfaction . according to the 1986 who definition , sexual violence against children
while being abused , the child is involved in a sexual activity that he or she does not fully comprehend , is unable to give informed consent to , or for which he or she is not prepared for developmentally .
csa includes exhibitionism , pornography , fondling or sexual intercourse . in another report , the who declared that the age of victims is decreasing and the scale of the problem is growing [ 1 , 2 ] . in the u.s .
, the number of detected and suspected csa cases was increasing in the 80s by an average of 10% annually .
this can be explained by growing public interest in the pathological phenomenon of sexual exploitation and greater public awareness .
the medline , and web of science databases were searched with no date limitations on may 2015 using the terms child abuse in conjunction with
urinary infection. autoalerts in medline were also run , and reference lists of original articles , review articles , and book chapters were searched for further eligible articles .
articles that did not address the topics were excluded , and the full text of the remaining articles was reviewed . in this article
we present a review of studies and literature concerning urinary symptoms in abused children to clarify the problem for a broad group of urologists .
we present common symptoms and premises that can point to the right diagnosis , and basic guidelines of proceeding after suspicion of abuse .
according to data from european countries , sexual abuse of children affects 10 - 40% of girls and 520% of boys [ 3 , 4 ] . in poland ,
girls are abused more often when compared to boys , however , the abuse towards boys is more often associated with physical violence . boys also experience more severe forms of csa .
most children , that is 75% to 85% , are abused by a male perpetrator known to the child .
the majority of victims describe a single type of sexual activity , but over 20% have experienced multiple types of forced sexual acts .
confirmation of possible csa is rarely a direct reason for a child to visit an urologist .
more frequently children are referred to a urologist because of urogenital system complaints , such as recurrent infections , hematuria , dysuria , chronic pain in the lower abdomen , urinary retention , daytime and nighttime incontinence or luts symptoms like , nocturia , urinary frequency , painful voiding or urgency .
pediatricians and urologists who routinely see patients with voiding problems are in an exceptional position to identify children who have been victimized .
it is necessary to maintain a high level of vigilance because physical findings may not be easily detectable .
any suggestion given by a child should raise the level of concern that sexual abuse has occurred , because children very infrequently feign stories of sexual abuse . in a study examining 551 cases of csa reported in the u.s .
, only 8 cases ( 1.5% ) were deemed false accusations of sexual abuse . studies concerning urinary symptoms in sexually abused adults confirm an association between the occurrence of sexual exploitation and urological symptoms [ 810 ] .
a similar observation concerns people with urinary symptoms and posttraumatic stress disorder [ 11 , 12 ] .
however , only a few papers were published about children and some have failed to demonstrate a statistically significant association ( table 1 ) . yet , urinary symptoms are often present in children exposed to sexual violence [ 9 , 1316 ] . in the pediatric population which has not been exposed to sexual abuse , urinary symptoms
they include daytime incontinence in 2.13.1% of children , urgency in 1.34.7% and nighttime incontinence in 1.58.9% [ 4 , 5 , 17 , 18 ] . one recent study , conducted on 1280 children , has shown that prevalence of enuresis was increased in children with allegations of sexual abuse when compared to the general pediatric population and concerned 13% of 59 year olds , 14.7% of 1016 year olds and 18.2% of 1718 year olds .
another study has shown that young rape victims were 2.7 times more likely to have pelvic floor dysfunction , including lower urinary tract disorders , than non - victimized controls .
, presented an incontinence rate of 30.76% and 23.3% in the sexually abused group and in the control group , respectively .
additionally , rates of daytime incontinence , nocturnal enuresis , diurnal incontinence , urgency , and continence maneuvers were 25.7% , 17.1% , 22.9% , 42.9% , and 20% , respectively , in the sexual touch group , while they were found to be 5.9% , 0% , 0% , 17.6% , and 5.9% , respectively , in the sexual penetration group .
klevan et al . showed that in a group of 428 sexually abused children , 20% of the victims complained of one or more genitourinary symptoms .
studies concerning genitourinary symptoms in sexually abused children kelly et al . in a large report from new
the authors showed that 62,9% of children had physical symptoms , 2.8% had abnormal genital findings , 2.5% had urinary tract infections and 1.9% contractd sexually transmitted infections . a study conducted by delago et al .
showed that in a group of 161 abused girls , 59.6% reported urogenital symptoms . among those who reported urogenital symptoms , 53.4% reported genital pain , 37.7% reported dysuria and 10,6% reported bleeding after inappropriate genital contact .
in contrast to their daughters , parents / guardians reported knowledge of 17.4% cases of genital pain , 18.6% of dysuria and 4.3% of genital bleeding .
in the same group , occurrence of dysuria was described in 47.7% and pain in the genitalia region in 71.6% of female minors who were subject to sexual violence with genital - genital contact . in girls who were abused by other types of contact ( digital - genital , oral - genital , object - genital ) , dysuria and pain occurred in 24.7% and 31.5% , respectively . in another study comparing urogenital symptoms after sexual abuse vs. irritant genital exposure , delago presented that significantly more girls in the sexual - abuse group ( 76% ) compared to girls in the irritant exposed group ( 24% ) used negative words such as uncomfortable , bad , or hurt , to describe how the contact felt .
additionally , significantly more girls in the sexual - abuse group ( 69% ) said this contact bothered her body and her feelings compared to only 6% of the irritant exposed group .
thirty- three per cent of girls from the sexual - abuse group stated reported dysuria after being touched on the genitalia compared to 12% of the irritant exposed girls .
the described relationship between the urinary symptoms and sexual abuse occurrence was previously connected to psychological rather than physiological abnormalities .
macaulay and et al . reported that sensory urgency , detrusor overactivity , and incontinence could be cured by intense psychotherapy even without bladder training .
however , recent researches on neurobiological basics such as stress and anxiety show that these phenomena directly affect the miction mechanism .
it occurs due to modulating function of neurotransmitters such as corticotrophin - releasing factor in the nervous system and in the urinary tract [ 26 , 27 , 28 ] .
it has also been proven in animal models that stress increases muscarinic - induced contractile responses in the bladder .
the results of these studies suggest that the urologic effects of csa experienced in childhood may persist into adulthood and that the urologic sequelae of csa may not resolve with psychiatric counseling alone .
urological treatment should be symptomatic and consist of timed voiding , double voiding , voiding diaries , improved bowel habits , anticholinergics , antimuscarinics and clean intermittent catheterization , as necessary .
the studies mentioned above suggested also that direct treatment of urologic symptoms ( e.g. urinary incontinence and urinary urgency ) using available behavioral methods , in addition to the direct treatment of psychological symptoms of csa ( e.g. depression , anxiety , poor self - esteem ) may result in symptom improvement and thus , presumed improvement in overall quality of life .
the investigators reported resolution or improvement in symptoms for most patients for which they had follow - up data .
the length of follow - up or the duration of symptom improvement was not provided . when sexual abuse is suspected it is important to properly collect the patient 's medical history and to implement an appropriate examination .
it is often expected that a doctor should diagnose sexual abuse only after performing basic examination of a child . however ,
tissue damage heals quickly , the child frequently presents with a delay , and furthermore , many forms of sexual harassment do not cause any physical damage .
questions about frequency of urination , presence of pain during miction , urgency , diurnal and nocturnal incontinence should be the routine when sexual harassment is suspected .
it is generally difficult for a child to disclose secrets , especially those concerning sexual abuse details .
this is due to the fact that the abuse often happens inside the child 's family or by trusted persons in the child 's life .
additionally , child usually feels responsible for what has happened and fears hurting others , causing trouble , and not being believed .
the environment where the examination and interview are conducted should be private , quiet , and familiar to the child .
the conversation should begin with subjects that are interesting for the child and questions should be matched to the child 's age .
the examiner should be patient and friendly and spend time getting acquainted with the child in order to establish the desired level of trust .
the interview should be conducted with the child alone [ 30 , 31 , 32 ] . a study on the effectiveness of various types of dialogue with sexually abused children revealed that asking
how questions , similar to the opening question how did that make your [ girl 's word for genitalia ] feel ?
some nonspecific behaviors including suicide gestures , fear of an individual or place , nightmares , sleep disorders , regression , aggression , withdrawn behaviour , depression , anxiety , promiscuity , general behavior problems , poor self - esteem , poor school performance , self - mutilation , phobias , eating disorders should arouse suspicion [ 30 , 34 , 35 ] .
additionally , while the child 's confession is important , the manner in which the child 's confession was expressed is also essential .
the statement should be documented literally , because it can then be used during court proceedings .
avoidance of guiding questions and communication with patients using their words and phrases , irrespectively of their correctness , helps to establish the validity of abuse allegations .
nevertheless it must be noted that about 90% of sexual abuse claims turn out to be true , so an assumption of their authenticity is obligatory and requires providing all forms of assistance to the victim with further assessment of the statement veracity .
knowledge of normal anatomy of children 's genitalia is crucial in identifying any deviations from the norm .
it should be mentioned that until the 80s of the last century , there was no proper description of the state of the external genitalia and perineum / anus area in children before puberty [ 38 , 39 ] .
the examination begins with an evaluation of the child 's general appearance , hygiene , and nutritional status .
after oral - genital contact , skin and mucosae damage and bruising , as well as disruption of the oral cavity frenula may appear .
the thighs , penis and scrotum should be carefully examined in search of bruises , scars , scratches , suction ecchymoses , bites marks and pathological secretions .
bite marks are common in sexual assaults and it is important to measure and photograph them carefully to allow matching or exclusion of the teeth of the alleged assailant .
torn frenulum or fracture of tunica albuginea , a so - called penile fracture accompanied with hematoma can , in the absence of history pointing to other causes of trauma , indicate sexual abuse of boys . in girls , the breasts ,
inner surface of the thighs , labia minora , labia majora and their posterior commissure , urethral orifice , hymen and its opening have to be examined .
vesicovaginal or rectovaginal fistula may be caused by the long presence of a foreign body in the vagina .
symptoms that also indicate sexual exploitation include recurrent urinary tract infections or encopresis . in girls ,
fresh / healed hymen damage , vaginal mucosa injury or / and vulvovaginitis can be present . in both sexes the perineal and anal area should be carefully examined for presence of any cracks , fissures , scars , hyperpigmentation , skin thickening , warts or other skin irregularities .
anal sphincter muscle tension also has to be assessed . yet , in many children , despite a history indicating anal manipulation , results of physical examination of both the anus and rectum are normal .
bleeding from the urethra in both sexes may be associated with penetration of the urethra by foreign bodies [ 14 , 19 , 34 , 40 , 41 , 42 ] .
abnormal genital findings are not common in sexually abused children . it was proven that less than 5% of girls who disclose sexual abuse have physical examination findings or laboratory evidence that confirms this diagnosis .
it is important to collect a proper medical history , because aforementioned symptoms and findings can be related to genital irritant exposures ( soap , shampoo ) , tight nylon underwear , bike or horse riding or accidental genital trauma .
however , both conditions can coexist , thus it is important to ask caregivers and children themselves about genital exposures to products , activities , and conditions thought to cause symptoms and about past histories of urogenital symptoms and what they think caused the symptoms .
an infant girl can be examined either on the examination table or while on a parent 's lap .
a vaginal inspection in older girls may be performed in a supine recumbent position , with the knees flexed and the heels against the buttocks ( the frog - leg position ) or knee - elbow position with the face looking down .
an examination of boys can be performed with the patient in the sitting , supine or standing position [ 45 , 46 ] .
evaluation of the anus may be performed with the patient in the supine , lateral recumbent or prone position with gentle retraction of the gluteal folds .
another symptom , which is worth mentioning , is the presence of sexually transmitted disease / infection ( std ) . in children ,
existing infection may be related to prolonged colonisation after perinatal acquisition , inadvertent non - sexual spread , prior peer sexual activity , or in many cases to sexual abuse .
it is believed that approximately 7075% of pediatric patients with documented sexually transmitted disease may have been exposed to sexual abuse .
the peak incidence of venereal disease in abused children is recorded to be between 10 and 14 years of age .
human papilloma virus , human immunodeficiency virus , syphilis , trichomonas vaginalis , chlamydia trachomatis , herpes simple virus infection can be perinatally acquired and do not always indicate sexual abuse . however , neisseria gonorrhoeae infection , the most frequent std found in abused children and reported to occur in 130% , of cases is probably the most useful indicator of sexual abuse .
gonorrhoeal infection in a child , who has not yet reached sexual maturity , is almost always associated with a history of sexual abuse [ 6 , 47 , 48 ] .
the incubation periods for sexually transmitted infections range from a few days for neisseria gonorrhoeae to several months for human papilloma virus .
the incubation periods and timing of an examination after an episode of abuse are critically important in detecting infections and confirming abuse .
awareness of the csa problem among paediatricians and urologists is very important , because they are often the only physicians who are able to recognize the problem .
csa diagnosis is possible only through the proper collection of a medical history and a thorough physical examination .
urologists have to remember that children exposed to sexual abuse rarely exhibit abnormal genital findings .
in fact , absence of genital findings is the rule rather than the exception . in most cases , the final diagnosis of sexual abuse
is based on the child 's history and behavior , along with the onset and exacerbation of urologic symptoms .
guidelines for the medical care of children suspected of being sexually abused recommend collecting a medical history concerning anogenital pain , bleeding , itching , discharge , or dysuria , but little has been published to describe the type and frequency of urogenital symptoms and signs reported by children after sexual abuse . a few of the above discussed studies draw more attention to functional disorders of the lower urinary tract in sexually abused children
. therefore the possibility of sexual abuse must be considered not only in case of genito - urinary trauma but also dysuria , chronic pain in the lower abdomen , urinary retention , daytime and nighttime incontinence or luts symptoms like , nocturia , urinary frequency , painful voiding or urgency .
testing for stds is not recommended as a common clinical practice , because the incidence of sexually transmitted diseases among victims of csa has been observed to be low .
std testing should be considered in children who are symptomatic and in those with a high possibility of having oral , genital , or anal contact with the perpetrator . on the contrary
it should be noted , that the presence of non - perinatally acquired gonorrhea , chlamydia , human immunodeficiency virus , or syphilis is considered diagnostic of sexual abuse and warrants immediate reporting to child protective services , regardless of additional evidence of csa . in all patients , perforimg urodynamic tests and an ultrasound for the assessment of urinary volume after voiding
the authors have read and complied with the journal 's policy on ethical consent and the standards of animal care .
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### Summary:
: introductionchild sexual abuse ( csa ) is generally defined as child exploitation that leads to achievement of sexual satisfaction . according to data from european countries , sexual abuse of children affects
1040% of girls and 520% of boys.material and methodsthe medline , and web of science databases were searched with no date limitation on may 2015 using the terms child abuse in conjunction with
urinary tract ,
urologist , urological dysfunction , urologic symptoms , luts or
urinary infection.resultsawareness of the csa problem among paediatricians and urologists is very important , because they are often the only physicians who are able to recognize the problem .
csa diagnosis is possible only through the proper collection of a medical history and a thorough physical examination.urologists have to remember that children exposed to sexual abuse rarely exhibit abnormal genital findings .
in fact , absence of genital findings is the rule rather than the exception . in most cases , the final diagnosis of sexual abuse
is based on the child 's history and behavior , along with the onset and exacerbation of urologic symptoms.conclusionsin this article , we present a review of studies and literature concerning urinary symptoms in sexually abused children to clarify the problem for a broad group of urologists .
we present common symptoms and premises that can point to the right diagnosis and basic guidelines of proceeding after suspicion of abuse .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: primary mucinous carcinoma of the skin ( mcs ) is a rare neoplasm of sweat gland origin [ 1 , 2 ] .
. recently reported that approximately 200 cases have been documented until now , and the mean annual age - standardized incidence of mcs during 1978 to 2003 was 0.07 per million person - years .
mcs most commonly occurs on the eyelids , scalp , and other sites on the head and neck [ 3 , 4 ] .
it is characterized clinically as asymptomatic , slow - growing nodules , cysts , or ulcers . although it is a benign tumor , an adequate amount of normal skin excision
snow and reizner reported a 30% local recurrence rate and a 2.7% rate of distant metastases [ 6 , 7 ] .
accordingly , death from mcs is rare , and it usually has a favorable prognosis .
we present a rare case of mcs of the jaw , which was resected twice and had a disease - free interval for more than 10 years but suddenly presented with multiple bone and lung metastases .
we believe that this is the first case reported of death due to distant metastasis of mcs with a disease - free interval of more than 10 years .
a 39-year - old japanese male presented with a 3 months history of a skin tumor on the left side of the jaw .
physical examination showed a dome - shaped , slightly erythematous nodule measuring approximately 2 cm in diameter ( fig . 1 ) .
punch biopsy was performed , and it was diagnosed as mucinous adenocarcinoma of the skin .
1a 39-year - old asian man presented with a 3-month history of a dome - shaped , slightly erythematous nodule measuring approximately 2 cm on the left side of the jaw a 39-year - old asian man presented with a 3-month history of a dome - shaped , slightly erythematous nodule measuring approximately 2 cm on the left side of the jaw the tumor was excised with 5-mm surgical margin and was reconstructed with local rotational flap .
the definitive histopathology showed small cellular nests of adenocarcinoma lying in pools of extracellular mucin that were separated by fibrocollagenous septae without involvement of underlying muscle .
( figure 2a , b ) the immunohistochemical staining revealed that the tumor cells were positive for ck7 , epithelioid membrane antigen ( ema ) , muc1 , muc2 , estrogen receptor ( er ) , and progesterone receptor ( pr ) .
2a , b the definitive histopathology showed small cellular nests of adenocarcinoma lying in pools of extracellular mucin that were separated by fibrocollagenous septae without involvement of underlying muscle .
there was no evidence of lymphatic invasion a , b the definitive histopathology showed small cellular nests of adenocarcinoma lying in pools of extracellular mucin that were separated by fibrocollagenous septae without involvement of underlying muscle .
there was no evidence of lymphatic invasion the patient again noticed a small tumor on the left side of the jaw in the area of the previous operation site 2 years after the primary operation .
however , the patient had chosen not to be examined by a physician and left it alone for 4 years . because of the rapid growth of the tumor , the patient visited our clinic .
at this point , the tumor measured approximately 6 cm in diameter ( fig .
the lesion was excised with at least 1-cm border of normal skin including the mandible ( fig .
a left radical neck dissection was performed , and the mandible was reconstructed with a free scapula flap .
the definitive pathology revealed mcs recurrence with no residual tumor cells in the excised normal skin area .
postoperatively , the patient was free of tumor and was followed up by the physician in charge every 3 months for 5 years and every 6 months for the next 5 years .
the patient was disease - free for ten consecutive years on physical examination , chest x - ray , neck echogram , and ordinary blood test .
although the patient did not have any symptoms , the chest x - ray at the 11th year follow - up revealed multiple lung metastases ( fig .
additional chest computed tomography ( ct ) , magnetic resonance imaging ( mri ) , and ri showed cervical vertebrate ( th5 ) tumor , and biopsy revealed metastasis of mcs .
the patient received radiotherapy for pain control and died 3 year after the diagnosis of metastasis .
3the patient had dropped out of postoperative follow - up and had visited the clinic 4 years after the surgery with a tumor measuring approximately 6 cm on the left side of the jaw arising in a previously operated sitefig .
4preoperative examination revealed mandible invasion with the tumor and one left neck lymph node metastasis .
therefore , the tumor was excised with more than 1 cm of surgical margin with a partial mandible resection and a left radical neck dissectionfig .
5a the chest x - ray performed at the 10-year follow - up did not show any obvious sign of lung metastasis .
b however , shadowing of multiple lung metastases was evident at the 11-year follow - up the patient had dropped out of postoperative follow - up and had visited the clinic 4 years after the surgery with a tumor measuring approximately 6 cm on the left side of the jaw arising in a previously operated site preoperative examination revealed mandible invasion with the tumor and one left neck lymph node metastasis .
therefore , the tumor was excised with more than 1 cm of surgical margin with a partial mandible resection and a left radical neck dissection a the chest x - ray performed at the 10-year follow - up did not show any obvious sign of lung metastasis .
b however , shadowing of multiple lung metastases was evident at the 11-year follow - up
primary mcs is rare , but there have been sporadic cases reported since it was first described by lennox et al . in 1952 and later reviewed by mendoza and helwing in 1971 .
mcs is usually present in middle aged or older persons and is more frequent in men than in women .
most mucinous tumors involving the skin are a result of metastases from various sites , including breast , upper airways , gastrointestinal tract , salivary and lacrimal glands and paranasal sinuses , and urinary tact .
it is important to distinguish between the metastatic tumor and mcs because mcs is generally more benign and has a very good prognosis compared to metastatic tumor of the skin .
differential diagnosis of the two is made by histological and systematic evaluation [ 11 , 12 ] .
histologically , mcs is described as a tumor consisting of islands of epithelial cells floating in pools of extracellular mucin separated by fibrocollagenous septa .
it is shown to express certain immunohistochemical markers such as ck7 , ema , and er and pr [ 1416 ] different from metastatic tumor of the skin .
mcs is typically slow growing with long duration of lesions prior to biopsy ; this can be as long as 20 years [ 17 , 18 ] .
however , it has a significant incidence of local recurrences , as high as 3645% .
direct invasion into skeletal muscle , periosteum , bone , and dura has been reported [ 16 , 17 ] .
warycha et al . recently reported a case of mcs with direct histopathological evidence of lymphatic invasion .
distant metastasis is extremely rare , and there have been only two recorded cases in the past [ 19 , 20 ] .
our case also showed local recurrence with direct bone invasion and lymph node metastasis even after excision of the tumor with a 5-mm surgical margin , which had been pathologically estimated as clear .
however , the definition of wide excision is not clearly documented . in our case ,
some authors recommend the use of moh s micrographic surgery in the head and neck area , given the risk of local recurrence and distant metastasis due to incomplete removal [ 13 , 16 ] .
martinez and young documented that the average surgical margin in cases reported was 12.5 mm in the least dimension .
we speculate from our case and other reports by various authors that the surgical margin should be more than 1 cm together with detailed pathological examination of lymphatic invasion .
since local recurrence is a frequent complication , our patient was followed up at three monthly intervals for the first 5 years and at six monthly intervals for the next 5 years . despite the fact that the patient was disease - free for more than 10 years after the second surgery with negative chest x - ray and neck lymph node echogram results , the patient had presented with multiple lung metastasis at his 11th year follow - up . to our knowledge , this is the first case reported for distant metastases after an interval of more than 10 years disease - free .
there is a possibility that the tumor had metastasized earlier , but the metastases was not recognized due to the tumor being asymptomatic and chest x - ray being insufficient for early diagnosis .
furthermore , the behavior of mcs as being slow growing and clinically asymptomatic may have delayed the diagnosis of the metastases .
thus , early diagnosis and resection of metastases is important for long - term prognosis . given the history of our case , we recommend annual follow - up with detailed systematic examination , such as whole - body ct and ri in the case of mcs with local recurrence and lymph node metastasis .
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### Summary:
: primary mucinous carcinoma of the skin ( mcs ) is a rare neoplasm .
clinically , it has a high local recurrence rate , but it is known to be a slow - growing benign tumor with a rare incidence of distant metastases .
we present a case of primary mcs on the jaw that underwent tumor resection twice and was disease - free for 10 years after the second surgery .
the patient had no evidence of local recurrence and distant metastasis until his 11th year follow - up . at that time
, he was diagnosed with lung and bone metastasis and died 3 years after this . to our knowledge , this is the first case of mcs that presented with metastasis with more than 10-year disease - free interval . since mcs is a slow - growing asymptomatic tumor , distant metastasis is difficult to diagnose without detailed radiological examination .
we believe that computed tomography and resonance imaging should be performed for early diagnosis of metastasis even for cases with long - term disease - free interval , especially cases of local recurrence .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the idea that terminal differentiation is permanently maintained , once development is complete , has been challenged by the observations that hepatocytes are highly responsive to stimuli inducing profound cell reprogramming and resulting in a mesenchymal transdifferentiation by the process known as epithelial - to - mesenchymal transition ( emt ) .
the emt is a complex phenomenon by which several types of epithelial polarized cells lose cell cell connections and acquire mesenchymal characteristics of motility and invasiveness ( 12 ) .
different emt subtypes can be categorized according to when this process occurs : ( i ) type 1 concerns developmental and organogenesis events ; ( ii ) type 2 plays a major role in wound healing , regeneration and fibrosis and ( iii ) type 3 characterizes epithelial tumour progression rendering cancer cells able to metastasize [ for review ( 13 ) ] .
hallmarks for emt include increased expression of vimentin , nuclear localization of -catenin and production of transcription factors able to inhibit e - cadherin expression .
in particular , master emt inducers have been identified in the transcriptional repressors belonging to the snail family , snail ( snai1 ) and slug ( snai2 ) ; these factors are able to determine emt induction targeting many epithelial genes starting from the direct inhibition of e - cadherin gene transcription(14 ) . the first indication that the snail gene family had a key role in triggering emt , by loss - of - function experiments in chick embryos ( 15 ) ,
was successively confirmed in several epithelial cell types and other vertebrate embryos ( 16 , 14 ) .
it is now widely demonstrated that snail levels are inversely correlated with e - cadherin in numerous tumours and contribute to the acquisition of an invasive phenotype ( 14,1619 ) .
many signalling pathways , including transforming growth factor ( tgf ) superfamily , epidermal growth factor ( egf ) , wnt , sonic hedgehog ( hh ) and notch , and oncogenic events , such as src or ras activation , are implicated in emt induction , both in physiology and pathology ( 20 , 21 ) .
notably , snail is the main effector of many of these emt inducers ( 22 ) .
in particular , tgf1 is considered the master emt inducer for malignant and non - malignant epithelial cells , including hepatocytes ( 23 ) .
tgf1 acts as a potent inducer of emt combining both smad - dependent and independent signalling pathways ( 24 , 25 ) .
the activation of snail promoter depends on the direct binding of smad3/smad4 ( 26 ) . in turn
, a complex between snail and smad3/smad4 represses the epithelial markers e - cadherin and occludin ( 26 ) .
tgf also promotes emt through activation of mapk , rho gtpases and pi3k ( 24 ) .
other emt transcriptional regulators , such as zeb1 , are also regulated by tgf1 in a smad - dependent manner ( 24 , 25 ) .
notably , snail ( 27 ) and zeb1 ( 28 ) are able to repress mir-200 family members , in turn targeting zeb1 ( 29 ) , and thus controlling the emt outcome by a feedback mechanism .
several other micrornas and some ncrnas , with their ability to target multiple components involved in epithelial integrity or mesenchymal traits , recently emerged as potent regulators of emt / met ( 3032 ) .
the emt reverse transdifferentiation event , the mesenchymal - to - epithelial transition ( met ) , allows the mesenchymal cells to redifferentiate into epithelial structures . met occurs in physiological ( i.e. in development ) and pathological situations ( i.e. cancer metastasis ) , where the migrating mesenchymal - like cells that have reached secondary sites reacquire cell cell contacts and polarity ( 33 ) .
notably , an event of met resulted necessary for the success of experimentally induced cellular reprogramming , where a cocktail of critical transcriptional factors prompts fibroblasts to mimic epithelial - like undifferentiated embryonic stem cells ( esc ) ( 34 , 35 ) . coherently with
the fact that met represents a reversion of emt , a down - regulation of emt - inducing transcription factors such as snail , slug , and zeb1 is invariably associated with met . as yet met molecular mechanisms are only partially characterized .
it is conceivable that the met process may involve a number of histotype - specific elements , as suggested by evidence revealing as the bmps - dependent signalling can promote met in a histotype and context - specific manner ( 24,35 ) .
the emt / met dynamics has also been proposed as a key element of stem cell biology ( 36 ) .
in fact , a common characteristic of embryonic and adult stem cells is the presence of both epithelial and mesenchymal traits that define the metastable stem / precursor phenotype .
a fine regulated balance of emt / met dynamic allows for stem cell self - renewal while its unbalance in either direction causes generation of precursors that differentiate into epithelial or mesenchymal cell types .
the molecular pathways controlling the emt / met dynamics of normal stem cells are expected to be similar to that of cancer stem cells , a specific population of metastable tumour cells able to initiate and maintain many types of cancer ( 3739 ) . of note
is the theoretical model for molecular mechanisms controlling emt / met dynamics based on the mir-34/snail and the mir-200/zeb mutual - inhibition feedback circuits ( 40 ) . in the liver ,
several types of cells have been shown to undergo emt / met : in particular , hepatocytes , both primary and established in line , when treated with tgf down - regulate epithelial and hepatic markers ( e - cadherin and albumin ) , while up - regulate mesenchymal genes ( vimentin and alpha - sma ) and acquire motility and invasiveness ( 4144 ) .
valdes and colleagues ( 45 ) reported that tgf treatment of primary hepatocytes selects an apoptosis - resistant cell population , which is subjected to an emt with an increase in snail and vimentin and negative regulation of e - cadherin , cytokeratin 18 and hepatocyte nuclear factors ( hnfs ) .
for most of these tgf effects , the activation of focal adhesion kinase ( fak ) signalling is required .
tgf , in fact , induces a src - dependent activation of fak which has been demonstrated to be necessary for ( i ) transcriptional up - regulation of mesenchymal and invasiveness markers and ( ii ) delocalization of membrane - bound e - cadherin ( 46 ) .
moreover , the emt process has been related to the dedifferentiation process that invariably occurs in freshly isolated hepatocytes within a few days of culture on a stiff layer of dried collagen .
recently , the mechanism controlling dedifferentiation of hepatocytes in primary cultures , in relation to the specific signalling network triggered by extracellular matrix , has been partially unveiled . in this case , a fak - mediated akt activation ( promoting a resistance to the tgf-induced apoptosis ) and erk1/2 signalling activation ( opening the route to a tgf-induced emt programme ) were also observed . antagonizing akt and erk1/2 signalling pathways caused the rescue of functional and morphological features , thus unveiling a mechanism controlling hepatocyte differentiation ( 47 ) .
cholangiocytes also transdifferentiate in mesenchymal - like cells when treated with tgf ( 48 ) or cultured in medium conditioned by myofibroblasts derived from fibrotic livers ( 49 ) .
regarding hscs , the liver cell type that most contributes to liver fibrosis , they have been suggested to be transitional cells . as a matter of fact
hsc retain precursor features in expressing a number of epithelial and mesenchymal markers and appear able in culture to become myofibroblasts by emt or hepatocytes with a met - like process ( 50 ) .
with respect to the relevance of the emt / met phenomena occurring in in vivo adult liver , the literature collected evidence both for and against it . concerning the hscs ,
if the idea that these are transitional cells , expressing both mesenchymal and epithelial genes , is accepted ( 50,51 ) , their activation into myofibroblasts , largely observed during liver fibrosis , corresponds to an emt ( 51,52 ) . instead , the possibility of hscs undergoing met in vivo is most debatable .
an elegant work by yang and collaborators ( 53 ) , taking advantage of a genetic cell lineage tracing , showed that hscs , when activated by liver injury or culture , became highly proliferative and started to express mesenchymal and epithelial markers . from these transitional cells ,
a population of genetically marked hepatocytes , able to repopulate large areas of the hepatic parenchyma , emerged .
( 54 ) , that metastable hepatic stem / progenitor cells , isolated from embryonic livers and established in clonally derived cell lines , give rise to both hepatocytes and hscs when injected into normal growing liver . regarding hepatocytes , the results gathered by zeisberg et al .
( 55 ) , based on a lineage tracing approach in a murine experimental model of liver fibrosis , suggested that collagen producing cells can also be derived from hepatocytes by emt and that these types of myofibroblasts contribute significantly to the progression of liver disease .
however , taura et al . ( 56 ) have followed , by a similar approach of cell fate mapping , the outcome of albumin expressing cells in injured liver , without identifying hepatocyte - derived fibroblasts .
the fig.1 summarizes in a schematic representation the physio - pathological emt / met dynamics of liver cells .
the emt in hepatocytes correlates with the down - regulation of the hepatic differentiation key factors hnfs ( hepatocyte nuclear factors ) , particularly hnf4. cicchini and colleagues demonstrated , indeed , that the tgf treatment of well - differentiated , non - tumourigenic , hepatocytic cell lines ( 57 ) induces a full emt , underlined by snail induction and e - cadherin , hnf1 and hnf4 ( 43 ) down - regulation .
snail appears to be at the cross - road of epithelial morphogenesis and differentiation of hepatocyte .
snail overexpression , in fact , appeared sufficient ( i ) to induce emt in hepatocytes ( with conversion of morphology , down - regulation of several epithelial adhesion molecules , reduction of proliferation and induction of matrix metalloproteinase two expression ) and , most relevantly , ( ii ) to directly repress the transcription of the hnf4 gene ( 43 ) .
the liver - enriched transcriptional factor ( left ) hnf4 is a well - known master of both liver morphogenesis and hepatocyte differentiation . during embryonic development ,
a highly regulated network among a number of lefts drives the differentiation process of the endodermal stem cell in differentiated parenchymal cells ( 58 ) : hnf41 , hnf1 , foxa2 , hnf6 and lrh-1 are key factors in this circuitry by acting as positive regulators of each other 's and of a repertoire of hepatic target genes .
in particular , hnf1 , foxa2 and hnf6 have roles in controlling the onset of the hepatic gene expression during specification of the liver progenitors , while hnf4 , although not having an impact on hepatic specification , is essential for subsequent differentiation of hepatic progenitors . during midgestation ,
this implies the activation of the expression of cell adhesion and junction molecules that in turn convert non - polarized cells in organized sheets of closely associated polarized epithelial cells . concerning liver morphogenesis , when hnf4 is specifically removed from foetal hepatoblasts , hepatic architecture is severely affected , with livers exhibiting loss of endothelial cells and disrupted hepatocellular polarity ( 60 ) .
in adult hepatocytes , hnf4 continues to have an important role in maintaining hepatocyte functions ( 61,62 ) and proliferative quiescence ( 63 ) .
this is confirmed by genome - wide chip studies in which hnf4 was found to occupy 12% of genes in human adult hepatocytes ( 64 ) .
notably , an inverse correlation between hnf4 and the emt master factor snail was demonstrated during hepatocyte differentiation ( 65 ) and hepatocellular carcinoma ( hcc ) progression .
snail expression , in fact , significantly increases along with hcc dedifferentiation , accelerating cancer invasion ( 66 ) .
moreover , emt and e - cadherin down - regulation have been shown to play an important role in hcc progression ( 67 ) .
on the other hand , the loss of hnf4 expression is determinant for hcc progression and its forced re - expression is able to promote the highly invasive undifferentiated tumour reversion towards a more differentiated epithelium and the reacquisition of cell - ecm contacts ( 68 ) .
moreover , hcc cells expressing hnf4 also re - established expression of the profile of liver transcription factors and hepatic genes that are associated with a differentiated hepatocyte phenotype .
notably , hnf4 overexpressing hepatoma cells are deficient for snail , expressed instead in the parental population ( 69 ) .
all this evidence suggests that snail could contribute to liver tumour progression through the down - regulation of hnf4. this is in agreement with other observations that dedifferentiated hepatoma cell lines constitutively express snail , while well - differentiated rat hepatoma cells are deficient for snail ( 43 ) .
various evidences demonstrated a role for hnf4 as a dominant regulator of the epithelial phenotype .
indeed , hnf4 not only regulates the developmental expression of adhesion molecules ( 60 ) but also when ectopically expressed in different cells , such as fibroblast ( 59 ) and f9 cells ( 70 ) , it is sufficient to trigger tight - junction and epithelial polarity molecules expression inducing a met .
interestingly , hnf4 expression in dedifferentiated hepatoma is sufficient to re - establish the hepatocyte markers gene expression and epithelial cell morphology and polarity ( 69 ) .
moreover , in hcc the forced expression of hnf4 induces reversion of highly invasive tumours towards a less invasive phenotype ( 68 ) .
notably , enforced expression of hnf4 , plus foxa1 , foxa2 or foxa3 , directly reprograms mouse fibroblasts into induced hepatocyte - like ( ihep ) cells ( 71 ) .
as mentioned above , the main hnf4 characterized function was the positive modulation of tissue - specific epithelial and hepatocyte gene expression , sufficient for the acquisition of an epithelial differentiated phenotype . moreover
, a new mechanism was recently unveiled by which hnf4 , inducing met maintains the hepatocyte - differentiated phenotype .
santangelo and colleagues ( 72 ) , indeed , demonstrated a novel hnf4 anti - mesenchymal role through the orchestrated repression of both master emt regulators and mesenchymal genes .
these authors provided evidence of repression of the mesenchymal programme , both during the hnf4-mediated met process of undifferentiated hepatoma or fibroblast cells , and in the normal fully differentiated hepatocytes that stably retain the epithelial phenotype .
in particular , in dedifferentiated hepatoma , forced expression of hnf4 appeared sufficient to down - regulate mesenchymal markers such as snail , slug , hmga2 , vimentin and fibronectin expression . in terminally differentiated hepatocytes ,
endogenous hnf4 was found stably recruited to the promoters of these emt inducers and mesenchymal genes .
using both cell cultures and liver - specific hnf4 knockout mouse models , a direct correlation between loss of hnf4 and up - regulation of the mesenchymal genes has been demonstrated .
histological examination of liver sections from alb - hnf4 -/- mice demonstrated that hepatocytes , with the known hypertrophic phenotype , express vimentin , desmin , fibronectin and -smooth muscle actin ( with no increase in non - parenchymal cells ) ( 61,72 ) .
these data integrate the well - established notion of the pivotal positive role of hnf4 in hepatocyte differentiation through expression of epithelial genes with the new concept of an active and fundamental role of hnf4 in the repression of the hepatocyte mesenchymal programme .
the capacity of hnf4-depleted hepatocyte to acquire a mesenchymal phenotype is intriguing and deserves future investigations on hnf4 ko models , especially in the light of the reports suggesting that quiescent hsc might be transitional cells derived from the partial emt of epithelial cells ( 73 ) .
the evidence reported by santangelo and colleagues ( 72 ) , together with the previous demonstration that snail directly represses hnf4 ( 43 ) , allows for the formulation of a simple cross - regulatory model between snail and hnf4 : the expression of each factor is mutually exclusive to the other , and this is because of the presence of repressor elements in each promoter .
this hnf4/snail circuit of reciprocal regulation between two master regulators provides a simple molecular mechanism for emt / met feedback and reversible differentiation processes in both physiology and pathology .
notably , the same authors extended the anti - mesenchymal role of hnf4 , by direct transcriptional regulation of emt master genes and mesenchymal markers , the other hepatocyte - enriched transcriptional factor hnf1 ( 72 ) , known to play an important role in hepatocyte differentiation and function ( 64 ) and to be positively regulated by hnf4. successively , also pelletier and colleagues , providing evidence that hnf1 inhibition triggers emt in human liver cell lines , concluded that hnf1 has a role in the maintenance of hepatocyte epithelial identity ( 74 ) .
moreover , was reported to be one of the few factors which ectopic expression in embryonic fibroblasts ( mefs ) appears sufficient to generate induced hepatocyte - like ( ihep ) cells ( 75 ) .
thus , both hnf4 and hnf1 transcriptional repression of critical mesenchymal genes is pivotal , not only for the regulation of the dynamic process of met but also for the maintenance of a stable epithelial phenotype .
several recent studies showed how the induction of emt in differentiated epithelial cells corresponds to the execution of a stemness programme .
in particular , an important work of mani and collaborators showed that treatment with tgf of immortalized cells of mammary epithelium , as well as ectopic expression of two master genes of the emt , twist or snail , induces , together with a mesenchymal phenotype , the expression of stem cell markers and the ability to form mammospheres , as mammary epithelial stem cells do ( 76 ) .
similarly , the treatment of tumoural mammary epithelial cells , allows for the acquisition of a cancer stem cell behaviour , such as the formation of mammospheres , the capacity to form colonies on soft - agar and increased efficiency of tumour formation .
( 77 ) , using a mammary tumour progression model , showed that the acquisition of stem and tumourigenic characteristics of cancer stem cells are driven by emt induction .
moreover , the coexpression of epithelial and mesenchymal markers in the epithelial stem cells characterized so far , suggests that the maintenance of a partial mesenchymal programme could be necessary for stemness behaviour . in line with this observation
is the finding that snail is expressed in hepatic stem / precursor cells resident in the murine livers and that this expression correlates with the expression of stemness markers ( 27 ) .
this unexpected finding , considering that the transcriptional repression is the only function so far attributed to snail , allowed for identifying other factors integrating / mediating snail activity . in particular , it has been shown that in liver stem / precursor cells , snail inhibits the hepato - specific programme through direct repression of the hnf4 gene and the epithelial micrornas ( mir)-200c and 34a , known as stemness - inhibiting micrornas for their targeting of stemness genes , while in the hepatocytes , hnf4 , together with a direct repression of snail gene , directly up - regulates mir-200 family members ( 200a , b and c ) and mir-34a transcription , thus further stabilizing the hepatocytic phenotype . altogether , these data unveiled snail , hnf4 and mirnas as elements controlling hepatic stem cell maintenance / differentiation , acting in a simple and direct molecular mini - circuitry in which master elements reciprocally repress their own expression while inversely controlling the expression of specific micrornas .
as mentioned above , the emergence of mesenchymal traits characterizes cells metastasizing from carcinomas and during hcc progression , an inverse regulation between snail and hnf4 is observed with snail expression directly correlating with the dedifferentiation grade of hcc , cancer invasion and poor prognosis ( 66 ) . in a comparable way , hnf4 expression ,
lost in more aggressive hcc , if restored , promotes reversion towards a less invasive phenotype , both repressing emt programme and promoting hepatocyte differentiation ( 69,78 ) .
therefore , the restoration of the functions hnf4 in hcc invasive represents an important milestone for the anticancer therapies .
however , recent data have shown that in an environment containing tgf , hnf4 restoration usually fails to counteract tumour progression .
the tumour promotion effects of tgf , indeed , result dominant on hnf4 activity , thus limiting the hnf4 gene transfer as a therapeutic approach of hcc .
the molecular basis of this dominance resides on some post - translational modifications , induced by the tgf signalling on hnf4 protein , that provoke the displacement of transcriptional factor from its target gene promoters , including snail .
gsk3 kinase has been individuated as one of the tgf targets mediating hnf4 functional inactivation ; gsk3 chemical inhibition , in fact , resulted in the hnf4 dna binding impairment , while a constitutively active gsk3 mutant impairs the tgf-induced inhibitory effect on hnf4 tumour suppressor activity ( 79 ) .
the balance between snail ( emt master gene ) and hnf4 ( met master gene ) in liver stem cells and liver cancer cells ( cancer stem cells or transformed hepatocytes ) ultimately influences the outcome of the transition between the mesenchymal / undifferentiated and the epithelial / differentiated phenotype .
this simple and direct molecular mini - circuitry of master elements ( fig.2 ) , able to reciprocally repress their own expression may theoretically provide the best device to trigger complex phenomena such as stemness and differentiation .
however , this necessarily implies that these master factors act in much more complex macromolecular systems , able to direct and modulate a whole transcriptional profile , influencing the early stages of gene expression . molecular circuitry controlling emt / met liver cell dynamics .
the balance between snail and hnf4 , based on their mutual negative regulation , controls epitheliality , mesenchymality and stemness of liver cells .
further studies are necessary to shed light on the complexity of the cellular output of the proposed mini - circuitry , based on the conceivable hypothesis that a transcriptional master gene acts by organizing a molecular platform that in turn is capable of driving a coherent cellular response which involves hundreds of target genes . in other terms
, both the emt / stemness master regulator snail and the met / hepatocyte differentiation master regulator hnf4 could behave as reprogramming transcriptional factors , triggering the necessary epigenetic changes on regulative regions of their own target genes . as
master regulators of stem cell fate and/or the reprogramming of a differentiated cell , they could directly recruit general chromatin modifiers to their target genes , regulating their transcriptional competency .
moreover , we believe that the hierarchical relevance of these master regulatory molecules , controlling a broad range of cellular functions , may allow for designing simple molecular therapies based on a gene transfer approach .
the epistatic relation among snail / hnf4 , a number of mirnas and their target genes , is further influenced by environmental cues such as tgf. in this context , the use of engineered molecular tools , insensitive to negative regulation by the microenvironment , will represent the successful approach to improve gene therapy strategies .
although promising in in vitro and preclinical studies , this strategy , when applied clinically , should take into account the tumour niche influence , which is capable of exerting direct functional impairment of therapeutic molecules .
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### Summary:
: the complex spatial and paracrine relationships between the various liver histotypes are essential for proper functioning of the hepatic parenchymal cells . only within a correct tissue organization , in fact
, they stably maintain their identity and differentiated phenotype .
the loss of histotype identity , which invariably occurs in the primary hepatocytes in culture , or in vivo in particular pathological conditions ( fibrosis and tumours ) , is mainly because of the phenomenon of epithelial - to - mesenchymal transition ( emt ) .
the emt process , that occurs in the many epithelial cells , appears to be driven by a number of general , non - tissue - specific , master transcriptional regulators .
the reverse process , the mesenchymal - to - epithelial transition ( met ) , as yet much less characterized at a molecular level , restores specific epithelial identities , and thus must include tissue - specific master elements . in this review , we will summarize the so far unveiled events of emt / met occurring in liver cells . in particular , we will focus on hepatocyte and describe the pivotal role in the control of emt / met dynamics exerted by a tissue - specific molecular mini - circuitry .
recent evidence , indeed , highlighted as two transcriptional factors , the master gene of emt snail , and the master gene of hepatocyte differentiation hnf4 , exhorting a direct reciprocal repression , act as pivotal elements in determining opposite cellular outcomes .
the different balances between these two master regulators , further integrated by specific micrornas , in fact , were found responsible for the emt / mets dynamics as well as for the preservation of both hepatocyte and stem / precursor cells identity and differentiation .
overall , these findings impact the maintenance of stem cells and differentiated cells both in in vivo emt / met physio - pathological processes as well as in culture .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the field of oncology is rapidly attempting to move to a new era of personalized therapy , where individualized therapeutic decisions are based on highly specific tumor profiling . for this to become a reality , the discovery and validation of new prognostic and predictive biomarkers are necessary .
this goal seems increasingly realistic thanks to high - throughput screening methods , particularly genomic profiling .
the large - scale analysis of gene expression has improved our knowledge of tumorigenesis , invasion , and metastasis .
more recently , gene expression assays have helped guide therapeutic decisions , such as the use of multigene assays for decisions regarding systemic therapy in breast cancer [ 1 , 2 ] . however , despite continued success in the preclinical setting , clinical translation has been slow and several tumor types present unique challenges to the use of genomic profiling .
one example is melanoma . the present staging system for melanoma , using breslow thickness , ulceration , mitotic rate , and the presence of regional and distant metastases , stratifies patients into heterogeneous groups , with wide variability in outcome or response to therapy .
clinically , this results in applying more aggressive surgical and adjuvant therapies to large populations , diluting the impact of therapy while exposing more patients to toxicity . for those treating melanoma ,
better prognostic and predictive markers in melanoma are sorely needed , but to date have been elusive .
the high - throughput analysis of genomic data requires fresh tissue from a large number of primary tumors .
this presents a unique challenge in melanoma where the primary is often only a few millimeters in size , with no residual tissue after the diagnosis has been made . for this reason ,
proteomics appears to be an ideal choice for the discovery of new prognostic and predictive biomarkers in melanoma .
genes are transcribed into mrna , but because cells can use alternative splicing , there is no one - to - one relationship between the genome and the transcript .
the transcripts are further translated into proteins , which often undergo posttranslational modifications ( ptms ) , or can be aberrant in cancer cells .
protein structure can also be influenced by environmental factors , including interaction with other proteins , degradation , or compartmentalization of proteins within protein complexes .
as the structure and availability of the final versions of the proteins ultimately determine the behavior of the cell , high - throughput screening methods for changes in protein expression may be better suited to identify biomarkers with prognostic or predictive value .
protein changes associated with the transition from melanocyte to atypia or dysplasia and ultimately to melanoma could be used to aid in diagnosis or to screen high - risk patients .
proteins associated with pathophysiology and malignant properties could be used to further classify melanoma , stratifying patients by risk of recurrence in order to better select surgical and adjuvant treatments .
likewise , protein expression ( baseline or changes in expression ) may predict response to specific therapies , so that selection of systemic therapies can be tailored to the individual patient . the detection of low levels of melanoma - associated proteins in the serum may also lead to early recognition of recurrent disease or monitoring the response to therapy for metastatic disease . despite the significant potential for tissue - based or serological biomarkers to help diagnose early stage disease , tailor therapy , or detect recurrence , very few biomarkers are in clinical use .
several tissue markers are used to help distinguish melanoma from other types of cancers , including s100 , mart-1 , and gp100/hmb45 . to date , however , there are no tissue - based biomarkers that are utilized clinically for prognostic classification .
this is despite the identification of multiple biomarkers , through genomic or immunohistochemical analysis , whose abnormal expression has been linked to poor outcome .
these include tumor suppressors / oncogenes / signal transducers ( p16 , pten , egfr , c - kit , c - myc , bcl-6 , her3 ) , cell - cycle associated proteins ( ki67 , cyclins a , b , d , e , p21 , geminin , pcna ) , regulators of apoptosis ( bcl-2 , bax , bak , ing3 , ing4 ) , proteins involved with cell adhesion and motility ( p , e and n - cadherin , -catenin , 1 and 3 integrins , matrix metalloproteinases ( mmps ) ) , and others ( hsp90 , rgs1 , ncoa3 , mcm4 , mcm6 ) [ 3 , 4 ] .
these include differentiation antigens ( s100 , mia , tyrosinase ) , proangiogenic factors ( vascular endothelial growth factor ( vegf ) , basic fibroblast growth factor ( bfgf ) , il-8 ) , cell adhesion and motility molecules ( soluble intracellular adhesion molecule 1 ( sicam-1 ) , soluble vascular cell adhesion molecule 1 ( svcam ) , mmp-1 , mmp-9 ) , cytokines ( il-6 , il-10 , soluble il-2 receptor ( sil-2r ) ) , and others ( ta90 immune complex , ykl-40 ) [ 35 ] .
the strongest prognostic serum biomarker is lactate dehydrogenase ( ldh ) , which correlates with tumor load in advanced disease and is the strongest independent prognostic factor in stage iv melanoma .
it is the only biomarker included in the ajcc staging system and is often used to stratify patients for randomized trials in stage iv disease .
there is limited benefit , however , to the measurement of ldh among patients with earlier stage disease , particularly in the followup of patients who appear tumor - free after surgical resection .
the beta subunit is expressed in cells of melanocytic lineage and is often used as an immunohistochemical marker for histological diagnosis of melanoma .
several studies have demonstrated an association between serum s100 levels and outcome , independent of stage .
s100 serum concentrations can be a useful marker for monitoring therapy response in patients with advanced disease .
while some european guidelines recommend routine s100 measurements as part of the surveillance of melanoma patients , [ 8 , 9 ] , there is limited evidence that this impacts outcome [ 10 , 11 ] .
proteomic approaches can be divided into two categories : those that characterize the entire protein complement of the cells or tissue of interest and those that examine only those proteins found in specific specimens ( primarily blood , but this could also include other fluids such as saliva or urine ) .
several groups have utilized functional proteomics to identify alterations in protein expression and posttranslational modifications to identify markers of melanoma progression as well as predictive markers , such as identifying proteins that may be associated with response to therapy ( table 1 ) . while this approach has been utilized across a spectrum of primary tumors , it is more difficult in melanoma secondary to the limited accessibility of primary melanoma tissues
. therefore most of this work has been carried out in melanoma cell lines .
two - dimensional electrophoresis ( 2de ) has been the mainstay tool for separating proteins for many years .
proteins in a 2-dimensional gel are separated in the first dimension based on isoelectric points and then in a second dimension based on molecular masses .
differences between the samples can be compared and relative quantities determined by quantifying the ratios of spot intensities in the 2d gels .
matrix - assisted desorption / ionization time of flight mass spectrometry ( maldi - tof ms ) can then be used to analyze small amounts of protein isolated from the gel . the mass information obtained can then be used for protein identification using an appropriate protein sequence database and search program .
bernard et al . used 2de and mass spectrometry to identify proteins that differentiated melanocytes from melanoma cell lines and therefore may be important in the early progression to melanoma .
two proteins , nuclophosmin / b23 and hepatoma - derived growth factor ( hdgf ) , were strongly upregulated in melanoma , while cathepsin d was downregulated in melanoma cell lines .
carta et al . also used 2de and mass spectrometry to examine the proteomes of cultured melanocytes and melanoma cell lines from primary and metastatic lesions .
they then used rt - pcr to evaluate mrna expression of these proteins and found that overexpression of hsp27 , hsp60 , and hspa8 and downregulation of prdx2 were observed more commonly in metastatic melanoma versus primary melanoma .
as opposed to identifying proteins associated with melanoma development and progression , sinha et al .
compared melanoma cell lines with varying degrees of resistance to commonly used anticancer drugs to identify proteins that may be responsible for resistance to therapy . starting with a single melanoma cell line , they created a panel of sublines that exhibited different levels of drug sensitivity . using 2de and matrix - assisted laser desorption / ionization - time of flight ( maldi - tof ) mass spectrometry for protein identification
, they identified a variety of proteins that were differentially expressed in chemoresistant melanoma cell lines , many of which were chaperones , including heat - shock proteins ( hsps ) .
these studies utilized electrophoresis to physically separate the proteins , requiring the use of melanoma cell lines .
used maldi - imaging mass spectrometry ( maldi - ims ) analysis , which acquires information from intact proteins directly from thin sections of the tissue .
this allows for the analysis of specific cellular regions and precludes the need to generate a cell line from which the proteins are isolated . using lymph nodes involved with metastatic melanoma from 69 stage iii patients , they identified two proteins that were associated with recurrence , cytochrome c and calmodulin , with a better prognosis as the intensity of both proteins increase . while this approach is applicable to patients with larger metastatic deposits , such as clinically involved lymph nodes , it is not useful for discovery of primary tumor biomarkers . for approximately 90% of melanoma patients ,
the entire primary tumor is excised during the initial biopsy , so proteomic investigations requiring fresh or frozen primary tumor tissue are not applicable .
many academic centers have collections of formalin - fixed paraffin - embedded ( ffpe ) melanoma specimens , with accompanying clinicopathologic and outcome data .
if these specimens could be used to scrutinize the proteome , the use of proteomics for melanoma biomarker discovery would take a giant leap forward .
unfortunately , ffpe tissues are typically refractory to proteomic investigations using today 's methodologies , largely due to the high level of covalently linked proteins arising from formalin fixation .
shotgun proteomics involves direct digestion of protein mixtures to complex peptide mixtures which are then separated and analyzed .
these approaches can be used to extract proteins or peptides from fixed tissues for analysis .
a newer approach , a modified shotgun proteomic strategy , termed direct tissue proteomics ( dtp ) , can extract and identify peptides and proteins directly from tissues using micro - reverse - phase ( rp ) lc - ms / ms and has been proposed for use in melanoma [ 18 , 23 ] .
while there are still several obstacles to overcome , dtp with efficient extraction of proteins from ffpe tissue could open up a new avenue of retrospective proteomics - based biomarker investigation in melanoma .
as discussed , examining the entire proteome of the cell of interest requires either the generation of a cell line or adequate harvestable tissue , which inherently limits and biases the study population .
blood carries not only plasma - specific proteins but also multiple proteins derived from other tissues , including tumors .
many proteins are secreted , shed , or lost into the circulation , either directly by tumor cells or indirectly after destruction of the tumor cells .
the development , validation , and use of serum tests hold several potential advantages over tests that require primary tumor tissue , particularly for melanoma . as an example , takikawa et al .
compared the serum proteome between healthy volunteers and melanoma patients using nanolc and maldi - tof - ms , and identified 9 proteins detectable in plasma from the melanoma patients but not healthy plasma .
ultimately they identified pro - platelet basic protein precursor ( ppbp ) as a protein whose level corresponded with outcome and may serve as a serological prognostic biomarker .
several investigators have utilized surface - enhanced laser desorption / ionization ( seldi ) and protein chip technology to find serum protein patterns that may be associated with the presence or the stage of melanoma .
while gene chips have allowed for the detection of thousands of genes from very small samples , the creation of protein chips has faced several obstacles . compared to dna ,
proteins are more difficult to attach to chip surfaces , and while pcr can be used to amplify dna , there is no method of amplifying minute amounts of protein .
the proteinchip biology system uses seldi - tof ms to retain proteins on a solid - phase chromatographic surface that are subsequently ionized and detected by tof ms [ 25 , 26 ] .
the surface of the proteinchip is designed to select proteins from extracts due to either chemical ( anionic , cationic , hydrophobic , hydrophilic ) or biochemical ( antibody , receptor , dna , enzyme ) properties .
this is a more user - friendly approach to proteomics ; seldi has several advantages over other technologies for high - throughput screening as it is rapid , of relatively low cost , and reproducible .
it requires smaller amounts of sample than 2de as protein profiles can be made from fewer cells .
this technology can be used to detect protein expression patterns and then compare these patterns between different population sets .
caron et al . used this technology to try and discriminate between serum samples from melanoma patients and healthy volunteers and demonstrated a good diagnostic accuracy of 98.1% ( sensitivity 96.7% , specificity 100% ) .
wilson et al . examined the serum from patients with ajcc stage i or ii melanoma who recurred ( n = 25 ) or did not ( n = 24 ) using seldi proteinchip mass spectrometry ( ms ) and identified three protein expression pattern differences that could discriminate between the two .
demonstrated the potential of this technology with artificial neural networks ( anns ) to discriminate between serum samples from 101 stage i melanoma patients and 104 stage iv melanoma patients , as well as from 28 stage iii patients who recurred from 27 stage iii patients who did not .
further research , focusing on the highest peak , ultimately identified serum amyloid a ( saa ) as a potential prognostic biomarker in melanoma .
as an example of this , greco et al . obtained serum from 50 patients undergoing biopsy for suspected melanoma . using 2de and maldi - tof - ms , they identified increases of transthyretin ( ttr ) and angiotensinogen ( agt ) and decreased expression of vitamin d binding protein ( dbp ) .
the investigators also examined serum samples after surgical removal of the melanoma and found that these were no longer elevated 1 month after surgery .
this is an important consideration in melanoma patients , particularly if one is seeking to develop a prognostic serum test .
this test would most likely be ordered after the diagnosis of melanoma and therefore might be greatly impacted by whether or not the entire tumor was removed with the diagnostic biopsy .
another drawback to serum proteomics is that most ( 97% ) of the proteins found in plasma belong to one of 7 major groups of high - abundance plasma proteins : albumin , immunoglobulins , fibrinogen , alpha-1 antitrypsin , alpha-2 macroglobulin , transferring , and lipoproteins . as these are primarily proinflammatory proteins , they are unlikely to represent prognostic or predictive biomarkers .
seldi pattern recognition studies do not depend on detecting low - abundance proteins , but depend instead on fluctuations of protein expression patterns . therefore this technology , as well as others ,
an alternate approach to examining the proteome directly is to screen for antibodies in the serum of patients with melanoma . as with serum - based proteomics , primary tumor tissue from each patient is not required , a significant advantage in melanoma patients .
another advantage is that antibodies are more sensitive and stable than proteins , which is clinically important in creating clinically useful diagnostic or prognostic tests .
antibody - based proteomics is particularly well suited to melanoma as the presence of an immune response to melanoma - associated antigens has been well documented [ 3235 ] .
monitoring the presence or absence of antibodies in the serum that recognize specific tumor antigens can provide insights into the propensity of melanoma to metastasize , serving as biomarkers of melanoma biology and perhaps identifying ideal targets for therapeutic intervention .
there are several high - throughput methods for the discovery of autoantibodies including serological screening of cdna expression libraries ( serex ) , phage display libraries and proteomics - based techniques .
serological protein analysis ( serpa ) uses 2de to separate proteins from tumor tissues or cell lines which are then transferred onto membranes by electroblotting and subsequently probed with sera from different populations of interest .
used this approach to identify 5 proteins that differentiated serum samples from melanoma patients and healthy volunteers ( eukaryotic elongation factor 2 ( eef2 ) , enolase 1 ( eno1 ) , aldolase a ( aldoa ) , glyceraldehyde-3-phosphate dehydrogenase ( gapdh ) , and heterogeneous nuclear ribonucleoprotein ( hnrnp - a2b1 ) . another proteomics - based approach to detecting serum autoantibodies is the use of protein microarrays .
protein microarrays spot proteins ( purified , recombinant , or extracted from tumor cell lysates ) onto microarrays which can be two - dimensional ( glass slides , nitrocellulose membranes and microtitre plates ) or three - dimensional ( beads , nanoparticles ) .
advantages include the fact that less sample and reagents are needed , and autoantibodies to proteins with posttranslational modifications , such as glycosylated proteins , can be detected .
there are , however , challenges to identifying the specific immune - reactive proteins in the respective protein fractions . rather than screening the entire proteome , liu et al .
dual - lectin ( cona and wga ) affinity chromatography was applied to extract both glycoproteins from the lysate of a cell line generated from an intra - abdominal melanoma metastasis .
liquid - based reverse phase separation and natural protein microarray were then applied to separate the enriched proteins and spot the separated fractions on nitrocellulose slides .
these were used to probe the sera from patients with newly diagnosed melanoma for antibodies that correlated with the presence of regional metastases .
after validation , antibodies to 4 proteins including 94 kd glucose - regulated protein ( grp94 ) , acid ceramidase ( asah1 ) , cathepsin d ( ctsd ) , and lactate dehydrogenase b ( ldhb ) were identified that differentiated node - negative from node - positive patients .
although the clinical potential of both tissue and serum - based proteomics in melanoma biomarker discovery seem strong , progress has been relatively limited to date .
the reasons for this are multifactorial , both related to the inherent obstacles specific to melanoma and problems with study design . for the field to advance , several issues need to be tackled . a key obstacle to biomarker discovery is reproducibility .
this has been a significant problem with proteomics . as an example , in a meta - analysis of prostate cancer proteomic data obtained with seldi - tof , published results seem to differ greatly between different groups , and even from within the same groups [ 38 , 39 ] .
as evidenced in table 1 , there is little overlap between the proteins identified by different groups using different techniques .
there are multiple approaches to proteomics , each with significant advantages and disadvantages depending on what the question is . compared with serum proteomics ,
tissue proteomics has a higher likelihood of identifying marker candidates based on the higher concentration of protein within the tissue than after dilution in peripheral blood . for melanoma ,
the use of cell lines is most feasible however results are immediately biased by ( 1 ) selecting patients with harvestable tumor , ( 2 ) selecting melanomas that grow well in vitro , and ( 3 ) by changes in protein expression induced by in vitro culturing .
variations in cell culture technique could yield different results from the same cell line . using tissue obtained directly from patients
avoids some of these issues , but limits the patient population and hence the questions that can be asked .
in addition , the results obtained can be greatly impacted by stroma , necrotic tissue , serum proteins , and blood cells within the specimen .
pure cancer cell populations can be created using fine needle aspiration , calcium starvation , immunomagnetic separation , or laser capture microdissection ( lcm ) , [ 4043 ] but this is extremely difficult to do when there is a limited supply of primary tumor tissue .
until newer technologies for examining ffpe tissues are more fully developed , this approach will be limited to select patient populations .
serum proteomics may identify fewer candidate proteins , but given the drawbacks of tissue proteomics in melanoma , this approach may be more translatable to clinical use . examining
the serum proteome is impossible without reducing the complexity of the protein mixture by removing highly abundant serum proteins , for which there are also several methods .
when the blood is drawn , how it is stored , and whether serum or plasma is used can potentially impact the results . therefore one can see that before any analysis is even performed , variations in the methods used to prepare the samples ( cell culturing , tissue procurement , extraction of highly abundant serum proteins ) can significantly impact the results .
the methods used to do this must be highly reproducible , as even small variations in buffers or agents can alter the results . it becomes easy to see how radically different results can be reached even when the same experimental technique is utilized . quite often ,
initial experiments are designed based on the available samples and technologies , without as much forethought into the clinical question that the findings hope to address . in melanoma , for example , tissue proteomics are often carried out on samples from resected lymph nodes and metastatic deposits , as there is ample tissue available .
clinically , however , this is a population with a very poor prognosis , and outside of very specific questions , it is less likely that biomarkers identified from these highly dedifferentiated samples would impact clinical decision making or serve as useful biomarkers in patients with early stage disease . it is imperative that translational oncology be hypothesis driven , whereby even discovery studies are designed with a specific clinical question in mind .
even something as simple as when blood samples are obtained , if they do not reflect when they would be drawn in the clinical setting , could negatively impact the results .
close collaboration between clinical experts in melanoma and basic scientists is imperative to results that have a high likelihood of clinical impact .
patient selection is also critical to results that are both reproducible and clinically relevant . in oncology
, it is quite common to discover a biomarker among a highly heterogenous group of patients that on univariate analysis is significantly associated with outcome , but in reality correlates so strongly with known staging factors ( tumor size , grade ) that on multivariate analysis it provides no independent prognostic information .
while these may be of scientific interest in unraveling the genes / proteins associated with dedifferentiation and metastases , they are of limited clinical benefit in stratifying patients beyond our current staging systems .
it is therefore imperative that samples be obtained from as homogenous a population as is feasible and in adequate numbers so that newly discovered biomarkers are analyzed in the context of the known prognostic and predictive factors used in clinical decision making .
often smaller and more heterogeneous sample sets are chosen for practical reasons , which unfortunately contribute to the large number of reported biomarkers that are never validated or demonstrate clinical utility . equally important is the appropriate selection of controls . for prognostic markers meant to differentiate between melanoma patients with different outcomes , it is imperative that the good cohort have adequate followup to be sure that this is truly a group at low likelihood of recurrence .
frequently these controls only have a median followup of 2 - 3 years . with longer followup , several of the
good players may recur , and with small sample sets the conversion of only 1 or 2 patients from good to bad can dramatically change the results .
likewise , the search for biomarkers associated with melanoma development , with potential use as a screening tool , often compares melanoma patients ( of varying stages ) to healthy volunteers .
the melanoma group should only include patients with early stage , recently diagnosed disease , and the control group should not be healthy volunteers but rather high - risk individuals with similar characteristics regarding age and sun exposure . while the field of proteomics and other -omics fields are replete with articles describing discovery , there are dramatically fewer articles validating previously published results .
several reports include internal validations , using a fraction of their samples for discovery and then validating the results in the complete set .
however , the bioinformatics tools used in discovery sets often seek to overfit the data , erring on the side of not missing a potential biomarker , but resulting in sensitivities and specificities that may not be reproducible .
even if an institution is able to validate their own findings , given the impact that sample preparation and patient selection can have , validation from other institutions is absolutely critical .
beyond interlaboratory variations , many biomarkers demonstrate varying expression based on patient characteristics ( age , race and ethnicity , genetic lineage , environmental exposures ) .
therefore , biomarkers discovered and validated on a population in one geographic area may not be validated on another , even though the techniques are the same and the populations appear matched by known prognostic factors ( breslow thickness , nodal status , etc . ) . unfortunately , there is limited enthusiasm for one institution to attempt and validate a published result .
validation requires larger numbers and can be costly and labor intensive . as many candidate biomarkers will not be validated , few researchers are interested in devoting time and money to a project that will likely not result in a publication , as there is limited interest on the part of prominent journals in publishing negative results .
this leads to significant publication bias , which all of us as editors and reviewers are in part responsible for .
as new proteomic - based biomarkers are discovered , it is increasingly important that a mechanism exists by which the most promising biomarkers can be validated using external samples .
this will require a collaborative effort on the part of the leading melanoma research centers .
as an example of this , the national cancer institute has created the early detection research , which hopes to promote biomarker discovery , validation , and translation into clinical practice for biomarkers associated with screening and risk .
similar disease - specific collaborative efforts , centered on prospectively collecting data , blood and tumor tissue from multiple centers not for biomarker discovery but rather for validation , will be necessary to validate prognostic and predictive biomarkers .
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### Summary:
: the present clinical staging of melanoma stratifies patients into heterogeneous groups , resulting in the application of aggressive therapies to large populations , diluting impact and increasing toxicity . to move to a new era of therapeutic decisions based on highly specific tumor profiling ,
the discovery and validation of new prognostic and predictive biomarkers in melanoma is critical .
genomic profiling , which is showing promise in other solid tumors , requires fresh tissue from a large number of primary tumors , and thus faces a unique challenge in melanoma . for this and other reasons , proteomics appears to be an ideal choice for the discovery of new melanoma biomarkers .
several approaches to proteomics have been utilized in the search for clinically relevant biomarkers , but to date the results have been relatively limited .
this article will review the present work using both tissue and serum proteomics in the search for melanoma biomarkers , highlighting both the relative advantages and disadvantages of each approach .
in addition , we review several of the major obstacles that need to be overcome in order to advance the field .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: advanced stages of the disease may result in both synchronous and metachronous metastases . however , colonic metastases from gastric cancer are very rare .
we describe a case of a signet ring cell carcinoma of the stomach metastasizing to the ascending colon ( fig .
in march 2008 , a 77-year - old man followed up in our institution for gastric cancer was found to have an ascending colonic adenocarcinoma .
clinical history was positive for prostate acinar adenocarcinoma treated with radical prostatectomy in 2003 ( pt2pn0 , g2 , gleason 2 + 3 , ck34- , be12- ) and chronic symptomatic nephrolithiasis . in january 2007
, the patient had been first diagnosed with a gastric adenocarcinoma in our institution after presenting common symptoms including gastric bleeding and weight loss . at that time
a routine work - up was performed including esophagogastroduodenoscopy ( egds ) with biopsies and contrast ct scanning of the chest and abdomen .
notably , the preoperative ct scan showed small , multiple bilateral lung micronodules ( maximum diameter 0.7 cm ) deserving strict follow - up .
preoperative laboratory findings included anaemia , resulting from bleeding ( hb 9,4 g / dl ) , and cea and ca19 - 9 levels within the range . on january 26
macroscopic pathology examination reported the presence of 2 different ulcerated lesions of 2.5 and 1.0 cm in the longest diameter , respectively .
the larger lesion infiltrated the entire wall to the serosa , while the smaller one infiltrated the submucosa .
final pathology identified an undifferentiated mixed adenocarcinoma with signet ring and intestinal differentiation , and a moderately differentiated adenocarcinoma of intestinal type , respectively .
twenty - eight lymph nodes were isolated and 12 were found involved by metastatic dissemination .
the stage was pt2b(m ) pn2 ( 12/28 ) mx ( stage iiia according to tnm , ajcc , ed .
the patient received an adjuvant chemotherapy with fluorouracil plus folinic acid according to de gramont regimen from march to september . during chemotherapy ,
the ca19 - 9 levels were 74 iu / ml and a ct showed stable lung nodules and no evidence of local or metastatic disease relapse .
just after the end of chemotherapy the patient presented at the follow - up visit with altered touch sensation of the right hand , recently occurring diplopia , a ca19 - 9 of 111 iu / ml and a new ct - detected sub - centimetrical nodule of the left lung with no subsequent dimensional increase at follow - up .
the patient was examined by a neurologist who diagnosed a mononeuropathy of the vi right cranial nerve ; a brain mri showed vascular encephalopathy .
later the patient developed pain to the left calf and thigh , foot neuropathy ( tingling ) and imbalance while walking with overall worsening of his performance status .
a fdg - pet scan was performed showing a single area of pathological uptake to the ascending colon .
this finding was confirmed by a colonoscopy demonstrating the presence of a neoplastic lesion typified as a poorly differentiated adenocarcinoma at pathology examination of biopsies .
then the patient was referred to the division of general and laparoscopic surgery , and he underwent a right hemicolectomy with loco - regional node excision .
the pathological examination demonstrated multiple mucosal and intramucosal localizations of poorly differentiated carcinoma with signet ring cell differentiation .
immunohistochemistry showed positivity for cytokeratin 7 ( ck7 ) , and negativity for cytokeratin 20 ( ck20 ) , cdx-2 and cdx-3 ( fig .
one month later , the clinical picture was rapidly complicated with the worsening of neurological symptoms including facial nerve deficit , with right hypoacusis and swallowing disturbances and leg pain .
brain mri showed progressing disease with complete obliteration of the right and part of the left meckel 's cavity , involvement of v facial nerve , and of the internal auditory conduct .
gamma knife and local radiotherapy were collegially discussed but not performed due to the poor performance status , and the patient was sent to best supportive care .
metastases rarely involve the intestinal tract ; however , post - mortem studies suggest a much higher incidence . as a matter of fact
, gut metastases have been extensively described for specific tumors such as melanoma , breast or lung cancer , and contiguous spreading of ovarian carcinomas .
generally this unusual localization has been associated to lauren 's diffuse type histology , linitis plastica and peritoneal dissemination [ 5 , 11 ] . in a retrospective radiological analysis of 23 cases of colorectal gastric cancer metastases , jang et al
. found that primary tumors showed poorly differentiated adenocarcinoma with signet ring features in 7 cases ( 30.4% ) and signet ring adenocarcinoma in 5 more cases ( 22% ) .
however , neither linitis plastica nor macroscopic peritoneal seeding was present in our patient at the time of the removal of the primary tumor and colorectal metastasis , respectively . when ct or different imaging techniques such as pet scan show the presence of a colorectal neoplasia in a patient with positive clinical history for gastric cancer , a colonoscopy - guided biopsy should be considered , keeping in mind the possibility of a false negative result because of inadequate sampling in up to 54%
. a possible explanation may be that metastatic carcinoma usually preserves the mucosa , and the positive yield from endoscopic biopsy is low . even with a deep biopsy specimen , the sparseness of tumor cells within the exuberant fibrosis may hinder the detection of linitis plastica . in our case the diagnosis of a poorly differentiated adenocarcinoma suggested a primary colorectal cancer .
cdx-2 and cdx-3 negativity suggested a non - colorectal origin of the tumor , confirmed by the negative ck20 staining . in order to exclude a localization from prostate cancer , ck7 staining ( which was positive ) and an accurate revision of slides form
these findings suggest that immunohistochemical profiling might prove useful in selected cases when a differential diagnosis must be assessed also on bioptic material .
nonetheless , gastric adenocarcinoma , especially if it is poorly differentiated or the signet ring cell type , should be considered as one of the common tumors that have the propensity for rare intestinal metastases .
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### Summary:
: the colon is a very rare metastatic localization . here
we report a case of colonic metastases from gastric adenocarcinoma whose clinical presentation was suggestive of a de novo adenocarcinoma of the ascending colon .
the authors discuss that in the presence of a previous history of gastric cancer , immunohistochemical analysis on endoscopic biopsies may help in the definition of a differential diagnosis .
furthermore , this rare metastatic localization might suggest a poor prognosis and a more accurate diagnostic work - up .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the incretin effect is the potentiation of the glucose - mediated insulin secretion due to the gut hormones , namely , glucose - dependent insulinotropic polypeptide ( gip ) and glucagon - like peptide-1 ( glp-1 ) .
they are released by the intestine in the blood stream after oral glucose load , such as during an oral glucose tolerance test or a meal .
the incretin effect has been demonstrated by comparing insulin concentration during oral and intravenous glucose administration that yielded the same peripheral glucose concentration ; however , insulin concentration was significantly higher after the oral load .
since this happened despite the same glucose levels than with the intravenous load , the difference in insulin concentration was ascribed to the effect of the incretin hormones . in type 2
diabetic patients , a reduction of this effect has been reported [ 3 , 4 ] and pharmacological agents have been developed to restore this effect , important for maintaining a good glucose homeostasis .
women with former gestational diabetes ( fgdm ) exhibit markedly increased risk for the later development of type 2 diabetes and related complications .
they often present metabolic abnormalities in insulin sensitivity compared to control subjects , but even greater differences have been observed for beta - cell function . in a previous study on fgdm ,
we have assessed beta - cell function by the analysis of two independent tests , intravenous ( ivgtt ) and oral ( ogtt ) glucose tolerance tests and found that the impairment in beta - cell function was observable only with ogtt .
we hypothesize that the incretin effect may play a pivotal role in the subtle derangement of beta - cell function observed in fgdm .
therefore , the aim of this study was to evaluate the incretin effect in a larger group of fgdm , who underwent both ivgtt and ogtt immediately after partum .
they were also divided according to their glucose tolerance to evaluate if it plays some role on the possible changes of the incretin effect in fgdm .
a total of 104 fgdm were studied within 6 months after delivery and compared to 35 healthy women after normal pregnancy ( cnt ) .
table 1 shows the main characteristics of the two groups ; body mass index ( bmi ) of fgdm was borderline higher , but in general still in the overweight range .
every subject randomly underwent a 75 g ogtt with sampling at 10 , 20 , 30 , 60 , 90 , 120 , 150 , 180 min and a 0.33 g / kg frequently sampled intravenous glucose test ( ivgtt ) with insulin ( 0.03 iu / kg , humulin r ; eli lilly , indianapolis , in , usa ) intravenous infusion at time 20 for 5 min .
less than 3 weeks elapsed between the two tests , without any diet or habit changes in between .
both tests lasted 3 h ; glucose and c - peptide were determined in duplicate by commercially available radioimmunoassay kits with an interassay coefficient of variation < 5% .
further details on the performance of the two tests were reported previously [ 7 , 8 ] . out of 104 fgdm , 77 resulted with normal glucose tolerance ( fgdmngt ) according to the ogtt criteria of the american diabetes association , 6 with type 2 diabetes and 21 with impaired glucose regulation ( fgdmigr ) , which included both impaired fasting glucose and impaired glucose tolerance .
all cnt exhibited normal glucose tolerance . for the purpose of this study , we calculated the area under the concentration curves ( auc ) for glucose ( aucgl ) and c - peptide ( auccp ) for 3 h in both tests , by using the trapezoidal rule .
the suprabasal , dynamic auc ( dauc ) were computed by subtracting from the auc the basal area ( i.e. , fasting value 180 min ) .
the beta - cell function describes the ability of glucose to stimulate insulin release from the beta - cell .
beta - cell function during ogtt ( bcog ) and that during ivgtt ( bciv ) were calculated according to the respective ratio dauccp / daucgl in both tests : units nmolcp / mmolgluc .
the incretin action occurs only during an oral administration of glucose ; thus , it can be estimated by subtracting the glucose stimulated secretion during the ivgtt from that evaluated during the ogtt : the formula 100 ( bcog bciv)/bcog yields therefore the percent incretin effect .
this approach has been already successfully exploited in previous studies [ 9 , 10 ] . in order to evaluate whether different glucose tolerance within the fgdm plays a role in the assessment of beta - cell function and incretin effect , these parameters were also computed in the single subgroups of normotolerant and impaired metabolism .
data are expressed as mean se ; means have been compared with the student 's t - test .
fasting and total auc glucose in both tests were markedly higher in fgdm ( table 1 ) ; fasting c - peptide was not different , while the dynamic c - peptide response to glucose stimulation only tended to be higher in fgdm , but only with borderline significance .
suprabasal auc of glucose ( daucgl ) , which represents the main stimulus to the secretory response of the beta - cell , was higher in fgdm than that of cnt for both tests ( 338 20 mmol / l 3 h versus 189 21 , p = 0.0001 for ogtt ; 206 13 versus 119 16 , p = 0.0002 for ivgtt ) .
dynamic insulin secretion , dauccp was not different between fgdm and cnt in both tests , but much higher ( p < 0.00001 ) during ogtt ( 285 9 nmol / l 3 h versus 257 15 , p = 0.13 fgdm versus cnt for ogtt ; 61 3 versus 55 5 , p = 0.36 for ivgtt ) .
beta - cell function and incretin effect are shown in table 2 , where fgdm was also divided into fgdmngt and fgdmigr , the latter presenting with higher bmi . from these subgroups
the 6 type 2 diabetics were excluded , since their small number allowed no statistical power for any possible comparison .
bcog was markedly higher than bciv in both fgdm and cnt ( p = 0.003 ) ; both bcog and bciv were lower in fgdm ( all together ) compared to cnt ; and were lower in fgdmigr compared to fgdmngt . when comparing the normotolerant fgdmngt to cnt , both bcog and bciv were not different , while beta - cell functions of fgdmigr were significantly lower than those of cnt .
incretin effect resulted similar between fgdm all together and cnt ; that of fgdmngt was not different from that of cnt ( p value ranging in both cases 0.20.8 ) ; while that of fgdmigr was significantly lower than that of women with normal pregnancy ( table 2 ) .
when incretin effect was normalized to bmi , to take into account that the main determinant of igr was the increased bmi , the differences in the incretin effect were even more substantial .
the value for cnt was 2.77 0.19% m / kg , still higher than that of fgdmigr ( 1.75 0.21 ; p = 0.019 ) , but also the difference with that of fgdmngt ( 2.33 0.11 ) became significant ( p = 0.038 ) .
incretin effect normalized to bmi was 2.21 0.10 ; p = 0.006 versus cnt ) .
within a short period after partum , beta - cell function , evaluated both with the oral and with the intravenous glucose tests , was reduced in a general population of overweight women who exhibited gestational diabetes mellitus during pregnancy .
indeed , in both tests , fgdm exhibited c - peptide release only slightly increased despite markedly higher glucose .
results of this study show that incretins do not play a fundamental role in this observed reduced beta - cell function characterizing fgdm : in fact , the surrogate index of incretin effect used here did not differ from the same index evaluated in a population of healthy women , who had a normal pregnancy , studied within the same period after partum . in both cnt and fgdm ,
the beta - cell function obtained with the ogtt was much higher than that with ivgtt , showing that incretins have a potent effect in both groups .
the elevated beta - cell response during ogtt could mask possible significant differences in the beta - cell sensitivity to glucose between fgdm and cnt ; however , no difference is also highlighted by the ivgtt , which provides the evaluation independent on incretins .
our results on beta - cell function seem to be in contrast with a previous study , where it is reported an unchanged beta - cell function in fgdm .
however , in that study , the authors used the 30 min insulinogenic index with insulin , which is known to be not fully reliable , while the present investigation exploited c - peptide evaluated during the whole 3 h duration of the test : a more reliable figure of the incretin - mediated sensitivity of the beta - cell to the glucose stimulation . to quantify this process
, we have used the percent ( normalized ) difference of the beta - cell function between the tests , which gauges the relative contribution of the incretins in fostering glucose - dependent insulin release .
we have used the beta - cell function instead of the simple aucs as previously done [ 3 , 9 , 10 ] , because the ogtt and the ivgtt did not yield isoglycemic patterns ; thus , we had to normalize the insulin release to glucose with the ratios dauccp / daucgl .
the incretin effect we estimated is a kind of general measurement and can not discriminate between the real effect of the incretins and the possible reduction in fgdm of the incretins production .
in fact , our measurement is an indirect surrogate , since we have not measured the incretin hormones concentration .
having for instance the pattern of glp-1 , we could apply another straightforward method that quantifies the direct incretin action , independently on the actual hormone secretion .
some investigators found a mildly reduced glp-1 response to oral glucose only during the first 30 min , while the entire 2 h glp-1 auc did not differ from that of the control subjects .
this was substantiated by other studies that reported no differences in the secretion of incretin hormones after oral glucose ingestion in women with a history of gestational diabetes .
therefore , we are quite confident that the incretin effect we observed in our study is prevalently due to the action of incretins in sensitizing the beta - cell .
a recent report showed that incretin effect is reduced with obesity , which is known to be characterized by insulin resistance and reduced glucose tolerance .
these findings in a general population were then verified in our fgdm , who were divided into normo- and impaired tolerant . to the best of our knowledge ,
. the reason may be in the fact that igr have a slightly higher bmi , though not reaching overt obesity yet .
this fact corroborates more our point , since it is known that obesity is accompanied by hyperinsulinemia before the onset of overt diabetes .
thus the circumstance that fgdmigr still presents reduced beta - cell sensitivity to glucose , despite higher bmi , appears to be an intrinsic defect of this population . in fact , when the incretin effect was normalized to bmi , fgdmngt too had a lower index , despite similar bmi than cnt . since the majority of fgdm return normal after delivery , in general
, we can claim that a reduced incretin effect likely remains a characteristic of this condition .
in conclusion , normotolerant women with previous gestational diabetes exhibit an incretin effect similar to that of healthy women , who had a normal pregnancy .
compromised incretin effect , proper of obese and type 2 diabetic subjects , characterizes instead fgdm with impaired glucose tolerance , probably related to their , though slightly , augmented body weight . when the incretin effect was evaluated after normalization to bmi , it resulted in reduced in both categories , giving the impression of an intrinsic characteristic of fgdm , regardless of their glucose tolerance .
the diminished incretin effect of fgdm seems therefore to reflect an early abnormality of the general beta - cell dysfunction in the progression toward type 2 diabetes .
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### Summary:
: background and aims . women with former gestational diabetes ( fgdm ) are characterized by impaired beta - cell function ( bc ) .
incretin hormones contribute to insulin secretion after oral administration of glucose .
we aimed to assess the possible role of incretins on altered insulin release in fgdm .
materials and methods .
we studied 104 fgdm women within 6 months after delivery and 35 healthy women after normal pregnancy ( cnt ) with a 75 g oral ( ogtt ) and a 0.33 g / kg intravenous ( ivgtt ) glucose test , both lasting 3 h. the ratio of suprabasal areas under the concentration curves for glucose ( daucgl ) and c - peptide ( dauccp ) evaluated bc during ogtt ( bcog ) and ivgtt ( bciv ) .
incretin effect was computed in all fgdm and in fgdm with normal tolerance ( fgdmngt ) and with impaired glucose regulation ( fgdmigr ) .
results .
daucgl of fgdm was higher ( p < 0.0001 ) than cnt for both tests ; while dauccp were not different .
bcog and bciv were lower in fgdm versus cnt ( 1.42 0.17nmolcp / mmolgluc versus 2.53 0.61 , p = 0.015 and 0.41 0.03 versus 0.68 0.10 , p = 0.0006 , respectively ) .
ie in cnt ( 66 4 % ) was not different from that of all fgdm ( 59 3 ) and fgdmngt ( 60 3 ) , but higher than that of fgdmigr ( 52 6 ; p = 0.03 ) .
ie normalized to bmi was 2.77 0.19 % m2/kg in cnt , higher than that of fgdmigr ( 1.75 0.21 ; p = 0.02 ) and also of fgdmngt ( 2.33 0.11 ; p = 0.038 ) . conclusion .
compromised ie characterizes fgdmigr . in both fgdm categories , regardless their glucose tolerance , ie normalized to bmi was reduced , signifying an intrinsic characteristic of fgdm .
therefore , the diminished ie of fgdm seems to reflect an early abnormality of the general beta - cell dysfunction in the progression toward type 2 diabetes .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: despite initially being thought of only as toxic gases , hydrogen sulfide ( h2s ) , nitric oxide ( no ) , and carbon monoxide ( co ) are now recognized as important endogenously produced signalling molecules known as gasotransmitters .
wang describes gasotransmitters as small gas molecules that are membrane permeable , endogenously generated , and which have functions at physiologically relevant concentrations .
h2s was the third identified gasotransmitter [ 1 , 47 ] . like no and co , h2s is also a toxic air pollutant [ 810 ] .
sulfur dioxide ( so2 ) and carbonyl sulfide ( cos ) are gaseous toxins that only recently have been shown to be endogenously produced and to transmit biological signals . in this paper , we will discuss the biology of the sulfur containing gasotransmitters and refer to their use as toxins .
our primary objective is to relate what is known in mammals to an understanding of the action of these compounds on invertebrate pests of agriculture . as such
, we have augmented the paper with comparative bioinformatics of genes involved in the synthesis and catabolism of h2s , so2 and cos .
this will facilitate future detailed genetic studies into the mode of action of these gasotransmitters / sulphurous fumigants the strongest evidence that so2 and cos are gasotransmitters comes from their effect on smooth muscle cells .
dilation of vascular smooth muscle is caused by the endothelial release of vasodilator substances referred to as endothelium derived relaxing factor ( edrf ) .
no is a major mediator of edrf - induced vasodilation , and h2s has been suggested as a secondary edrf component .
however , edrf causes hyperpolarization in smooth muscle cells , but neither no nor h2s cause this effect .
it has been suggested that edrf contains more than one component that causes hyperpolarization , designated endothelium derived hyperpolarizing factors ( edhfs ) [ 14 , 15 ] .
both so2 and cos are produced by the porcine coronary artery ( pca ) , and both have short half - lives of 1 - 2 seconds , similar to edhf [ 11 , 16 , 17 ] .
sulfur occupies a unique position in biology due to its ability to transfer electrons to and from substrates .
these range from negative two in thiols ( rsh ) to plus six in sulfate anions ( so4 ) and include fractional oxidation states such as 0.5 , found in the disulphide radical anion ( rssr ) .
it also influences the catalytic and metal binding characteristics of the element as well as the activity of the sulfurous gasotransmitters .
for example , exposure to sulfur containing gases has a profound effect on cellular metabolic and redox systems [ 2325 ] .
we will discuss each of h2s , so2 , and cos , including their chemical properties , their metabolism , and their transport .
we will also identify the orthologous sulfur metabolism and transport genes in the genetically tractable model organism caenorhabditis elegans ( c. elegans ) as well as drosophila melanogaster ( d. melanogaster ) and saccharomyces cerevisiae ( s. cerevisiae ) . c. elegans orthologues of mammalian genes involved in sulfation have recently been reviewed and will not be discussed here .
we propose that fumigants are effective poisons specifically , because they are able to disrupt endogenous gaseous signalling .
this hypothesis has a close corollary that fumigants or their close derivatives may have medically useful effects as modifiers of gasotransmitters at sublethal doses
it is also highly toxic as evidenced by its use in the first world war as a chemical warfare agent .
h2s is also a significant air pollutant , particularly in sewerage treatment plants , where it can accumulate to dangerous levels .
the toxicity of these gases was initially presumed to be caused by the reversible inhibition of cytochrome c oxidase ( cox ) , the terminal electron acceptor of the electron transport chain ( etc ) .
thus , while h2s does inhibit cox at high concentrations of approximately 80 ppm similar to cyanide , at low concentrations h2s actually stimulates oxygen consumption .
when h2s concentration is high in colonocytes , complex i of the etc operates in reverse mode and accepts electrons from quinone in order to reduce nad to nadh .
inhibition of respiration caused by h2s is accompanied by a reversion of the etc complex ii .
exposure to 150 ppm of h2s has been shown to induce a suspended animation like state in mice . c. elegans acclimatized in 50 ppm of h2s results in thermotolerant and an increase in longevity .
resistance to high temperatures in c. elegans often correlates with increased lifespan . the lethal dose , 100% for c. elegans is 150 ppm of h2s .
however , acclimatized c. elegans are able to survive being exposed to 500 ppm .
h2s also affects the cardiovascular , neural , digestive , respiratory , endocrine , and immune systems at physiological concentrations ( table 1 ) .
h2s is endogenously produced during the metabolism of sulfur containing amino acids , in solution h2s dissociates to hs and h .
these biological activities have led to h2s being acknowledged as the third gasotransmitter following no and co [ 1 , 47 ] .
h2s is enzymatically generated via the desulfhydration of cysteine by two pyridoxal - phosphate ( plp ) dependent enzymes cystathionine--synthase ( cbs ) and cystathionine--lyase ( cse / cth ) . as well as a plp - independent enzyme 3-mercaptopyruvate sulfurtransferase ( 3mst / mpst ) .
both cbs and cse are located in the cytosol , whereas 3mst is present in the cytosol and the mitochondria .
cbs is the primary source in the brain whereas cse is the primary source of h2s in blood vessels .
disruption of cse results in an elevation of blood pressure . both cbs and cse affect not only the levels of h2s , but also the metabolism of sulfur containing amino acids and the redox state of the cell via their effect on the availability of glutathione ( gsh ) .
cbs catalyzes the first step in the catabolism of homocysteine to cystathionine , whereas cse catalyzes the synthesis of cystathionine to cysteine ( figure 1(a ) ) [ 54 , 55 ] .
availability of the sulfur containing amino acid cysteine is a critical factor in the synthesis of glutathione ( gsh ) [ 56 , 57 ] .
roughly half of the intracellular gsh in the liver is derived from the transsulfuration pathway .
gsh and glutathione disulphide ( gssg ) are the main thiol / disulphide couple involved in cellular redox maintenance ( 2gsh / gssg ) [ 59 , 60 ] .
h2s increases -glutamylcysteine , which is a precursor to gsh and causes a recovery of cysteine transport [ 42 , 43 ] .
the heme in the cbs enzyme is redox - active and is capable of reversibly regulating the activity of the enzyme according to the redox state . under reducing conditions cystathionine production
the redox responsiveness of these two pathways is likely important in order to maintain an appropriate intracellular glutathione pool [ 58 , 62 ] .
a third enzyme , 3mst , participates in a two - step pathway of h2s synthesis .
firstly , aspartate aminotransferase ( aat / asat / aspat / got ( glutamic oxaloacetic transaminase ) ) deaminates cysteine in the presence of -ketoglutarate to generate 3-mercaptopyruvate and glutamate . secondly , 3-mercaptopyruvate is desulfhydrated to pyruvate and h2s by 3mst ( figure 1(b ) )
the inhibition results from oxidation of a catalytic cysteine in the active site of 3mst to sulfenate .
this inhibition helps to conserve cysteine in the cell , contributing to the maintenance of cellular redox homeostasis .
a paralogue of 3mst called rhodanese ( rhod ) is the principle enzyme involved in the detoxification of h2s in the mitochondria .
h2s is rapidly oxidized to thiosulfate ( s2o3 ) and then converted to sulfite ( so3 ) and sulfate ( so4 ) .
vertebrate 3mst , which has 59% homology to rhod can also potentially detoxify cyanide and h2s [ 67 , 70 ] .
the s. cerevisiae protein cys4/ygr155w , c. elegans sequences zc373.1 and f54a3.4 , h. sapiens ( cbs ) , and d. melanogaster ( cbs / cg4840 ) form an orthologous cluster of sequences in the phylogenetic tree ( figure 2 ) . of these sequences ,
there is also a somewhat more divergent yeast sequence ( ygr012w ) that defines a second orthologous cluster containing four c. elegans paralogues but no sequences from the other two organisms ( figure 2 ) .
the s. cerevisiae protein cys3/yal012w d. melanogaster eip55e / cg5345 , h. sapiens ( cse ) , c. elegans sequences cth-2/zk1127.10 and cth-1/f22b8.6 form an orthologous cluster of sequences in the phylogenetic tree ( figure 3 ) .
s. cerevisiae protein met17 , catalyzes the reaction between o - acetylhomoserine and sulfide , leading to the production of homocysteine [ 72 , 73 ] .
s. cerevisiae proteins str3 and irc7 are cystathionine--lyase proteins not found in h. sapiens , which are involved in the biosynthesis of methionine [ 74 , 75 ] .
the c. elegans sequence cbl-1/c12c8.2 forms a second orthologous cluster with s. cerevisiae protein irc7 ( figure 3 ) .
the s. cerevisiae protein tum1/yor251c , h. sapiens rhod and 3mst as well as seven c. elegans paralogues mpst-1 through mpst-7 form an orthologous cluster of sequences in the phylogenetic tree ( figure 4 ) .
it is interesting to note that despite the gene being present in bacteria , yeast , nematodes , and mammals , no orthologous sequences exist in the d. melanogaster genome or in any arthropoda sequences in genbank .
one clade contains the s. cerevisiae aat1/ykl106w and h. sapiens aat - m proteins , both of which are known to be located in the mitochondria .
the other clade contains the s. cerevisiae aat2/ylr027c and h. sapiens aat - c proteins which are cytoplasmic .
the d. melanogaster protein got-2/cg4233 and c. elegans got- 2.1/c44e4.3 and got-2.2/c14f11.1 proteins fall in with the mitochondrial orthologues ( figure 5 ) , which suggests that these proteins are mitochondrial as well .
the d. melanogaster protein got-1/cg8430 and c. elegans got-1.1/t01c8.4 , got-1.2/t01c8.5 and got- 1.3/c14e2.2 proteins fall into the cytoplasmic clade ( figure 5 ) , which suggests that these proteins are cytosolic .
carbonyl sulfide was first described in 1841 . it is an air pollutant that also has been used as a fumigant [ 78 , 79 ] .
cos is also naturally present in the atmosphere , in water , soil , and plants .
cos is biologically generated in bacteria via the enzyme thiocyanate hydrolase , but this enzyme is not present in eukaryotes .
interestingly , cos is detectable in both porcine coronary artery ( pca ) and cardiac muscle and is able to induce arterial dilation . as of the writing of this review
it has been shown , however that stimulation of pca with acetylcholine causes an increase in synthesis of cos within the coronary artery .
this suggests that muscarinic acetylcholine receptors ( machrs ) and not nicotinic acetylcholine receptors ( nachrs ) are involved in regulating cos synthesis , because machrs but not nachrs are found in the coronary artery .
cos is converted via -carbonic anhydrase ( -cah ) to h2s and co2 . in eukaryotes
the toxicity of cos is mediated by h2s as inhibition of -cah activity decreased the toxicity of cos .
after exposure to cos , the redox balance of the cell is disrupted and genes that respond to oxidative stress such as glutathione reductase and superoxide dismutase are upregulated .
the gene expression effect of exposure to cos is similar to that of phosphine exposure .
the genes responsible for the synthesis of cos has not yet been identified , but it is known that -carbonic anhydrase ( -cah ) is responsible for the conversion of cos to carbon dioxide and hydrogen sulfide .
it has six family members , two of which ( cah-3 and cah-4 ) have been demonstrated to encode functional -cah enzymes ( table 2 ) .
additionally c. elegans , s. cerevisiae , and d. melanogaster also contain a class of cah which is not found h. sapiens [ 89 , 90 ] .
like the gases mentioned previously , so2 is a toxic air pollutant [ 91 , 92 ] .
it also has the distinction of being the oldest recorded chemical fumigant , as it was used by ancient egyptians , greeks , and romans .
it was also used as a chemical warfare agent in a conflict between the athenians and the peloponnesians circa 431 b.c . as well as during the roman siege of dura - europos in 256 c.e . .
sulfite , a dissociation product of so2 , is used as a preservative in beverages and food .
so2 is likely to be a signalling molecule as it is produced endogenously from the metabolism of sulfur containing amino acids .
additionally , so2 has been found to produce biological effects at physiological concentrations , such as vasodilation in isolated rat aortic rings and a decrease in blood pressure of male rats [ 99 , 100 ] . for these reasons , so2 has been suggested to be a gasotransmitter .
so2 can also dissociate to its derivatives in solution , which may also be biologically active .
for example , so2 dissociates into sulfite ( so3 ) and bisulfite ( hso3 ) in a 3 : 1 ratio in a neutral solution .
furthermore , both so3 and hso3 can be oxidized to so4 via sulfite oxidase ( sox ) .
vasodilation via so2 , however , has been found to be much greater than dilation induced by so2 derivatives .
it is , therefore , unlikely that activity attributed to so2 is actually due to the action of derivative compounds .
cysteine catabolism to cysteinesulfinate is dependent upon cysteine dioxygenase ( cdo ) [ 97 , 104 ] .
the key enzyme in the generation of so2 is aat , which is constantly being expressed ( figure 1(c ) ) .
nonenzymatic generation of so2 occurs at neutrophils as a result of oxidative stress , which causes the conversion of h2s to sulfite .
exposure to so2 has been found to cause lipid peroxidation as well as increase the levels of enzymes that protect cells against oxidative damage caused by reactive oxygen species , including superoxide dismutase , glutathione peroxidase and catalase .
exposure to so2 also induces chromosomal aberrations , chromatid ex - changes and micronuclei formation , as shown in cultured human blood lymphocytes [ 113 , 114 ] .
sulfite oxidase ( sox ) is involved in oxidative detoxification of sulfite [ 102 , 115 ] .
deficiency of sox has previously been demonstrated to increase so2 , so3 , and hso3 toxicity [ 116 , 117 ] .
it is expected the oxidative damage caused by exposure to so2 would be tissue specific .
however it is found that exposure of so2 caused nearly equal oxidative damage , suggesting that so2 toxicity is systemic .
phylogenetic analysis was not carried out on the other proteins involved in the synthesis or breakdown of so2 as no gene duplication had occurred , resulting in a simple one - to - one correspondence between nematode and human sequences .
the human gene for cysteine dioxygenase ( cdo-1 ) carries out the initial step in sulfur dioxide synthesis from cysteine . c. elegans has a single counterpart which is also called cdo-1 ( table 3 ) .
the second step in sulfur dioxide synthesis is aspartate amino transferase , which is also used elsewhere in sulfur metabolism and is the subject of figure 5 .
the final step in the synthesis of sulfur dioxide is the nonenzymatic decomposition of sulfinyl - pyruvate to sulfur dioxide and pyruvate .
the oxidation of sulfur dioxide is carried out by sox-1 in humans , the orthologous c. elegans gene is h13n06.4 ( table 3 ) .
h2s and so2 have been found to act synergistically with no to enhance the vasorelaxant effect [ 100 , 120 ] .
the vasorelaxant effect of h2s in rat aortic rings can be decreased by removal of the endothelium , interruption of no synthase or blocking of ca - dependent k channels .
however , others have not observed synergistic vasorelaxation when h2s and no treatments are combined but instead see a decrease in vasorelaxation .
synthesis of h2s is increased when exposed to no due to the activation of the cyclic guanosine monophosphate pathway , which potentially increases the activity cse .
it has also been found that metabolism of co is also enhanced when exposed to h2s .
additionally , no and h2s can result in an increase in cysteine uptake [ 42 , 126 ] .
in contrast , h2s has been found to suppress no synthesis in rats by down regulating the aortic l - arginine - dependent no pathway .
exposure to so2 is found to increase no pathway . despite the poor understanding of the cross - talk between gasotransmitters , it is clear that their functions are tightly integrated .
after the sulfur containing gases are endogenously produced , they can either be immediately released or stored for later release in response to a physiological signal . unlike the short half - lives of cos and so2 ,
sulfur from the sulfur containing gases can be stored in two forms , acid - labile sulfur or bound sulfane - sulfur .
sulfur is released from bound sulfane - sulfur by reduced glutathione and cysteine , or at ph higher than 8.4 [ 131 , 132 ] .
acid - labile sulfur is generally found as iron - sulfur enzymes in the mitochondria .
sulfur is released from acid - labile sulfur at a ph of < 5.4 , with little or no h2s released at ph 6 .
bound sulfane - sulfur is generally located in the cytoplasm though there is also evidence of long distance transport [ 131 , 133 ] .
one mechanism of transport has been determined in lucina pectinata in which the heme group of hemoglobin i ( hbi ) binds and transports sulfide [ 97 , 134 ] . in the c1 hb from riftia pachyptila , the sulfide is bound to zinc ions .
neither hbi nor c1 hb are found in c. elegans , though other globular proteins exits which could potentially bind to sulfide , providing a mechanism for long distance sulfide transport .
cos and so2 are able to freely diffuse across the hydrophobic cellular membrane without facilitation via membrane channels [ 136138 ] .
this situation is analogous that of ammonia transport , which is also able to freely diffuse across the cellular membrane . despite this ability , however , three distinct transport systems exist that actively transport ammonia across cell membranes .
the three sulfur containing gases h2s , so2 , and cos act as gasotransmitters in vertebrates .
the primary bioassay that is used to study the three compounds is vasodilation , though metabolic arrest has also been demonstrated in the case of h2s and all three compounds are known to affect the redox state of cells .
though the compounds have barely been studied in invertebrates , h2s has been shown to mediate lifespan extension and heat tolerance in c. elegans as well as desiccation tolerance in d. melanogaster .
exposure of c. elegans to so2 induces ovoviviparity , which is a stress response in c. elegans .
the toxicity of the chemicals when administered at concentrations greater than normal endogenous levels likely reflects their role as potent neurological and physiological signalling molecules .
characterisation of the roles of these molecules in the model organism , c. elegans , will facilitate the genetic analysis of their function and toxicology with benefits to be gained in agriculture and medicine .
a first step toward genetic analysis is to determine the extent to which the metabolic pathways exist in the primary eukaryotic genetic model organisms ; s. cerevisiae , c. elegans , and d. melanogaster .
studies in this organism will be of limited value in understanding how the compounds act in a multicellular animal , however .
d. melanogaster and indeed all insects are missing one of the metabolic genes altogether , which will limit the studies that can be considered in this species . the model system c. elegans
contains all of the mammalian genes involved in the metabolism of the sulfur containing gases . c. elegans has an additional interesting property .
most genes for synthesis of h2s have been duplicated in c. elegans even though single genes exist in the other organisms .
this situation likely reflects the stereotypic biology of c. elegans in which specific genes act in specific cell types to a greater extent than in other organisms .
this may provide a research advantage as genetic manipulations may allow gasotransmitter signalling to be disrupted more specifically than in other organisms .
c. elegans is ideal for the genetic investigation of gasotransmitter action and toxicity as the nematodes are cultured on agar medium which facilitates simultaneous exposure to dissolved chemicals and gases .
c. elegans reproduces rapidly as a self - fertilizing hermaphrodite which facilitates the creation of mutant strains .
there are also well - defined techniques for transformation and genetic manipulation of gene expression .
furthermore , the stereotypic development of c. elegans means the origin of each cell in the adult is known and the physiological role of each cell is reproducible . because the organisms are transparent , the physiology of individual cells in the living organism also can often be studies microscopically using fluorescent probes .
genetic analysis can be carried out in the forward " direction , which refers to the traditional approach of mutagenesis of all genes in the genome followed by a screen for mutant individuals that exhibit a specific effect ( e.g. , resistance to h2s ) .
genetic analysis can also be carried out in the reverse direction , which refers to the molecular genetic approach of disrupting a characterised gene that ought to affect a process and then analysing the result .
an example would be to individually suppress each cse gene in c. elegans to see which of them result in phenotypes related to h2s synthesis .
genetic analysis can also be combinatorial , an approach that is greatly facilitated in genetic model organisms , which usually have large collections of characterised mutant strains that are distributed to researchers on request .
an example of a combinatorial approach would be to determine the effect of h2s depletion on lifespan in strains carrying known longevity mutations .
this would indicate whether the effect of h2s on lifespan is related to any previously described lifespan enhancing mutations .
major issues remain to be investigated regarding the roles of sulfur containing gases in biology , particularly in invertebrates .
these include the possibility of unique roles of the gases within specific subcellular compartments , in specific tissues or at specific times during development .
genetic analysis can be used to identify interactions between gaseous signals and other signalling pathways as well as the influence of redox state on the activity of the gases .
understanding the mechanisms of action can also be used to identify novel fumigants or fumigation synergists of commercial importance .
model organism genetics can also be used for the identification and genetic manipulation of physiological parameters of medical significance that are controlled by the sulfur containing gases .
such physiological states include thermotolerance , desiccation tolerance , reversible metabolic arrest , and hypoxic preconditioning .
all of these research targets can be addressed effectively and meaningfully in genetic model organisms such as c. elegans .
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### Summary:
: gasotransmitters are biologically produced gaseous signalling molecules . as gases with potent biological activities , they are toxic as air pollutants , and the sulfurous compounds are used as fumigants .
most investigations focus on medical aspects of gasotransmitter biology rather than toxicity toward invertebrate pests of agriculture .
in fact , the pathways for the metabolism of sulfur containing gases in lower organisms have not yet been described . to address this deficit
, we use protein sequences from homo sapiens to query genbank for homologous proteins in caenorhabditis elegans , drosophila melanogaster , and saccharomyces cerevisiae . in c. elegans , we find genes for all mammalian pathways for synthesis and catabolism of the three sulfur containing gasotransmitters , h2s , so2 and cos . the genes for h2s synthesis have actually increased in number in c. elegans .
interestingly , d. melanogaster and arthropoda in general , lack a gene for 3-mercaptopyruvate sulfurtransferase , an enzym for h2s synthesis under reducing conditions .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: . obsessive compulsive disorder ( ocd ) too is one such disorder which can coexist with other anxiety disorders , mood and psychotic disorders . of these , depressive symptoms are the commonest comorbidity .
mania in ocd can occur either as an independent comorbidity or as a result of an antidepressant - induced switch in a patient on anti - ocd drugs .
whatever the cause may be , this comorbidity implies that there can be a host of differences in the presentation , course , treatment guidelines and prognosis .
a 17-year - old first born male patient who was premorbidly of an easy temperament had a strong family history of mental illness .
he consulted a psychiatrist for ocd of five years duration and was prescribed clomipramine 75 mg , fluoxetine 20 mg and risperidone 1 mg . a week after this consultation , he presented to our out patient department ( opd ) with a history of obsessions of contamination , sexual images , compulsions of washing , checking , repetitions and ritualistic compulsions .
there was no history of attention deficit hyperactivity disorder ( adhd ) or tourette 's syndrome .
he also had depressive symptoms i.e. sadness , suicidal behavior , decreased sleep and delusion of reference , which he said was of one month duration .
patient was admitted as he also had suicidal ideas and plans and was given fluoxetine 40 mg along with clomipramine 75 mg .
his hamilton rating scale for depression ( ham - d ) and y - brown obsessive compulsive scale ( y - bocs ) scores were 42 and 32 respectively . during the stay in the hospital ,
he was found to have agitation and aggression , increased speech output , increased psychomotor activity , grandiose ideas about his physical power and sexual imagery regarding the treating staff and the nurses .
he was then started on divalproex sodium and dose built up to 1 500 mg , risperidone gradually increased to 12 mg , clonazepam 1 mg and parenteral antipsychotics .
as there was no reduction in symptoms , quetiapine was started and the dose built to 400 mg . despite the high dose of antipsychotics , there was no extra pyramidal side effects ( eps ) .
not finding an adequate response and due to the presence of suicidal ideas , he was started on electroconvulsive therapy and after one sitting of modified electro convulsive therapy ( ect ) , his manic symptoms worsened .
his aggression and increased verbal output reduced minimally after increasing the dose of quetiapine to 600 mg and his ymrs scores reduced to 30 .
he was discharged on request with divalproex sodium 1 500 mg , risperidone 4 mg and quetiapine 600 mg and was advised regular follow - up . during the follow - up , he was found to have prominent symptoms of both mania and ocd , though he reported a 50% reduction of manic symptoms .
the oc symptom cluster of this patient was not typical of that reported in this comorbidity .
the bipolarity was of type i. an interesting finding was that both ocd and mania were prominent in intensity .
one study was by reddy et al . which was an assessment of psychiatric comorbidity in children and adolescents with ocd .
fifty - four children with ocd were assessed using a structured interview schedule and only one subject had bipolar disorder .
another study by zutshi et al . in nimhans on clinical features reported that obsessions and compulsions worsened with the severity of depression and completely disappeared with mania .
reported obsessions of contamination and pathological doubts with cleaning and spitting rituals in their case . a case report by sathyanarayana et al
cosoff and hafner found that 30% of inpatients with bipolar disorder met criteria for ocd .
there is a high rate of comorbidity between ocd and bipolarity , as reported by chen and dilsaver too .
the epidemiologic catchment area ( eca ) study suggested 18 times higher risk for developing ocd in bipolar euthymic patients in comparison with general population .
but , kruger et al . and strakowsky et al . found variable rates of comorbidity between bipolar disorder and ocd from 8 to 35% in bipolar inpatients suffering from ocd .
this difference in the presentation may be with regards to the clinical features , course or prognosis of the illness .
patients with ocd comorbid with bipolar mood disorder present early in life compared with pure ocd and the psychopathology of ocd involves more of existential , philosophical , hoarding , sexual obsessions and odd superstitions.[1012 ] youth with comorbid ocd and bipolar disorder ( bpd ) had greater comorbidity , poor functioning and more hospitalization , probably because of the element of bipolarity in them . a study done by zutshi et al . on 28 ocd patients with bipolarity showed a less severe ocd , episodic course , family loading and a greater comorbidity of depression , social phobia and generalized anxiety disorder .
obsessions and compulsions worsened with the severity of depression and completely disappeared during mania in a patient with ocd comorbid with bipolarity as reported by gordon and rasmussen .
a lifetime comorbidity of bipolarity has to be kept in mind if a patient with ocd presents with an episodic course , as opined by perugi et al .
his study on 135 patients with episodic ocd showed , in 27% of them , a significantly higher rate of family history of mood disorder and lifetime comorbidity with bp ii disorder .
kruger et al . found comorbid ocd to be more common in bp ii in comparison with bp i. but , koyuncu et al . found no statistically significant difference between the frequency of comorbid ocd in bp i and bp ii .
bpd also responds poorly to mood stabilizing antipsychotics like olanzapine in the presence of ocd .
reported that 30% of patients on selective serotonin reuptake inhibitor ( ssris ) may develop manic or hypomanic symptoms . in the above study , six of 20 patients on ssris at doses as low as 10 mg of fluoxetine developed manic or hypomanic symptoms
the authors were unable to explain as to whether mania / hypomania appears in ocd children without comorbid mood disorder .
they were also uncertain whether patients on high - dose ssris with ocd are more likely to have a switch than those with a mood disorder .
this is a complex comorbidity to treat as ocd requires high doses of ssris which precipitates mania . a sound knowledge of etiology and the pathology operating gives an insight into the comorbidity .
it is yet to be determined as to which is prudent : treating with only one drug or resorting to complex combination therapy .
though there have been studies on ocd in psychosis , there is a need to thoroughly evaluate for mania / hypomania in ocd .
this comorbid disorder requires a systematic exploration as there is not much epidemiological data on its incidence in india .
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### Summary:
: obsessive compulsive features occurring in mania have been well documented .
though there have been some studies on obsessive compulsive disorder ( ocd ) comorbid with mania in the western countries , there are very few case reports and studies in india .
our aim is to report one such case here , who presented with oc features which are not typical of the symptom cluster of the ocd commonly seen with mania in earlier reports .
also , the comorbidities in ocd should be recognized as this can have important diagnostic and therapeutic implications .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the exact etiology of benign prostatic hyperplasia ( bph ) is still not fully elucidated .
it is known , however , that complex epithelial - stromal interactions in the setting of a fitting hormonal milieu are responsible for bph development .
estrogens have long been suspected to play an important role in prostate growth , but their role is incompletely understood .
estrogenic action is mediated by specific intracellular estrogen receptors ( ers ) and their activation , which can occur independent of the serum estrogen level .
two subtypes of er have been identified , er alpha ( er ) and er beta ( er ) , in human prostate .
er is expressed primarily in prostatic stromal cells and er expression is chiefly localized to prostatic epithelium . however , the localization of these receptors is not exclusive and remains contentious .
many studies have demonstrated increased er expression and differential expression of receptor subtypes in bph specimens as well as cell cultures .
recent work with knockout mice models has been invaluable in understanding the specific roles of er and er in prostate growth and differentiation .
the current evidence suggests a proliferative role for er and an antiproliferative role for er. royuela et al . investigated the differential expression of er and er by using immunohistochemistry ( ihc ) methods and assessed er levels in normal , hyperplastic , and carcinomatous prostatic tissue .
however , quantitative data are still sparse and lacking regarding the expression of ers , and the relationship between receptor levels and measures of bph and lower urinary tract symptoms ( luts ) have not been explored previously .
we hypothesized that er levels in prostatic tissue should correlate with the various measures of bph and luts .
the aim of the present study was to semiquantitatively assess the differential expression of er subtypes in prostatic tissue in men with bph by use of ihc methods and to explore their relationship with various clinical measures of bph .
this case - control study was conducted in our department after receiving clearance from sms medical college , jaipur ethics committee ( irb no .
a total of 45 patients with a diagnosis of clinical bph with bothersome luts ( moderate to severe international prostate symptom score [ ipss ] ) undergoing transurethral resection of the prostate ( turp ) were included in the study ( group a ) .
exclusion criteria were endocrine disorders , recent or long - term use of any hormonal agents causing androgen manipulation ( e.g. , dutasteride ) , significant comorbidities like stroke or neurogenic bladder affecting luts , previous lower urinary tract surgery , active urinary tract infections , current indwelling catheter or history of urinary retention within 1 month of inclusion , diagnosis of prostate or bladder cancer , vesical calculus , urethral stricture , and prostate - specific antigen ( psa)>4 ng / dl .
control samples were histologically normal prostatic tissue obtained from 22 patients with bladder cancer without evidence of bladder outlet obstruction who underwent surveillance cystoscopy ( group b ) .
preoperatively , the patients ' medical history and physical examination results , including digital rectal examination and urinalysis , were obtained .
also , bph - related parameters such as serum psa , prostate volume , maximal flow rate ( qmax ) , ipss , and postvoid residual urine volume ( pvr ) were recorded .
serum hormonal assays of total testosterone and estradiol were measured in an early morning blood sample .
er distribution and quantification and ki-67 were assessed by use of ihc techniques as described below .
all formalin - fixed prostatic tissues were embedded in paraffin and 5 samples were randomly selected from each prostate .
sections were further processed by heating at 6070 in an oven for 30 to 40 minutes and dewaxing with xylene and alcohol for 2 cycles of 10-minute duration each .
the slides were then deionized in distilled water for 5 minutes and washed in peroxidase solution for 10 to 15 minutes , after which tris buffer was applied for 5 minutes .
microwave antigen retrieval was carried out by placing the slides in citrate buffer ( retrieval box ; citrate buffer antigen retrieval protocol ) in a decloaking chamber ( biocare medical inc . , concord , ca , usa ) at 125. after adequate decloaking and cooling , slides were rinsed with tris buffer and sections were marked .
a total of 3 to 4 drops of background sniper ( biocare medical inc . ) was applied for 15 minutes .
after application of polymer for 30 minutes , slides were again rinsed with tris buffer .
diaminobenzidine was applied for 5 minutes and the samples hydrated . after applying hematoxylin for 2 minutes ,
slides were rinsed and dehydrated with alcohol and xylene for 2 cycles of 10-minute duration and then mounted .
hypothalamus tissue sections for er and breast cancer tissue for er were taken as positive controls ( fig .
the following antibodies were used : er mouse monoclonal antibody in 1:200 dilution ( acris antibodies inc . , san diego , ca , usa ) , er monoclonal antibody in 1:50 dilution ( acris antibodies inc . ) , and pretitrated mouse monoclonal anti - ki-67 antibodies ( clone mb67 , diagnostic biosystems , pleasanton , ca , usa ) .
quantitative immunolabeling of er subtypes was scored by use of a semiquantitative scale incorporating both the proportion of positively stained target cells ( scored on scale of 05 ) and the staining intensity ( scored on scale of 03 ) , similar to the allred score used in breast cancer .
the proportion score ( ps ) was given as 0 ( none ) , 1 ( 1% ) , 2 ( 1%10% ) , 3 ( 10%33% ) , 4 ( 33%66% ) , and 5 ( > 66% ) .
the intensity score ( is ) was given as 0 ( no staining ) , 1 ( weak staining ) , 2 ( intermediate ) , and 3 ( strong ) .
a sum of ps and is score of 2 or less was considered negative and all other scores were considered positive . under 40 magnification , the area with highest intensity was identified .
under 400 , 100 cells were counted per field and the percentage of er was calculated as the number of positively stained cells per 100 cells counted and an is also calculated .
independent scores for er in epithelium ( eer ) and stroma ( ser ) and er in epithelium ( eer ) and stroma ( ser ) were measured .
similarly , for the ki-67 assay , after tissue processing , immunoquantification was performed by calculating the percentage of positively stained cells .
then at 400 magnification , 1,000 cells were counted , 500 cells from stroma and 500 cells from epithelium , and the ki-67 index was calculated by counting 500 to 1,000 random nuclei under the light microscope at 400 magnification .
continuous data were analyzed by using 2-tailed t - test , and pearson correlation coefficient was used to correlate the various measures of bph and luts with quantitative measures of er and er in the prostatic stroma and epithelium . a p - value of < 0.05 was considered statistically significant .
all formalin - fixed prostatic tissues were embedded in paraffin and 5 samples were randomly selected from each prostate .
sections were further processed by heating at 6070 in an oven for 30 to 40 minutes and dewaxing with xylene and alcohol for 2 cycles of 10-minute duration each .
the slides were then deionized in distilled water for 5 minutes and washed in peroxidase solution for 10 to 15 minutes , after which tris buffer was applied for 5 minutes .
microwave antigen retrieval was carried out by placing the slides in citrate buffer ( retrieval box ; citrate buffer antigen retrieval protocol ) in a decloaking chamber ( biocare medical inc . , concord , ca , usa ) at 125. after adequate decloaking and cooling
a total of 3 to 4 drops of background sniper ( biocare medical inc . ) was applied for 15 minutes .
after application of polymer for 30 minutes , slides were again rinsed with tris buffer .
diaminobenzidine was applied for 5 minutes and the samples hydrated . after applying hematoxylin for 2 minutes ,
slides were rinsed and dehydrated with alcohol and xylene for 2 cycles of 10-minute duration and then mounted .
hypothalamus tissue sections for er and breast cancer tissue for er were taken as positive controls ( fig .
the following antibodies were used : er mouse monoclonal antibody in 1:200 dilution ( acris antibodies inc .
, san diego , ca , usa ) , er monoclonal antibody in 1:50 dilution ( acris antibodies inc . ) , and pretitrated mouse monoclonal anti - ki-67 antibodies ( clone mb67 , diagnostic biosystems , pleasanton , ca , usa ) .
quantitative immunolabeling of er subtypes was scored by use of a semiquantitative scale incorporating both the proportion of positively stained target cells ( scored on scale of 05 ) and the staining intensity ( scored on scale of 03 ) , similar to the allred score used in breast cancer .
the proportion score ( ps ) was given as 0 ( none ) , 1 ( 1% ) , 2 ( 1%10% ) , 3 ( 10%33% ) , 4 ( 33%66% ) , and 5 ( > 66% ) .
the intensity score ( is ) was given as 0 ( no staining ) , 1 ( weak staining ) , 2 ( intermediate ) , and 3 ( strong ) .
a sum of ps and is score of 2 or less was considered negative and all other scores were considered positive . under 40 magnification , the area with highest intensity was identified . under 400 , 100 cells were counted per field and the percentage of er was calculated as the number of positively stained cells per 100 cells counted and an is also calculated .
the total score from 5 sections was summed and a mean score was calculated . independent scores for er in epithelium ( eer ) and stroma ( ser ) and er in epithelium ( eer ) and stroma ( ser ) were measured .
similarly , for the ki-67 assay , after tissue processing , immunoquantification was performed by calculating the percentage of positively stained cells .
then at 400 magnification , 1,000 cells were counted , 500 cells from stroma and 500 cells from epithelium , and the ki-67 index was calculated by counting 500 to 1,000 random nuclei under the light microscope at 400 magnification .
continuous data were analyzed by using 2-tailed t - test , and pearson correlation coefficient was used to correlate the various measures of bph and luts with quantitative measures of er and er in the prostatic stroma and epithelium . a p - value of < 0.05 was considered statistically significant .
the mean ( range ) age of the patients was 66.1 years ( 4580 years ) and 64.2 years ( 5575 years ) in groups a and b , respectively .
the mean serum total testosterone was 351 and 395 ng / dl in groups a and b , respectively , and serum estradiol was 28 and 22.4 pg / dl in groups a and b , respectively
. there was a significant difference in mean prostate size , pvr , ipss , and qmax between groups a and b ( p<0.01 ) .
there was no statistically significant difference in mean psa between group a ( 2.05 ng / dl ) and b ( 1.8 ng / dl ) ( p=0.10 ) .
ihc evaluation of prostatic specimens by use of monoclonal antibody to er subtypes demonstrated variable staining patterns in both stroma and epithelium as well as between bph patients and controls ( fig .
a , positive immunostaining ( defined as ihc score>2 ) for er was found in stromal nuclei from 30 prostates ( 66.7% ) and in epithelial nuclei from 27 prostates ( 60% ) , whereas in group b , only 4 patients each ( 18.2% ) showed positive immunostaining in stroma and epithelium .
also , positive immunoreactivity for er was observed in epithelial nuclei from 31 prostates ( 80% ) and stromal nuclei from 5 prostates ( 11% ) in bph patients . in controls ,
er expression was observed in epithelial nuclei of 12 patients ( 54.5% ) and stromal cells in only 2 patients ( 9% ) .
thus , the expression of er was heterogeneous in both bph patients and normal controls .
overall , we found that immunostaining was stronger for er in stroma and er in the epithelium and the immunostaining was confined mostly to the basal epithelial cells for both er subtypes .
additionally , we also observed that positively stained cells in both stroma and epithelium tended to cluster together and lie in close proximity ( fig .
semiquantitative ihc scoring was carried out as described previously for both er subtypes in both stroma and epithelium ( fig .
3 ) . there was a significant difference in ihc score for er between bph patients and controls in both stroma ( p0.001 ) and epithelium ( p=0.008 ) , respectively .
the er ihc score also was significantly higher in the epithelium of bph patients ( p=0.01 ) .
however , we could not find any significant difference in stromal er ihc score between the 2 groups ( p=0.28 ) .
all bph patients showed positive immunostaining for ki-67 , whereas only 14 patients ( 63.6% ) in the control group were positive .
the ki-67 index was significantly higher in bph patients than in controls ( 0.460.42 vs. 1.231.0 , p=0.02 ) . among the various clinical parameters , prostate size correlated significantly with psa ( p=0.001 ) and ipss ( p=0.003 ) .
likewise , there was significant correlation between ipss and qmax ( p=0.01 ) ( table 2 ) .
there was a significant positive correlation between ser and age ( r=0.37 , p=0.013 ) , psa ( r=0.320 , p=0.03 ) , prostate size ( r=0.51 , p=0.001 ) , and ipss ( r=0.32 , p=0.03 ) .
eer positively correlated with serum estradiol ( r=0.53 , p=0.001 ) , serum estradiol / total testosterone ratio ( r=0.44 , p=0.003 ) , prostate size ( r=0.38 , p=0.01 ) , and ipss ( r=0.29 , p=0.04 ) .
there was a positive correlation between eer and serum testosterone but it was not statistically significant ( r=0.262 , p=0.08 ) .
no significant correlation was seen with ser. both eer and eer showed good positive correlation ( r=0.25 ) ; however , again this was statistically insignificant ( p=0.09 ) ( fig .
these results clearly indicated that ers ( especially ser ) are associated with various clinical measures of luts ( like ipss ) .
semiquantitative ihc scoring was carried out as described previously for both er subtypes in both stroma and epithelium ( fig .
3 ) . there was a significant difference in ihc score for er between bph patients and controls in both stroma ( p0.001 ) and epithelium ( p=0.008 ) , respectively .
the er ihc score also was significantly higher in the epithelium of bph patients ( p=0.01 ) .
however , we could not find any significant difference in stromal er ihc score between the 2 groups ( p=0.28 ) .
all bph patients showed positive immunostaining for ki-67 , whereas only 14 patients ( 63.6% ) in the control group were positive .
the ki-67 index was significantly higher in bph patients than in controls ( 0.460.42 vs. 1.231.0 , p=0.02 ) .
among the various clinical parameters , prostate size correlated significantly with psa ( p=0.001 ) and ipss ( p=0.003 ) .
likewise , there was significant correlation between ipss and qmax ( p=0.01 ) ( table 2 ) .
there was a significant positive correlation between ser and age ( r=0.37 , p=0.013 ) , psa ( r=0.320 , p=0.03 ) , prostate size ( r=0.51 , p=0.001 ) , and ipss ( r=0.32 , p=0.03 ) .
eer positively correlated with serum estradiol ( r=0.53 , p=0.001 ) , serum estradiol / total testosterone ratio ( r=0.44 , p=0.003 ) , prostate size ( r=0.38 , p=0.01 ) , and ipss ( r=0.29 , p=0.04 ) .
there was a positive correlation between eer and serum testosterone but it was not statistically significant ( r=0.262 , p=0.08 ) .
no significant correlation was seen with ser. both eer and eer showed good positive correlation ( r=0.25 ) ; however , again this was statistically insignificant ( p=0.09 ) ( fig .
these results clearly indicated that ers ( especially ser ) are associated with various clinical measures of luts ( like ipss ) .
localization of ers in the prostate has been a matter of intense debate as conflicting results have been reported by various researchers .
most animal studies have reported that er is primarily localized to the stromal compartment and that er is expressed mainly in the prostatic epithelium .
probable explanations for the variations in results include procedural differences such as the type of tissue studied or the antibodies used .
few studies to date have assessed er distribution in bph patients and normal prostate . to understand the role of ers in prostate biology , it is imperative to study their distribution in human prostate .
we are probably the first to use an ihc - based semi - quantitative assay to objectively assess the er content in the prostate .
we found that er was distributed in both stromal and epithelial compartments in a significant number of bph patients ( 67% and 60% in stroma and epithelium , respectively ) .
in contrast to older studies and similar to a few newer studies , we found er expression in some basal epithelial as well as stromal cells .
er positivity was seen in 78% of bph patients in epithelium but was minimally expressed ( 11% ) in the stromal compartment .
royuela et al . found that 30% of patients with bph had er positivity in epithelium .
compared with the expression in normal controls , expression of both er subtypes was significantly higher in bph patients .
this differential expression of ers in both stromal and epithelial compartments may be related to the different role of ers in prostate growth .
when we compared er expression in bph patients and controls , both receptor subtypes were found to be significantly overexpressed in bph patients with the exception of stromal er. the ihc score for er was significantly higher for bph patients in both stroma and epithelium .
thus , up - regulation of these receptors provides indirect objective evidence for their possible role in prostatic hyperplasia .
many studies support the concept that ser is responsible for estrogen - mediated actions in target epithelial cells . increased accumulation of estradiol in stromal cells obtained from bph specimens also suggests a possible role of er in bph .
studies in estrogen receptor knockout ( erko ) mice have demonstrated that ser is responsible for estradiol - induced squamous metaplasia in adult prostates .
similarly , studies using erko and erko mice have shown that stromal hyperplasia , epithelial pin lesions , and inflammatory cell infiltration are mediated through stromal er . in our study , in addition to their up - regulation , we also found that ser showed significant correlations with various measures of bph like psa , prostate size , and ipss .
the close association of prostate size and psa with ser thus provides a hint to its role in mediating stromo - glandular proliferation , which is a hallmark of bph .
we could not explain the positive relationship between ser and psa , as psa is an androgen - driven gene product .
probably , certain unknown er - mediated mechanisms do exist that are responsible for up - regulation of ar - controlled genes and products .
although there was no correlation between ser and the serum estradiol level in our study , ers can act peripherally independent of serum estradiol levels . recently , shapiro et al . also reported localization of er in both stroma and epithelium in the fetal prostate . further complicating the role of ers in bph , risbridger et al . using
tissue recombination demonstrated that both epithelial and stromal er are required to induce a complete estrogenic response in the prostatic epithelium .
more recently , nicholson et al . using erko mice demonstrated that er was the key mediator of bladder complications of bph and that these complications can be prevented by using selective estrogen receptor modulators .
we also found very strong associations between eer levels and various measures of bph , such as prostate size and ipss .
notably , significant correlations between serum estradiol and the serum estradiol / total testosterone ratio and eer levels were also found in our study .
we commonly observed a close spatial proximity between er - positive stromal and epithelial cells , which is an ideal setting for a paracrine mode of communication between both types of cells .
thus , our results do provide some indirect evidence for the important role of er in the pathogenesis of bph and the existence of a complex interplay between epithelial and stromal components .
therefore , we believe that estrogenic action may be primarily mediated by ser in the pathogenesis of human bph . our findings showed that er immunoreactivity was highest in epithelium and minimally observed in the stroma .
although we found a significant correlation between eer and serum estradiol , meaningful associations with other measures of bph could not be derived .
although the available literature suggests er to be the predominant receptor type in prostate , their role remains ill - defined .
however , studies using erko mice have provided indirect evidence for the role of ers in prostate growth .
. reported that er probably has a role in normal growth and differentiation of the prostate because no prostate phenotype was observed in erko mice .
similarly , imamov et al . showed that erko mice had less differentiated prostate . in contrast krege et al . demonstrated that erko mice do develop prostatic hyperplasia with aging , suggesting a negative role for er in the regulation of glandular epithelial cell proliferation
the role of er in stromal proliferation has shown contrasting results with erko mice and remains inconclusive . in our study
, the findings like significant er immunoreactivity in epithelium and its relationship with serum estradiol do suggest that certain unknown mechanisms might be involved in the pathogenesis of bph , which needs further analysis .
thus , the role of er still merits further analysis and scrutiny for a better understanding of the pathogenesis of bph .
the presence of multiple isoforms of er further complicates the investigation of this receptor as these er isoform variants can act as constitutive activators , enhancers , or negative regulators of estrogenic actions .
in addition , ihc assays may vary in their sensitivity , technique of antigen retrieval , and ability to detect unknown isoforms .
our study findings demonstrate the differential expression of er and er in epithelial and stromal tissues in prostate .
importantly , up - regulation of er in bph patients as well as significant correlation between various measures of bph and er levels in the prostate lends support to the hypothesis that ser may be the key mediator of estrogenmediated prostatic hyperplasia .
also , eer and ser might be complementary in their actions , probably through paracrine effects of estrogens on the prostate epithelium .
the role of er in bph remains controversial and we could not conclusively arrive at any opinion . however , our findings do provide some evidence supporting the notion that estrogen may play a crucial role in the pathogenesis of bph . also , this difference in compartmental expression , as well as differential binding of the two ers for various ligands , enhancers , and coactivators , might explain the differential action of estrogens on the prostate gland and can be targeted for treatment of various prostate diseases in the near future .
first , this was a cross - sectional study and thus the dynamic correlation between the measures of luts and estrogen receptors can not be derived from our study .
second , our study was based on ihc only and thus far - reaching conclusions should not be derived solely based on these results .
er and er are expressed differentially in the stromal and epithelial compartments of the prostate .
er in stroma appears to be the key mediator of estrogenic action in the prostate .
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### Summary:
: purposeestrogens act through interaction with 2 receptor subtypes , er alpha ( er ) and er beta ( er ) , in human prostate .
the aim of the present study was to semiquantitatively assess the differential expression of er subtypes in human benign prostatic hyperplasia ( bph ) by use of immunocytochemistry ( ihc ) methods and to explore their relationship with various measures of bph.materials and methodsa total of 45 patients with bph undergoing transurethral resection of the prostate and 22 patients with bladder cancer with normal prostate undergoing surveillance cystoscopy were studied as cases and controls , respectively .
quantitative immunolabeling of er subtypes was scored by use of a semiquantitative scale .
also , correlations were assessed between er levels in prostate and various measures of bph.resultsoverall , we found strong immunostaining for er in stroma and for er in epithelium , respectively .
the ihc score for er differed significantly between bph patients and controls in both stroma ( p0.001 ) and epithelium ( p=0.008 ) , respectively .
the er ihc score was also significantly higher in the epithelium of bph patients ( p=0.01 ) .
also , we found a significant correlation between prostatic er levels and various clinical measures of bph.conclusionsers may play an important role in the pathogenesis of bph .
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: pancreatogenic diabetes , classified as type 3c by the american diabetes association,1 is associated with diseases of the exocrine pancreas including pancreatitis , benign and malignant neoplasm , cystic fibrosis , hemochromatosis , fibrocalculous pancreatopathy , and trauma and pancreatectomy . among the 89 % of the general diabetes population with type 3c diabetes in western countries ,
23 % are those who underwent pancreatectomy.2,3 pancreatectomized patients are at high risk for type 3c diabetes , as well as type 2 , because surgery inevitably results in a deficit in the exocrine and endocrine pancreas , and also can promote the progression of underlying disease . due to improved diagnostic modalities and a more refined understanding of pancreatic neoplasm pathogenesis , pancreatectomies for benign or low - grade malignant tumors are more frequent , and the life expectancy of patients undergoing pancreatectomy has increased in recent years . as the frequency of pancreatectomy and length of life expectancy increase , so does the importance of the risk of pancreatogenic diabetes associated with pancreatic surgery .
distal pancreatectomy ( dp ) is the standard procedure used for removal of lesions in the body and tail of the pancreas .
long - term disturbances in glucose metabolism are a major concern after dp because previous studies have found that postoperative diabetes develops in from 4.8 to 38 % of patients after dp.48 physiological factors reported to correlate with postoperative pancreatic endocrine function include preoperative fasting plasma glucose ( fpg ) , body mass index ( bmi ) , and postoperative complications.911 limitations in these studies , such as unspecified preoperative diabetic status of the patients and inconsistent standards used for the diagnosis of postoperative diabetes , make it difficult to reliably identify risk factors for postoperative diabetes .
although the mass of pancreatic beta cells has been identified as an important determinant of plasma glucose levels in rodents , dogs , monkeys , and humans,1215 to our knowledge , very few studies have directly investigated the volume reduction of human pancreatic parenchyma as a risk factor for diabetes , and no previous study systematically quantified resection volumes in a population of patients . to study potential risk factors for new - onset diabetes in preoperatively non - diabetic patients , we sought to reliably quantify the volume reduction of human pancreatic parenchyma and to determine its longitudinal metabolic consequences following dp using multi - detector row computed tomography ( mdct ) imaging volumetry .
a series of 98 consecutive patients who underwent dp at our institution between january 2005 and december 2011 was originally chosen from our prospectively maintained clinical database for this retrospective study .
data from 37 ( 38 % ) of these candidates were excluded due to preoperative diabetes , as defined either by the who criteria of fpg 126 mg / dl detected on two or more separate days , or this abnormal fpg level detected once and plasma glucose 200 mg / dl measured 2 h after a 75-g glucose drink , or based on their treatment with oral anti - diabetic agents or insulin .
the final study population consisted of 61 non - diabetic patients who had undergone dp .
the preoperative data used for this study had been recorded within 14 days prior to surgery .
nutritional status and pancreatic endocrine functions were assessed based on measurements of body weight , serum albumin , fpg , and serum hemoglobin a1c ( hba1c ) .
hba1c values represent the national glycohemoglobin standardization program ( ngsp ) equivalent values ( in percent ) and in all cases were converted from previous japan diabetes society standard substance and measurement methods ( jds hba1c , in percent ) using the following formula : ngsp hba1c ( % ) = jds hba1c ( % ) + 0.4 % . the percent resected volume ( prv ) of pancreatic parenchyma , excluding tumor volume , was determined from abdominal mdct measurements .
patient data were collected until the time of diagnosis of new - onset diabetes or tumor recurrence .
all 61 patients were followed up for at least 3 months . for evaluating postoperative course , we defined and graded postoperative pancreatic fistula ( popf ) using the classification methods of the international study group of pancreatic fistula,16 with popf grade b or c defined as clinically important pancreatic fistula .
postoperative complications were designated as level i to v based on the clavien classification.17 prvs were determined retrospectively , using preoperative mdct images in all patients .
continuous 0.8-mm 64-row mdct images were acquired following administration of intravenous contrast material prior to surgery .
mdct data were transferred to a computer workstation ( aquarius ; elk , osaka , japan ) for measurement of pancreas volume . to delineate the actual pancreatic resection lines
, we compared preoperative ct with postoperative ct . excluding tumors , cystic lesions , any dilation in the pancreatic duct and bile duct , and vessels
, we outlined the borders of the pancreatic parenchyma and the resection lines on every ct slice , and we then computed the resected and remnant areas of pancreatic parenchyma for each slice ( fig . 1 ) .
the volume ( in milliliters ) of the pancreatic parenchyma per slice was calculated as the product of the pancreas area ( in square millimeters ) times the slice thickness ( in millimeters ) .
resected and remnant volumes of the pancreatic parenchyma were computed as the sum of the slice volumes .
prv was determined using the following formula : \documentclass[12pt]{minimal }
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\begin{document}$$ { \mathrm{prv}}\left ( \% \right ) = \left [ { { \mathrm{resected}}\,{\mathrm{volume}}\,{\mathrm{of}}\,{\mathrm{normal}}\,{\mathrm{pancreas } } \div { \mathrm{total}}\,{\mathrm{volume}}\,{\mathrm{of}}\,{\mathrm{normal}}\,{\mathrm{pancreas } } } \right ] \times 100 $ $ \end{document}. prv was calculated in 52 cases . in the remaining nine cases ,
this value could not be measured accurately because of pancreatic edema or tumors with unclear borders that had invaded peri - pancreatic organs.fig .
outlined areas are the remnant parenchyma ( black outline ) , resected parenchyma ( light gray outline ) , and tumor ( dark grey outline ) , excluding vessels .
the dashed line is the pancreatic resection line . to determine percent resected volume , the volume ( in milliliters ) of the pancreatic parenchyma per slice
was calculated as the product of the pancreas area ( in square millimeters ) times the slice thickness ( in millimeters ) mdct pancreas volumetry .
outlined areas are the remnant parenchyma ( black outline ) , resected parenchyma ( light gray outline ) , and tumor ( dark grey outline ) , excluding vessels .
the dashed line is the pancreatic resection line . to determine percent resected volume , the volume ( in milliliters ) of the pancreatic parenchyma per slice
was calculated as the product of the pancreas area ( in square millimeters ) times the slice thickness ( in millimeters ) postoperative new - onset diabetes was diagnosed retrospectively based on the who criteria of fpg 126 mg / dl detected on two or more separate days , or this abnormal fpg level detected once and plasma glucose 200 mg / dl measured in 2 h after a 75-g glucose drink .
the onset day of diabetes was defined as the latter day on which abnormal blood test results were detected . in this study population
, no patient was administered anti - diabetic therapy with oral agents or insulin before the development of diabetes , as defined by the criteria of this study .
patient characteristics are reported as means standard deviation ( sd ) , and results are presented as means standard error ( se ) or , where indicated , medians ( range ) .
categorical variables are expressed numerically as percentages . for analyses of repeated measurements of body weight , serum albumin , fpg , and serum hba1c
prior to and 3 , 6 , and 12 months after surgery , we used an analysis of variance ( anova ) and the mauchly test , which evaluates the sphericity assumption .
we used the student s t test or mann whitney test for continuous variables and fisher s exact test for categorical variables . a multiple logistic regression analysis yielding odds ratios and 95 % confidence intervals ( cis )
was used to identify risk factors for postoperative new - onset diabetes ( with p < 0.05 ) .
the optimal hba1c and prv cutoffs for predicting the occurrence of postoperative new - onset diabetes were estimated using receiver operating characteristic ( roc ) curves .
all analyses were performed using jmp 9.0 for macintosh ( sas institute inc , cary , nc , usa ) .
a series of 98 consecutive patients who underwent dp at our institution between january 2005 and december 2011 was originally chosen from our prospectively maintained clinical database for this retrospective study .
data from 37 ( 38 % ) of these candidates were excluded due to preoperative diabetes , as defined either by the who criteria of fpg 126 mg / dl detected on two or more separate days , or this abnormal fpg level detected once and plasma glucose 200 mg / dl measured 2 h after a 75-g glucose drink , or based on their treatment with oral anti - diabetic agents or insulin .
the final study population consisted of 61 non - diabetic patients who had undergone dp .
the preoperative data used for this study had been recorded within 14 days prior to surgery .
nutritional status and pancreatic endocrine functions were assessed based on measurements of body weight , serum albumin , fpg , and serum hemoglobin a1c ( hba1c ) .
hba1c values represent the national glycohemoglobin standardization program ( ngsp ) equivalent values ( in percent ) and in all cases were converted from previous japan diabetes society standard substance and measurement methods ( jds hba1c , in percent ) using the following formula : ngsp hba1c ( % ) = jds hba1c ( % ) + 0.4 % . the percent resected volume ( prv ) of pancreatic parenchyma , excluding tumor volume , was determined from abdominal mdct measurements .
patient data were collected until the time of diagnosis of new - onset diabetes or tumor recurrence .
all 61 patients were followed up for at least 3 months . for evaluating postoperative course , we defined and graded postoperative pancreatic fistula ( popf ) using the classification methods of the international study group of pancreatic fistula,16 with popf grade b or c defined as clinically important pancreatic fistula .
continuous 0.8-mm 64-row mdct images were acquired following administration of intravenous contrast material prior to surgery .
mdct data were transferred to a computer workstation ( aquarius ; elk , osaka , japan ) for measurement of pancreas volume . to delineate the actual pancreatic resection lines
, we compared preoperative ct with postoperative ct . excluding tumors , cystic lesions , any dilation in the pancreatic duct and bile duct , and vessels
, we outlined the borders of the pancreatic parenchyma and the resection lines on every ct slice , and we then computed the resected and remnant areas of pancreatic parenchyma for each slice ( fig . 1 ) .
the volume ( in milliliters ) of the pancreatic parenchyma per slice was calculated as the product of the pancreas area ( in square millimeters ) times the slice thickness ( in millimeters ) .
resected and remnant volumes of the pancreatic parenchyma were computed as the sum of the slice volumes .
prv was determined using the following formula : \documentclass[12pt]{minimal }
\usepackage{amsmath }
\usepackage{wasysym }
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\usepackage{amssymb }
\usepackage{amsbsy }
\usepackage{mathrsfs }
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\setlength{\oddsidemargin}{-69pt }
\begin{document}$$ { \mathrm{prv}}\left ( \% \right ) = \left [ { { \mathrm{resected}}\,{\mathrm{volume}}\,{\mathrm{of}}\,{\mathrm{normal}}\,{\mathrm{pancreas } } \div { \mathrm{total}}\,{\mathrm{volume}}\,{\mathrm{of}}\,{\mathrm{normal}}\,{\mathrm{pancreas } } } \right ] \times 100 $ $ \end{document}. prv was calculated in 52 cases . in the remaining nine cases ,
this value could not be measured accurately because of pancreatic edema or tumors with unclear borders that had invaded peri - pancreatic organs.fig .
outlined areas are the remnant parenchyma ( black outline ) , resected parenchyma ( light gray outline ) , and tumor ( dark grey outline ) , excluding vessels .
the dashed line is the pancreatic resection line . to determine percent resected volume , the volume ( in milliliters ) of the pancreatic parenchyma per slice
was calculated as the product of the pancreas area ( in square millimeters ) times the slice thickness ( in millimeters ) mdct pancreas volumetry .
outlined areas are the remnant parenchyma ( black outline ) , resected parenchyma ( light gray outline ) , and tumor ( dark grey outline ) , excluding vessels .
the dashed line is the pancreatic resection line . to determine percent resected volume , the volume ( in milliliters ) of the pancreatic parenchyma per slice
was calculated as the product of the pancreas area ( in square millimeters ) times the slice thickness ( in millimeters )
postoperative new - onset diabetes was diagnosed retrospectively based on the who criteria of fpg 126 mg / dl detected on two or more separate days , or this abnormal fpg level detected once and plasma glucose 200 mg / dl measured in 2 h after a 75-g glucose drink .
the onset day of diabetes was defined as the latter day on which abnormal blood test results were detected . in this study population
, no patient was administered anti - diabetic therapy with oral agents or insulin before the development of diabetes , as defined by the criteria of this study .
patient characteristics are reported as means standard deviation ( sd ) , and results are presented as means standard error ( se ) or , where indicated , medians ( range ) .
categorical variables are expressed numerically as percentages . for analyses of repeated measurements of body weight , serum albumin , fpg , and serum hba1c
prior to and 3 , 6 , and 12 months after surgery , we used an analysis of variance ( anova ) and the mauchly test , which evaluates the sphericity assumption .
we used the student s t test or mann whitney test for continuous variables and fisher s exact test for categorical variables . a multiple logistic regression analysis yielding odds ratios and 95 % confidence intervals ( cis )
was used to identify risk factors for postoperative new - onset diabetes ( with p < 0.05 ) .
the optimal hba1c and prv cutoffs for predicting the occurrence of postoperative new - onset diabetes were estimated using receiver operating characteristic ( roc ) curves .
all analyses were performed using jmp 9.0 for macintosh ( sas institute inc , cary , nc , usa ) .
while no patient met the who criteria for diabetes preoperatively , nine had impaired fasting glucose ( ifg ) , defined as fpg of 110125 mg / dl .
the indications for dp included pancreatic tumors in 55 of the 61 patients ( 90 % , 25 malignant and 30 benign tumors ) , alcohol - induced chronic pancreatitis in three patients , autoimmune pancreatitis mimicking pancreatic cancer in two patients , and a pseudocyst following acute pancreatitis in one patient .
three patients had a first - degree family history of type 2 diabetes.table 1clinical characteristics of 61 non - diabetic patients who underwent distal pancreatectomymale patients24 ( 39)age ( years)62 14bmi ( kg / m)21.2 3.8preoperative hba1c ( % ) 5.8 0.41preoperative ifg9 ( 16)preoperative albumin ( mg / dl)4.0 0.64preoperative total cholesterol ( mg / dl)182 45preoperative pancreatic alpha - amylase ( iu / l)59 ( 4264)operative time ( min)333 88intraoperative blood loss ( ml)427 ( 53524)malignancy25 ( 41)percent resected volume ( % ) 38 17popf grade b16 ( 26)postoperative complication clavien s grade ii22 ( 36)postoperative hospital stay ( days)18 ( 758)mortality ( % ) 0values are means sd , medians ( range ) , or n ( % ) hba1c hemoglobin a1c , ifg impaired fasting glucose , fpg fasting plasma glucose , popf postoperative pancreatic fistula clinical characteristics of 61 non - diabetic patients who underwent distal pancreatectomy values are means sd , medians ( range ) , or n ( % ) hba1c hemoglobin a1c , ifg impaired fasting glucose , fpg fasting plasma glucose , popf postoperative pancreatic fistula mdct imaging volumetric data showed a wide range of volumes of whole , remnant , and resected pancreatic parenchyma and of tumors in patients with or without new - onset diabetes ( table 2 ) . while the mean prv for all 61 cases was 38 % ( range 985 % ) , the mean prv for the new - onset diabetes group was 49 % , which was significantly higher than the prv of 32 % for the non - diabetic group.table 2ct volumetry in dp patientsall patientsnew - onset diabetes groupno new - onset diabetes groupp valuenumber of patients with prv data522032whole normal parenchyma ( ml)56.6 ( 16.0128.2)54.6 ( 27.089.4)56.6 ( 16.0128.2)0.58remnant normal parenchyma ( ml)36.5 ( 4.4116.4)25.1 ( 4.465.8)38.6 ( 6.6116.4)0.047resected normal parenchyma ( ml)18.7 ( 3.557.7)25.8 ( 9.957.7)16.5 ( 3.555.3)0.004tumor or cystic lesion ( ml)5.4 ( 0543.7)4.1 ( 038.7)7.4 ( 0.2543.7)0.11prv ( % ) 38 17 ( 985)49 15 ( 2085)32 15 ( 959 ) < 0.001values are medians ( range ) or means sd ( range ) .
whitney u test , except for use of student s t test for prvct computed tomography , dp distal pancreatectomy ct volumetry in dp patients values are medians ( range ) or means sd ( range ) .
whitney u test , except for use of student s t test for prv ct computed tomography , dp distal pancreatectomy we compared four physiological parameters in new - onset diabetic versus non - diabetic patients at four time points : before and 3 , 6 , and 12 months after surgery .
three months after surgery , there were significant increases in fpg and hba1c in both groups ( table 3 ) .
disturbances in glucose control occurred within the first 3 months after surgery , and did not significantly progress after that time in either group.table 3fpg and serum hba1c before and 3 , 6 , and 12 months after surgeryall patients ( n = 61)p valuenew - onset diabetes group ( n = 22)p valueno new - onset diabetes group ( n = 39)p valuefpg ( mg / dl ) before surgery96 1.9101 3.893 1.9 3 months after surgery109 2.8<0.001121 5.30.008102 2.60.006 6 months after surgery111 4.90.29133 11.60.1799 2.40.75 12 months after surgery114 5.80.19137 12.20.15100 3.00.55hba1c ( % ) before surgery5.8 0.056.1 0.065.6 0.06 3 months after surgery6.2 0.10<0.0016.7 0.190.0035.9 0.070.002 6 months after surgery6.3 0.240.737.0 0.510.815.9 0.071.00 12 months after surgery6.4 0.180.137.1 0.360.495.9 0.060.059values
data were analyzed using student s paired t test for each groupdifferences compared to values before surgerydifferences compared to values at 3 months after surgery fpg and serum hba1c before and 3 , 6 , and 12 months after surgery values are means se .
data were analyzed using student s paired t test for each group differences compared to values before surgery differences compared to values at 3 months after surgery during the post - dp follow - up period ( median 26 months , range 388 months ) , 22 patients ( 36 % ) developed new - onset diabetes ( median onset time 8 months , range 0.542 months ) . in most of the 39 patients without new - onset diabetes , fpg and hba1c increased significantly during the follow - up period ; however , values remained stable in eight of these 39 patients ( change in hba1c 0.1 % ) , and one patient displayed improvement in glycemic control , as exhibited by a 0.4 % decrease in hba1c . while we observed significant between - group differences in the changes in fpg ( fig .
0.001 ) over time , there were no significant differences in changes in body weight ( fig .
2c ) ( p = 0.36 ) or serum albumin ( fig .
because mauchly tests for the sphericity assumption were not significant for these factors ( p = 0.21 , 0.82 , 0.28 , and 0.30 , respectively ) , the reported p values are for univariate anova.fig .
2changes in parameters before and 3 , 6 , and 12 months after surgery : a fpg , b hba1c , c body weight , and d serum albumin . values from patients who developed new - onset diabetes ( solid lines ) were compared with non - diabetic patients ( dashed lines ) using anova , with evaluation of the sphericity assumption by the mauchly test .
postoperatively , there were significant between - group differences in changes in fpg ( p = 0.003 ) and hba1c levels ( p < 0.001 ) .
no significant between - group difference in body weight ( p = 0.36 ) or albumin ( p = 0.58 ) was observed changes in parameters before and 3 , 6 , and 12 months after surgery : a fpg , b hba1c , c body weight , and d serum albumin .
values from patients who developed new - onset diabetes ( solid lines ) were compared with non - diabetic patients ( dashed lines ) using anova , with evaluation of the sphericity assumption by the mauchly test .
postoperatively , there were significant between - group differences in changes in fpg ( p = 0.003 ) and hba1c levels ( p < 0.001 ) .
no significant between - group difference in body weight ( p = 0.36 ) or albumin ( p = 0.58 ) was observed univariate analyses identified three statistically significant risk factors for postoperative new - onset diabetes : preoperative hba1c 5.7 % , prv > 44 % , and age ( table 4 ) .
multivariate logistic regression analysis also identified hba1c 5.7 % [ odds ratio 15.6 ( 95 % ci 2.80147 ) ,
p = 0.001 ] and prv > 44 % [ odds ratio 11.3 ( 95% ci 2.1292.1 ) , p = 0.004 ] as independent risk factors for postoperative new - onset diabetes ( table 5 ) .
regarding family history , one of three patients with first - degree family history of type 2 diabetes , of whom prv was 85 % , developed new - onset diabetes at 2 months after surgery .
we assessed the sensitivity and specificity of the hba1c and prv parameters using the roc curves .
the areas under the roc curves were 0.831 for hba1c and 0.793 for prv . using these curves , hba1c of 5.7 % and prv of 44 % were determined to be the cutoffs for predicting the occurrence of postoperative diabetes .
the sensitivity , specificity , and positive and negative predictive values derived from these curves were 0.82 , 0.64 , 0.56 , and 0.86 for hba1c and 0.75 , 0.81 , 0.71 , and 0.84 for prv , respectively.table 4univariate analysis of risk factors for postoperative new - onset diabetesnew - onset diabetes group ( n = 22)no new - onset diabetes group ( n = 39)p valuemale patients9 ( 41)15 ( 38)1.00age ( years)67 3.059 2.20.025bmi ( kg / m)22
0.7820 0.590.075preoperative hba1c 5.7 % 18 ( 82)14 ( 36)0.001preoperative ifg6 ( 27)3 ( 8)0.059preoperative albumin ( mg / dl)3.9 0.134.0 0.100.59preoperative total cholesterol ( mg / dl)176 9.6186 7.30.42preoperative pancreatic alpha - amylase ( iu / l)58 ( 6243)59 ( 4264)0.98operative time ( min)312 19347 150.14intraoperative blood loss ( ml)372 ( 51125)527 ( 53524)0.17malignancy8 ( 36)17 ( 44)0.79prv > 44 % 15 ( 75)6 ( 19)<0.001popf grade b6 ( 27)10 ( 26)1.00postoperative complication clavien s grade ii7 ( 32)15 ( 38)0.78postoperative hospital stay ( days)16 ( 754)18 ( 758)0.60adjuvant chemotherapy7 ( 32)15 ( 38)0.78values are means se , medians ( range ) or n ( % ) hba1c hemoglobin a1c , fpg fasting plasma glucose , popf postoperative pancreatic fistulap values were obtained using fisher s exact testp values were obtained using student s t testp values were obtained using mann
whitney u testtable 5multivariate logistic regression analysis of risk factors for postoperative new - onset diabetesodds ratio95 % cip valueage1.030.961.110.42preoperative ifg1.520.1814.70.69preoperative hba1c 5.7 % 15.62.801470.001prv > 44 % 11.32.1292.10.004odds ratio by 1 year post - dp univariate analysis of risk factors for postoperative new - onset diabetes values are means se , medians ( range ) or n ( % ) hba1c hemoglobin a1c , fpg fasting plasma glucose , popf postoperative pancreatic fistula p values were obtained using fisher s exact test p values were obtained using student s t test p values were obtained using mann
whitney u test multivariate logistic regression analysis of risk factors for postoperative new - onset diabetes odds ratio by 1 year post - dp
while no patient met the who criteria for diabetes preoperatively , nine had impaired fasting glucose ( ifg ) , defined as fpg of 110125 mg / dl .
the indications for dp included pancreatic tumors in 55 of the 61 patients ( 90 % , 25 malignant and 30 benign tumors ) , alcohol - induced chronic pancreatitis in three patients , autoimmune pancreatitis mimicking pancreatic cancer in two patients , and a pseudocyst following acute pancreatitis in one patient .
three patients had a first - degree family history of type 2 diabetes.table 1clinical characteristics of 61 non - diabetic patients who underwent distal pancreatectomymale patients24 ( 39)age ( years)62 14bmi ( kg / m)21.2 3.8preoperative hba1c ( % ) 5.8 0.41preoperative ifg9 ( 16)preoperative albumin ( mg / dl)4.0 0.64preoperative total cholesterol ( mg / dl)182 45preoperative pancreatic alpha - amylase ( iu / l)59 ( 4264)operative time ( min)333 88intraoperative blood loss ( ml)427 ( 53524)malignancy25 ( 41)percent resected volume ( % ) 38 17popf grade b16 ( 26)postoperative complication clavien s grade ii22 ( 36)postoperative hospital stay ( days)18 ( 758)mortality ( % ) 0values are means sd , medians ( range ) , or n ( % ) hba1c hemoglobin a1c , ifg impaired fasting glucose , fpg fasting plasma glucose , popf postoperative pancreatic fistula clinical characteristics of 61 non - diabetic patients who underwent distal pancreatectomy values are means sd , medians ( range ) , or n ( % ) hba1c hemoglobin a1c , ifg impaired fasting glucose , fpg fasting plasma glucose , popf postoperative pancreatic fistula
mdct imaging volumetric data showed a wide range of volumes of whole , remnant , and resected pancreatic parenchyma and of tumors in patients with or without new - onset diabetes ( table 2 ) .
while the mean prv for all 61 cases was 38 % ( range 985 % ) , the mean prv for the new - onset diabetes group was 49 % , which was significantly higher than the prv of 32 % for the non - diabetic group.table 2ct volumetry in dp patientsall patientsnew - onset diabetes groupno new - onset diabetes groupp valuenumber of patients with prv data522032whole normal parenchyma ( ml)56.6 ( 16.0128.2)54.6 ( 27.089.4)56.6 ( 16.0128.2)0.58remnant normal parenchyma ( ml)36.5 ( 4.4116.4)25.1 ( 4.465.8)38.6 ( 6.6116.4)0.047resected normal parenchyma ( ml)18.7 ( 3.557.7)25.8 ( 9.957.7)16.5 ( 3.555.3)0.004tumor or cystic lesion ( ml)5.4 ( 0543.7)4.1 ( 038.7)7.4 ( 0.2543.7)0.11prv ( % ) 38 17 ( 985)49 15 ( 2085)32 15 ( 959 ) < 0.001values are medians ( range ) or means sd ( range ) .
whitney u test , except for use of student s t test for prvct computed tomography , dp distal pancreatectomy ct volumetry in dp patients values are medians ( range ) or means sd ( range ) .
whitney u test , except for use of student s t test for prv ct computed tomography , dp distal pancreatectomy
we compared four physiological parameters in new - onset diabetic versus non - diabetic patients at four time points : before and 3 , 6 , and 12 months after surgery .
three months after surgery , there were significant increases in fpg and hba1c in both groups ( table 3 ) .
disturbances in glucose control occurred within the first 3 months after surgery , and did not significantly progress after that time in either group.table 3fpg and serum hba1c before and 3 , 6 , and 12 months after surgeryall patients ( n = 61)p valuenew - onset diabetes group ( n = 22)p valueno new - onset diabetes group ( n = 39)p valuefpg ( mg / dl ) before surgery96 1.9101 3.893 1.9 3 months after surgery109 2.8<0.001121 5.30.008102 2.60.006 6 months after surgery111 4.90.29133 11.60.1799 2.40.75 12 months after surgery114 5.80.19137 12.20.15100 3.00.55hba1c ( % ) before surgery5.8 0.056.1 0.065.6 0.06 3 months after surgery6.2 0.10<0.0016.7 0.190.0035.9 0.070.002 6 months after surgery6.3 0.240.737.0 0.510.815.9
0.071.00 12 months after surgery6.4 0.180.137.1 0.360.495.9 0.060.059values are means se .
data were analyzed using student s paired t test for each groupdifferences compared to values before surgerydifferences compared to values at 3 months after surgery fpg and serum hba1c before and 3 , 6 , and 12 months after surgery values are means se .
data were analyzed using student s paired t test for each group differences compared to values before surgery differences compared to values at 3 months after surgery during the post - dp follow - up period ( median 26 months , range 388 months ) , 22 patients ( 36 % ) developed new - onset diabetes ( median onset time 8 months , range 0.542 months ) . in most of the 39 patients without new - onset diabetes , fpg and hba1c increased significantly during the follow - up period ; however , values remained stable in eight of these 39 patients ( change in hba1c 0.1 % ) , and one patient displayed improvement in glycemic control , as exhibited by a 0.4 % decrease in hba1c . while we observed significant between - group differences in the changes in fpg ( fig .
0.001 ) over time , there were no significant differences in changes in body weight ( fig . 2c ) ( p = 0.36 ) or serum albumin ( fig .
because mauchly tests for the sphericity assumption were not significant for these factors ( p = 0.21 , 0.82 , 0.28 , and 0.30 , respectively ) , the reported p values are for univariate anova.fig .
2changes in parameters before and 3 , 6 , and 12 months after surgery : a fpg , b hba1c , c body weight , and d serum albumin .
values from patients who developed new - onset diabetes ( solid lines ) were compared with non - diabetic patients ( dashed lines ) using anova , with evaluation of the sphericity assumption by the mauchly test .
postoperatively , there were significant between - group differences in changes in fpg ( p = 0.003 ) and hba1c levels ( p < 0.001 ) .
no significant between - group difference in body weight ( p = 0.36 ) or albumin ( p = 0.58 ) was observed changes in parameters before and 3 , 6 , and 12 months after surgery : a fpg , b hba1c , c body weight , and d serum albumin .
values from patients who developed new - onset diabetes ( solid lines ) were compared with non - diabetic patients ( dashed lines ) using anova , with evaluation of the sphericity assumption by the mauchly test .
postoperatively , there were significant between - group differences in changes in fpg ( p = 0.003 ) and hba1c levels ( p
no significant between - group difference in body weight ( p = 0.36 ) or albumin ( p = 0.58 ) was observed
univariate analyses identified three statistically significant risk factors for postoperative new - onset diabetes : preoperative hba1c 5.7 % , prv > 44 % , and age ( table 4 ) .
multivariate logistic regression analysis also identified hba1c 5.7 % [ odds ratio 15.6 ( 95 % ci 2.80147 ) ,
p = 0.001 ] and prv > 44 % [ odds ratio 11.3 ( 95% ci 2.1292.1 ) , p = 0.004 ] as independent risk factors for postoperative new - onset diabetes ( table 5 ) .
regarding family history , one of three patients with first - degree family history of type 2 diabetes , of whom prv was 85 % , developed new - onset diabetes at 2 months after surgery .
we assessed the sensitivity and specificity of the hba1c and prv parameters using the roc curves .
the areas under the roc curves were 0.831 for hba1c and 0.793 for prv . using these curves , hba1c of 5.7 % and prv of 44 % were determined to be the cutoffs for predicting the occurrence of postoperative diabetes .
the sensitivity , specificity , and positive and negative predictive values derived from these curves were 0.82 , 0.64 , 0.56 , and 0.86 for hba1c and 0.75 , 0.81 , 0.71 , and 0.84 for prv , respectively.table 4univariate analysis of risk factors for postoperative new - onset diabetesnew - onset diabetes group ( n = 22)no new - onset diabetes group ( n = 39)p valuemale patients9 ( 41)15 ( 38)1.00age ( years)67 3.059 2.20.025bmi ( kg / m)22 0.7820 0.590.075preoperative hba1c 5.7 % 18 ( 82)14 ( 36)0.001preoperative ifg6 ( 27)3 ( 8)0.059preoperative albumin ( mg / dl)3.9 0.134.0 0.100.59preoperative total cholesterol ( mg / dl)176 9.6186 7.30.42preoperative pancreatic alpha - amylase ( iu / l)58 ( 6243)59 ( 4264)0.98operative time ( min)312 19347 150.14intraoperative blood loss ( ml)372 ( 51125)527 ( 53524)0.17malignancy8 ( 36)17 ( 44)0.79prv > 44 % 15 ( 75)6 ( 19)<0.001popf grade b6 ( 27)10 ( 26)1.00postoperative complication clavien s grade ii7 ( 32)15 ( 38)0.78postoperative hospital stay ( days)16 ( 754)18 ( 758)0.60adjuvant chemotherapy7 ( 32)15 ( 38)0.78values are means se , medians ( range ) or n ( % ) hba1c hemoglobin a1c , fpg fasting plasma glucose , popf postoperative pancreatic fistulap values were obtained using fisher s exact testp values were obtained using student s t testp values were obtained using mann
whitney u testtable 5multivariate logistic regression analysis of risk factors for postoperative new - onset diabetesodds ratio95 % cip valueage1.030.961.110.42preoperative ifg1.520.1814.70.69preoperative hba1c 5.7 % 15.62.801470.001prv > 44 % 11.32.1292.10.004odds ratio by 1 year post - dp univariate analysis of risk factors for postoperative new - onset diabetes values are means se , medians ( range ) or n ( % ) hba1c hemoglobin a1c , fpg fasting plasma glucose , popf postoperative pancreatic fistula p values were obtained using fisher s exact test p values were obtained using student s t test p values were obtained using mann
whitney u test multivariate logistic regression analysis of risk factors for postoperative new - onset diabetes odds ratio by 1 year post - dp
first , in the majority of preoperatively non - diabetic patients , dp led to disturbances in glucose metabolism , and there was a 36 % incidence of new - onset diabetes postoperatively .
second , in dp patients , prv and preoperative hba1c were independent risk factors for new - onset diabetes .
our results enable us to provide evidence - based preoperative counseling and individualized postoperative surveillance . prior to surgery , we can now offer patients specific information about their individual risk of postoperative diabetes .
postoperatively , appropriate surveillance may detect the development of impaired glucose metabolism [ i.e. , impaired glucose tolerance ( igt ) , ifg , and diabetes ] at an early stage and enable early intervention .
intensive glucose control has been reported to decrease the risks of major cardiovascular events and death in patients with newly diagnosed type 2 diabetes.18 also , in patients with igt who are pre - diabetic , the early introduction of anti - diabetic agents has been reported to diminish the development of type 2 diabetes.19 the american diabetes association recommends intensive annual monitoring , lifestyle modification , and sometimes use of anti - diabetic agents in patients with igt , ifg , or hba1c of 5.76.4 % for the prevention and delay of developing type 2 diabetes.20 therefore , early detection and intervention for endocrine insufficiency are essential for dp patients .
prior reports have estimated the incidence of new - onset diabetes after dp at between 9 and 38 % of preoperatively non - diabetic patients.4,6,8,21 the numerous limitations of these studies ( such as unspecified preoperative diabetic status of study patients , inconsistent standards for diagnosis of postoperative diabetes , and selection of cohorts of patients with chronic pancreatitis ) make it difficult to evaluate the basis for this wide range of diabetes incidence . in the current study ,
the incidence of postoperative new - onset diabetes in preoperatively non - diabetic patients was 36 % .
we attribute this relatively high measure of incidence to our application of a definitive classification system and close follow - up .
the results of this study identify prv > 44 % as an independent risk factor for postoperative new - onset diabetes in preoperatively non - diabetic dp patients .
although beta cell mass has previously been reported to be significantly related to plasma glucose control,14,22,23 volumetric assessments in relation to postoperative endocrine function of the pancreas remain scarce .
previous studies in large animals13,15 and humans22 have demonstrated that a 50 % loss in beta cells elevates plasma glucose .
hemi - pancreatectomy , with an estimated 50 % reduction in pancreatic volume after transection on the superior mesenteric vein ( smv).9,11 in our study , the median prv in 29 patients with transection on the smv was 46 % , but we observed a wide range of values in these cases ( prv from 18 to 67 % ) , as well as among all cases of dp ( prv from 9 to 85 % ) .
variations in prv can also be attributed to differences in the patients pancreatic sizes and shapes , as well as differences in pancreatic tumor characteristics ( i.e. , location and the involvement of the main pancreatic duct that causes atrophy of the distal pancreas ) .
our use of mdct - based measurements of pancreas volume resulted in more precise prv values and thereby provides evidence that greater resection of pancreatic tissue increases the incidence of new - onset diabetes in preoperatively non - diabetic dp patients .
thus , although pancreatic resection must be tailored to suit the tumor character ( benign or malignant ) , location , and extent of tumor invasion , our data suggest that parenchyma - sparing pancreatectomies ( such as middle pancreatectomy or tumor enucleation ) are more likely to maintain postoperative pancreatic endocrine function and reduce the risk of diabetes . in this study , we frequently observed a delay in diabetes onset in the 22 new - onset diabetics ( median time 8 months , range 0.542 months ) , with only five showing signs of diabetes within 3 months . however , both groups of dp patients displayed significant increases in fpg and hba1c levels within 3 months following surgery , but without further increases thereafter .
these data lead us to hypothesize that , while surgical reduction of pancreatic parenchyma volume quickly impairs glucose metabolism , the observed lag in diabetes onset depends on other factors , such as the amount and overall health of the remaining endocrine pancreas that control plasma glucose . in patients with insufficient functional reserve of the remnant pancreas to compensate for beta cell deficit ( with severity depending on the volume of the pancreas removed ) , overt diabetes would develop in the early postoperative period ( within 3 months postoperatively ) .
the functional reserve of the endocrine pancreas could be estimated based on the preoperative hba1c value , which was identified as a risk factor predictive of postoperative diabetes in this study . in patients with late - onset diabetes ( later than
3 months after surgery ) , beta cell compensation would considerably influence the diabetes onset time . in the field of islet cell transplants , although obese individuals are generally at high risk of diabetes , it has been reported that the high demand for insulin in obese donors without diabetes promotes the necessary increase in islet cell hypertrophy and proliferation.24 islet cells that remain after pancreatectomy are likely in a similar situation that stimulates islet hypertrophy and thus a compensatory increase in insulin secretion in the endocrine pancreas .
eventually , however , this pre - diabetic state may progress to overt diabetes once the endocrine pancreas is exhausted and fails to control glucose homeostasis .
also , additional factors that vary the timing of late - onset postoperative diabetes include normal progression of underlying diseases , such as pancreatitis , as well as acquired risk factors for type 2 diabetes ( e.g. , weight gain or aging ) .
our analyses identified preoperative hba1c as a second risk factor for postoperative new - onset diabetes .
hba1c is increasingly viewed as a superior index of chronic hyperglycemia relative to plasma glucose ( which varies during the day ) , and the american diabetes association recently added hba1c 6.5 % to its diagnostic criteria for the detection of early diabetes , with slightly lower hba1c values ( from 5.7 to 6.4 % ) categorized as signaling an increased risk of diabetes.1 in our study , the cutoff value at which hba1c became a risk factor was 5.7 % . among the study
s 61 patients ( none of whom met the who criteria for diabetes , fpg 126 mg / dl ) , preoperative hba1c was 6.5 % in two patients and between 5.7 and 6.4 % in another 30 patients . of these 32 individuals , 18 patients ( 56 % ) developed post - operative diabetes .
however , it is noteworthy that four additional patients with hba1c < 5.7 % , but relatively high prv ( from 47 to 61 % ) , also developed diabetes .
the metabolic consequences of pancreatic resection are multifaceted and can be affected by glucoregulatory hormone concentrations , the balance between production and utilization of glucose , changes in insulin sensitivity and nutritional status , surgical complications,25,26 and tumor character ( malignant or benign ) . despite decreases in insulin secretion , some studies have reported post - pancreatectomy improvements in glucose control in malignant cases.27,28 because malignant pancreatic tumors are known to produce substances that impair the action of insulin and decrease insulin sensitivity , a patient s diabetic status can sometimes improve after tumor removal.29,30 of the nine patients in our study who showed stable glycemic control ( eight with hba1c 0.1 % ) or improved control ( one with hba1c reduced by 0.4 % ) during the post - dp follow - up period , five had malignant tumors .
the one patient with improved glycemic control had a highly advanced cancer , as well as preoperative hba1c and bmi levels of 6.2 % and 28.7 kg / mm , respectively , indicating pre - diabetes .
this patient lost 13 % of his body weight within 3 months after surgery , and it is likely that this loss helped suppress the progression of type 2 diabetes .
adequate preoperative functional reserve of the endocrine pancreas ( hba1c < 5.7 % ) and maximizing the volume of the pancreatic parenchyma preserved are two key determinants of successful postoperative glycemic control .
our findings enable reliable preoperative evaluation of the risk of developing diabetes and to perform postoperative surveillance appropriately .
late - onset diabetes needs to be recognized as a common sequela of dp , and longitudinal follow - up and preventive intervention ( weight control and anti - diabetic agents for pre - diabetic patients ) should be introduced in high - risk patients .
this article is distributed under the terms of the creative commons attribution license which permits any use , distribution , and reproduction in any medium , provided the original author(s ) and the source are credited .
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### Summary:
: introductionpancreatogenic diabetes after pancreatectomy is of growing importance due to the increasing life expectancy of pancreatectomized patients .
although reduction of pancreatic volume is thought to affect glucose metabolism , a consistent relationship has yet to be determined .
this study aimed to investigate functional consequences of distal pancreatectomy ( dp ) in preoperatively non - diabetic patients.methodsthis study included 61 non - diabetic patients who underwent dp .
clinical data were obtained , and the percent resected volume ( prv ) of each pancreas was determined via multi - detector row computed tomography volumetry.resultsduring the follow - up period ( median 26 months ) , 22 patients ( 36 % ) developed new - onset diabetes within a median onset time of 8 months ( range 0.542 months ) postoperatively .
the remaining 39 patients also showed impaired glucose metabolism .
multivariate analysis identified preoperative hemoglobin a1c
5.7 % ( odds ratio 15.6 , p = 0.001 ) and prv > 44 % ( odds ratio 11.3 , p = 0.004 ) as independent risk factors for new - onset diabetes.conclusionskey determinants of postoperative glycemic control include preoperative functional reserve of the endocrine pancreas and the volume reduction of pancreatic parenchyma .
our findings enable reliable preoperative evaluation of the risk of postoperative diabetes and appropriate postoperative surveillance , which is helpful for early intervention in high risk patients .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the danish hernia database is subdivided into an inguinal hernia database and a ventral hernia database .
this article refers to the danish ventral hernia database ( dvhd ) that includes repairs of all abdominal wall hernias excluding inguinal and femoral hernias .
thus , the database includes all primary ( umbilical , epigastric , and others ) as well as secondary hernias ( incisional and parastomal ) .
with reference to ventral hernia repair , the database is designed to provide national surveillance of current danish surgical practice and clinical postoperative outcomes .
this database facilitates mapping of the incidence of surgery , aspects of surgical techniques , and postoperative complications .
it is specifically intended that the data generated by the database must contribute to reduction of postoperative morbidity and hernia recurrence . moreover
, it seeks to evaluate new treatment strategies and facilitate nationwide implementation of evidence - based treatment strategies .
the database includes all adult ( 18 years ) danish patients operated on under elective or emergency conditions for ventral hernia in a danish surgical department ( public , n=22 or private , n=10 ) .
all centers contributed with registration of hernia procedures since the launch of the database in 2007 .
data entry is most often performed by the operating surgeon immediately after surgery on a secured website using the patient s unique danish civil registration number .
the variables that are recorded include demographic data , detailed hernia description , and technical aspects related to the surgical repair ( table 1 ) .
data entry is kept simple and uniform , and it is possible to monitor different variables depending on the type of hernia repair . in order to eliminate missing data , the system does not accept upload of insufficient registrations .
data registration is mandatory and has been validated against patient files ( gold standard ) demonstrating more than 94% overall agreement on parameters , such as type of hernia , hernia size , mesh product , and mesh fixation.1
a continuous follow - up is performed by a preprogrammed and automatic merge of data from dvhd with data from the danish national patient register ( dnpr),2 which holds data from all patient contacts , to the danish health care providers ( private and public ) , including operations .
this merging of data relies on the unique danish civil registration number of the patient .
this combination of data is performed on a monthly basis to provide quality assessment given by four defined clinical indicators ( table 2 ) .
such measures may include reoperation for hernia recurrence , specific diagnoses , and other surgical procedures .
since the establishment of dvhd in 2007 , there has been an intensive scientific activity resulting in national collaboration and many international publications within the field ( http://www.herniedatabasen.dk/index.php/downloads/litteraturliste/ ) . based on the combination of the prospectively collected data from the dvhd and follow - up in the dnpr ,
high volume data have been analyzed and have provided evidence for surgical improvement.3,4 high complication rates have been documented for all types of elective ventral hernia repairs3,58 and after emergency repairs , which are associated with up to 15-fold increase of morbidity.8,9 the nationwide studies have pointed out several areas for surgical improvement for the different types of ventral hernias to reduce risk for early and late complications and recurrence .
these include the advantageous application of a sublay mesh during open repair of an incisional hernia7 and use of a mesh for open umbilical or epigastric hernia repair to reduce recurrence.10 combining data from the dvhd with data from patient files , patient questionnaires , and clinical examinations revealed that mesh repairs reduce the risk for recurrence significantly,7 even in small repairs and without increased risk of pain.10,11 additionally , large - size data from dvhd have shown that laparoscopic intraperitoneal mesh fixation with absorbable as compared with titanium tacks is associated with an increased risk of hernia recurrence .
contrary to previous expectations by manufacturers of mesh fixation devices , there was no difference in long - term pain between patients receiving absorbable tacks and patients operated on with titanium tacks.12 data from dvhd have been combined with information obtained from dnpr and clinical examinations to determine the cumulated incidence difference between a recurrent hernia diagnosed by clinical examination and reoperation for hernia recurrence .
clinical recurrences were four- to fivefold higher than the number of reoperations for recurrence.13 earlier reports based on reoperation rates for hernia recurrence thus severely underestimate the real frequency of hernia recurrence .
the link between specific databases according to a unique danish civil registration number for each patient allows for combining scientifically interesting data from various databases .
findings were recently published combining data from dvhd with information from the danish inguinal hernia database .
interestingly , patients operated on for a direct or recurrent inguinal hernia as compared with surgery for an indirect inguinal hernia were significantly more prone to ventral hernia repair suggesting a specific predisposition to herniogenesis.14 it has been suggested in small studies that abdominal aortic aneurism shares common pathological mechanisms with the development of incisional hernia .
merging data from dvhd , the danish vascular surgery registry and dnpr allowed for the largest study ever in this field .
it demonstrated that both obesity and aortic reconstruction due to abdominal aortic aneurism as compared with aortoiliac occlusive disease significantly increased the risk of subsequent incisional hernia repair.15 however , contrary to findings of previous low - powered studies , the presence of abdominal aortic aneurism in a large screening population was not associated with diagnosis of inguinal hernia.16 the prospective danish hernia databases were among the first in the field and the only ones requiring mandatory registration by all surgeons conducting hernia repairs .
it is crucial for the quality of the databases that a high registration rate is maintained .
this is facilitated by a number of ongoing initiatives , including meetings for surgeons providing feedback information twice annually .
moreover , lists of unregistered procedures are generated on a monthly basis and distributed to the surgical centers . finally , a national report is published every year on main statistics and center - based reporting rates to the registries .
the national rate of registration to the dvhd is 80% as compared to the rate for the danish inguinal hernia database that reaches 90% .
there is an ongoing initiative from the steering committee of dvhd to motivate all surgeons to report their operations in order to increase the national registration rate .
moreover , there is political focus on annual reports which are sent to the administrators and chairman of each surgical center informing on the local registration rate .
however , there are no judicial options to increase the registration rate . the data collected from the hernia databases combined with information from dnpr and other specific databases provide scientific evidence for revised recommendations and guidelines following discussion between participating surgeons at regular meetings .
based on the combination of the prospectively collected data from the dvhd and follow - up in the dnpr , high volume data have been analyzed and have provided evidence for surgical improvement.3,4 high complication rates have been documented for all types of elective ventral hernia repairs3,58 and after emergency repairs , which are associated with up to 15-fold increase of morbidity.8,9 the nationwide studies have pointed out several areas for surgical improvement for the different types of ventral hernias to reduce risk for early and late complications and recurrence .
these include the advantageous application of a sublay mesh during open repair of an incisional hernia7 and use of a mesh for open umbilical or epigastric hernia repair to reduce recurrence.10
combining data from the dvhd with data from patient files , patient questionnaires , and clinical examinations revealed that mesh repairs reduce the risk for recurrence significantly,7 even in small repairs and without increased risk of pain.10,11 additionally , large - size data from dvhd have shown that laparoscopic intraperitoneal mesh fixation with absorbable as compared with titanium tacks is associated with an increased risk of hernia recurrence .
contrary to previous expectations by manufacturers of mesh fixation devices , there was no difference in long - term pain between patients receiving absorbable tacks and patients operated on with titanium tacks.12
data from dvhd have been combined with information obtained from dnpr and clinical examinations to determine the cumulated incidence difference between a recurrent hernia diagnosed by clinical examination and reoperation for hernia recurrence .
clinical recurrences were four- to fivefold higher than the number of reoperations for recurrence.13 earlier reports based on reoperation rates for hernia recurrence thus severely underestimate the real frequency of hernia recurrence .
the link between specific databases according to a unique danish civil registration number for each patient allows for combining scientifically interesting data from various databases .
findings were recently published combining data from dvhd with information from the danish inguinal hernia database .
interestingly , patients operated on for a direct or recurrent inguinal hernia as compared with surgery for an indirect inguinal hernia were significantly more prone to ventral hernia repair suggesting a specific predisposition to herniogenesis.14 it has been suggested in small studies that abdominal aortic aneurism shares common pathological mechanisms with the development of incisional hernia .
merging data from dvhd , the danish vascular surgery registry and dnpr allowed for the largest study ever in this field .
it demonstrated that both obesity and aortic reconstruction due to abdominal aortic aneurism as compared with aortoiliac occlusive disease significantly increased the risk of subsequent incisional hernia repair.15 however , contrary to findings of previous low - powered studies , the presence of abdominal aortic aneurism in a large screening population was not associated with diagnosis of inguinal hernia.16
the prospective danish hernia databases were among the first in the field and the only ones requiring mandatory registration by all surgeons conducting hernia repairs .
it is crucial for the quality of the databases that a high registration rate is maintained .
this is facilitated by a number of ongoing initiatives , including meetings for surgeons providing feedback information twice annually .
moreover , lists of unregistered procedures are generated on a monthly basis and distributed to the surgical centers . finally , a national report is published every year on main statistics and center - based reporting rates to the registries .
the national rate of registration to the dvhd is 80% as compared to the rate for the danish inguinal hernia database that reaches 90% .
there is an ongoing initiative from the steering committee of dvhd to motivate all surgeons to report their operations in order to increase the national registration rate .
moreover , there is political focus on annual reports which are sent to the administrators and chairman of each surgical center informing on the local registration rate .
the data collected from the hernia databases combined with information from dnpr and other specific databases provide scientific evidence for revised recommendations and guidelines following discussion between participating surgeons at regular meetings .
the majority of core structural tasks within the database is controlled and maintained by government organizations ( regionernes kliniske kvalitetsudviklings program ) .
data access : each participating center may obtain their data . in order to obtain data from external centers , approval is required from the danish data protection agency and regionernes kliniske kvalitetsudviklings program .
the registration requires a limited contribution from all surgeons and is an excellent tool for observing changes over time , including adjustment of several confounders .
the registration system permits post hoc subgrouping of patients at high risk and may investigate even rare clinical events .
finally , this national database registry has led to a high number of scientific publications in recent years .
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### Summary:
: aimthe danish ventral hernia database ( dvhd ) provides national surveillance of current surgical practice and clinical postoperative outcomes .
the intention is to reduce postoperative morbidity and hernia recurrence , evaluate new treatment strategies , and facilitate nationwide implementation of evidence - based treatment strategies .
this paper describes the design and purpose of dvhd.study populationadult ( 18 years ) patients with a danish civil registration number and undergoing surgery under elective or emergency conditions for ventral hernia in a danish surgical department from 2007 and beyond .
a total of 80% of all ventral hernia repairs performed in denmark were reported to the dvhd.main variablesdemographic data ( age , sex , and center ) , detailed hernia description ( eg , type , size , surgical priority ) , and technical aspects ( open / laparoscopic and mesh related factors ) related to the surgical repair are recorded .
data registration is mandatory .
data may be merged with other danish health registries and information from patient questionnaires or clinical examinations.descriptive datamore than 37,000 operations have been registered .
data have demonstrated high agreement with patient files .
the data allow technical proposals for surgical improvement with special emphasis on reduced incidences of postoperative complications , hernia recurrence , and chronic pain.conclusiondvhd is a prospective and mandatory registration system for danish surgeons .
it has collected a high number of operations and is an excellent tool for observing changes over time , including adjustment of several confounders .
this national database registry has impacted on clinical practice in denmark and led to a high number of scientific publications in recent years .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: despite advances in medical procedures , the prognosis of inflammatory cardiomyopathy ( cmi ) , a cause for dilated cardiomyopathy , is poor .
the character of inflammatory response is the pivotal parameter for the prognosis of patients with cmi .
the delicate balance between protective and deleterious immune mechanisms is a decisive factor in the evolution of myocardial damage , of which the complex mechanisms involved are not yet completely understood . beyond others , the innate immune system , cardiac cytokines , autoantibodies , and probably also mesenchymal stromal cells ( msc )
msc are of special interest , since they produce growth factors and cytokines mediating endogenous activation of resident cardiac stem cells in a paracrine manner , and have profound immunomodulatory features .
msc mediate their complex immunomodulatory effects by interacting with cells from both the innate and adaptive immune system resulting in skewing the immune response towards an anti - inflammatory / tolerant phenotype .
they suppress t - cell proliferation , modulate dendritic cell function into a regulatory phenotype , and alter their cytokine secretion profile towards an upregulation of anti - inflammatory cytokines such as interleukin- ( il- ) 10 and downregulation of inflammatory cytokines .
msc counteract tissue injury via their capacity to promote endogenous tissue regeneration and via immunomodulation after selective migration to the site of injury , a process in which stromal derived factor- ( sdf- ) 1 is essential .
administration of msc as application route in cmi , whose efficacy has been demonstrated in experimental studies of acute myocarditis [ 8 , 13 ] . at present ,
application of msc in patients with cmi , clarification in the potential of msc to migrate and home to the heart in patients with cmi is warranted .
first , regenerating cells are recruited to the site of damage ; thereafter they adhere to the vessel wall or migrate into the tissue .
therefore , the aim of this study was to investigate the migration and homing potential of endogenous circulating msc in patients with virus negative cmi .
patients with clinical indication for an emb were consecutively recruited between november 2008 and june 2009 in our own centre .
indications for emb were reduced ejection fraction in the presence of a normal coronary angiogram ( n = 16 ) , symptoms of heart failure despite normal left ventricular ejection fraction ( lvef ) ( n = 7 ) , lv hypertrophy ( n = 2 ) , or cardiac arrhythmias ( n = 4 ) .
we excluded patients with proof of virus genomes in emb of human herpes virus 6 , epstein barr virus , enterovirus , adenovirus , and parvovirus b19 , for the latter with genome equivalence > 500/g .
in addition , exclusion criteria were coronary heart disease , antiviral , immunomodulatory , or immunosuppressive therapy within the last 6 months , acute myocarditis , clinical or biochemical evidence of the presence of concomitant chronic inflammatory disease , chronic renal insufficiency ( creatinine 1.4 mmol / l ) , inability to understand the consent form , participation in or consent to participate in another study , or malignant disease .
all study participants gave their written informed consent , and the study was approved by the ethics committee of the charit , berlin .
physical examinations , clinical assessments including echocardiography and ecg , as well as laboratory controls were analysed prospectively .
the assessment of clinical complaints and heart failure symptoms according to the nyha classification and the completion of a questionnaire were carried out at the initial visit .
all patients underwent m - mode and 2d echocardiography to evaluate lv end diastolic diameter ( lvedd ) .
echocardiographic measurements were analysed independently in a blinded fashion by two experienced operators . peripheral blood mononuclear cells ( pbmc )
first , a regional gate was defined to exclude debris and platelets defined by forward / sideward scatter . in order to detect msc ,
cd45cd34cd11b events identified with directly conjugated monoclonal antibodies against human cd45 , cd34 ( both fitc , bd ) , and cd11b ( af488 , bd ) were used .
they were negative for this marker combination ( r1 + r2 ) and further analysed for the presence of cd105 or cd90 ( both apc , bd ) and cd73 ( pe , bd ) .
however , due to the rare counts of cells fulfilling these criteria in a number of patients , further statistical analysis was hindered .
thus , due to the very close correlation of cd45cd34cd11b with cd45cd34cd11bcd73cd90 ( r = 0.67 , p < 0.0001 ) and with cd45cd34cd11bcd73cd105cd90 ( r = 0.72 , p < 0.0001 ) , we chose to use cd45cd34cd11b cells for further analysis .
measurements were carried out in duplicate and the mean value was used for further calculations .
all antibodies were tested with cultivated msc on passage 6 and with cultivated fibroblasts for their sensitivity and specificity .
as described previously , all patients underwent sampling from the femoral vein and great cardiac vein for measurement of msc and cytokine levels before an emb specimen was taken . in patients scheduled for coronary angiography
, additional blood samples were obtained from the aortic root before injection of the contrast agent .
the transcardiac gradients ( tcgs ) were expressed in percent changes from values obtained from either the aortic root or , if not obtainable there , the femoral vein .
a negative transcardiac gradient thus means that the number of cells is smaller in the coronary sinus compared to the aortic root and suggests that cells are retained in the heart .
there were no differences in tcgs between the 2 methods . in patients , in whom both aortic root and femoral vein were sampled ,
emb were obtained from the right ventricular septum within two days after angiographic evaluation of lvef using standard techniques .
two biopsies were used for the histological evaluation ( paraffin embedded ) according to the dallas criteria and the immunohistological analysis of inflammation ( frozen sections ) , respectively . the cut - off value of 9.0 lymphocyte function - associated antigen-1 ( lfa-1 , cd11a ) positive cells / mm and 5.5 area fraction ( af)% human leucocyte antigen ( hla ) class i and/or 1.2 af% cd54/icam-1 were used to differentiate between samples with or without cardiac inflammation .
dna and rna were extracted simultaneously from biopsy specimens , and the amplification of viral genomes was conducted by nested pcr as described .
circulating levels of n - terminal pro - brain natriuretic peptide ( nt - probnp ) and sdf-1 levels in pre- and postcoronary blood samples were quantified with respective elisa kits ( r&d , wiesbaden ) according to the manufacturers ' instructions .
rna from human biopsies was prepared and reverse transcribed using high capacity cdna reverse transcription kit ( applied biosystems , foster city , usa ) .
quantitative real - time polymerase chain reaction ( pcr ) was used to quantify human sdf-1 ( abi prism 7900 ht sequence detection system software version 2.2.2 .
, perkin elmer ) ( eppendorf mastercycler epgradient realplex , hamburg , germany ) expression .
the sequences of the primer sets used in this study were as follows : human sdf-1 for : 5-atgcccatgccgattcttc-3 and rev : 5-ggagtgttgagaattttgagatgct-3 , and human ribosomal l32 : for : 5-aggagagacaccgtctgaacaag-3 and rev : 5-gaaccaggatggtcgctttc-3. msc were determined in lv sections with transversely sectioned cardiomyocytes immunostained with cd105 and cd90 in the absence of the markers cd45 and cd34
high power fields ( 400 , 200 m 200 m , 8 fields per section ) with transversely sectioned cardiomyocytes were recorded to calculate msc to cardiomyocyte ratio .
nuclei were stained with 4,6-diamino-2-phenylindole ( dapi , dilution , 1 : 200 ; sigma ) .
ki-67 in nuclei was evaluated with the use of anti - ki-67 antibodies ( diagnostic biosystems , pleasanton , usa ) .
myocytes were recognized by means of mouse monoclonal antibodies against sarcomeric -actin ( dilution 1 : 50 , sigma ) . finally , sections were mounted and examined under a fluorescence microscope ( leica ) .
human adult msc were isolated from iliac crest bone marrow aspirates of healthy donors after their written approval according to binger et al . .
msc were cultured in dulbecco 's modified eagle 's medium ( dmem ; biochrom ) supplemented with 10% fetal bovine serum ( fbs ) , 1% penicillin / streptomycin , 1% glutamine , 2% hepes , and 2 ng / ml of basic fibroblast growth factor ( tebu - bio , offenbach , germany ) and plated at a density of 5 10 cells / cm before use in the respective experiments .
cultivated msc were triple negative for the markers cd45 , cd34 , and cd11b but stained positively for the markers cd73 , cd29 , cd105 , cd106 , cd90 , and cd44 , thereby confirming sensitivity and specificity of our antibody sets ( figure 1(a ) ) .
hl-1 cells were plated in a 6-well plate at a density of 300,000 cells / well in claycomb medium ( sigma ) supplemented with 10% fbs , 1% penicillin / streptomycin , 100 m norepinephrine ( sigma ) , and 2 mm l - glutamine ( biochrom ag , berlin , germany ) . after twenty - four hours , cells were washed and cultured for an additional 24 h in serum starvation medium ( dmem 11966 medium ( invitrogen , carlsbad ) supplemented with 0.1% fbs , 5 mm glucose , and 1% penicillin / streptomycin ) in the presence or absence of 10 ng / ml of recombinant tnf- ( r&d systems ) .
then , the supernatant ( conditioned medium ) was collected and stored at 20c until further use . conditioned medium of unstimulated or tnf--stimulated hl- 1 cells , in the presence or absence of 5 g / ml of anti - sdf- ( r&d systems ) and corresponding mouse isotype control ( santa cruz biotechn inc .
, cambridge , usa ) or 2.5 g / ml of anti - mcp-1 ( r&d systems ) and corresponding rat isotype control ( santa cruz biotechn inc . ) was added to the bottom chamber of the chemotaxis chamber ( chemotx , 8 m pore , neuroprobe , gaithersburg , md , usa ) .
a total of 3 10 msc , resuspended in dmem ( sigma ) , containing 0.01% fbs , 2 mm l - glutamine , 20 mm hepes ( invitrogen ) , and 1% penicillin / streptomycin , were plated in the upper chemotaxis chamber . after 24 hours of incubation at 37c , the lower side of the filter was washed with pbs and fixed in 50% acetone/50% methanol .
next , cells were stained with crystal violet ( sigma ) and quantified by spectophotometric measurement at 560 nm .
data are depicted as the migration of msc versus conditioned medium of unstimulated hl-1 cells ( basal ) set as 1 and represented as mean sem of n = 4 wells / condition . in the case of migration assays of msc towards serum of patients , 1% of patient serum
was added to the bottom chamber of the chemotaxis chamber ( chemotx , 8 m pore , neuroprobe , gaithersburg , md , usa ) in the presence or absence of anti - sdf- and corresponding mouse isotype control .
a total of 3 10 msc , resuspended in dmem ( sigma ) , containing 0.01% fbs , 2 mm l - glutamine , 20 mm hepes ( invitrogen ) , and 1% penicillin / streptomycin , was plated in the upper chemotaxis chamber . after 24 hours of incubation at 37c , the lower side of the filter was washed with pbs and fixed in 50% acetone/50% methanol .
a msc standard was plated out on a separate membrane and after 2 hours , the membrane was fixed in 50% acetone/50% methanol .
the optical density of the wells on the filter was analyzed via image j and the corresponding cell number per well calculated .
comparisons between the two groups were analysed by t - test ( two - sided ) for normally distributed variables .
nonnormally distributed continuous variables ( msc , hs - crp , lfa-1 , nt - probnp ) were compared by the mann - whitney u test and are presented as median and interquartile range [ iqr ] .
multivariate linear regression analysis and nonparametric bivariate correlation ( spearman rank correlation coefficient ) were used to correlate counts of circulating msc or msc in emb with cardiac inflammation , ntprobnp , sdf-1 , mcp-1 , and lvef . to identify independent determinants of msc counts , a multivariate linear regression analysis for the abovementioned parameters
statistical significance was assumed , if a null hypothesis could be rejected at p 0.05 .
twenty - three ( 79% ) patients showed an increased cardiac inflammation response in emb .
patients with cardiac inflammation had a similar lvef and a slightly increased lvedd compared to patients without inflammation . except for these , no differences regarding concomitant medication , age , gender , or duration of symptoms were apparent .
circulating msc defined by the absence for the markers cd45 , cd34 , and cd11b and by staining positive for cd73 , cd105 , and cd90 counted for 0.010 [ 0.00250.048]%/pmnc with similar counts in patients with or without cardiac inflammation .
when considering only the negative marker combination ( figure 1(b ) ) , msc comprised 0.62 [ 0.381.15]%/pbmcs , again with similar counts in patients with or without cardiac inflammation ( 0.52 [ 0.291.0 ] versus 0.76 [ 0.381.34]%/pbmc ) .
no correlation was seen between circulating msc and cardiac inflammation , lvef , leukocyte count , or hs - crp , indicating that inflammation per se has no direct effect on circulating msc counts .
transcardiac gradients of circulating msc were measured after simultaneous sampling of the aorta and the coronary sinus in all patients . as illustrated in figure 2(a ) , patients with cardiac inflammation ( n = 23 ) had a significant 29.9% reduction of msc after transcardiac passage ( p < 0.01 , figure 1(c ) ) , in contrast ( p < 0.001 ) to patients without cardiac inflammation ( n = 6 )
. since sdf-1 is a potent chemoattractant for msc , sdf-1 mrna was quantified in emb .
there was a negative transcardiac gradient of msc in patients with sdf-1 mrna in their emb > median ( > 2.7-fold compared to gapdh ; p < 0.05 , figure 2(b ) ) .
cardiac inflammation and sdf-1 mrna levels were inversely correlated with the transcardiac gradients of circulating msc ( cardiac inflammation : r = 0.39 , p < 0.05 , figure 2(c ) ) .
furthermore , there was a negative correlation between the transcardiac gradients of circulating msc and nt - probnp ( r = 0.46 , p < 0.05 , data not shown ) , but not with lvef . by multivariate analysis , including lvef , nt - probnp , cardiac inflammation ( lfa - macrophages ) , and cardiac sdf-1 mrna , cardiac inflammation remained the only significant independent predictor for declined numbers of circulating msc after transcardiac passage ( p < 0.001 for trend ( anova ) , b = 0.73 , p < 0.005 ) .
interestingly , systemic sdf-1 levels were significantly induced in patients with cardiac inflammation compared to patients without cardiac inflammation ( figure 2(d ) ) with no further increase after transcardiac passage in both , patients with or without cardiac inflammation .
furthermore , msc migration was only tendentiously ( p = 0.1 ) more pronounced versus postcoronary or venous serum of patients with cardiac inflammation compared to serum of patients without inflammation ( data not shown ) .
however , no sdf-1-dependency could be detected , as shown in a blocking experiment ( data not shown ) .
as shown in the representative image , msc can be identified in the myocardium ( figure 3(a ) ) .
figure 3(b ) illustrates that patients with cardiac inflammation showed a trend towards increased numbers of msc ( cd45cd34cd90cd105 , 0.80 0.67 versus 1.89 1.03/100 mm , p = 0.058 ) in their emb compared to patients without inflammation and showed a strong correlation between msc and cardiac inflammation ( r = 0.64 , p = 0.0001 , not shown ) .
time to diagnosis was identical in both subgroups ( 3.7 2.3 versus 3.5 3.2 month , p = 0.7 ) . in agreement with the key role of sdf-1 in the retention of msc ,
sdf-1 mrna levels in emb correlated with numbers of msc in emb ( r = 0.64 , p = 0.001 , not show ) .
indeed , as shown in figure 3(c ) , the numbers of msc were significantly higher ( p < 0.001 ) in the group of patients with sdf-1 mrna expression above the median . by multivariate
analysis , including lvef , nt - probnp , cardiac inflammation , and sdf-1 , sdf-1 was the strongest predictor for increased numbers of msc in emb ( p < 0.001 for trend ( anova ) , b = 0.91 , p < 0.005 ) .
these findings thus support a pivotal role of sdf-1 in the cardiac retention of msc in the setting of cmi . as shown in figure 3(d ) , there was a significant inverse correlation between the number of msc in emb and transcardiac gradients of circulating msc ( r = 0.47 , p < 0.05 ) .
highest numbers of msc in the emb with the highest transcardiac gradients of circulating msc are a first hint that msc home to the myocardium . to further investigate whether the increased numbers of msc in emb were due to a potential replication of these cells in the heart , we analyzed ki67 as nuclear marker for proliferation in msc .
as shown in the representative pictures in figure 3(e ) , there was no costaining of ki67 in msc in emb detectable , further supporting the constant migration of msc . due to the very rare number of ki67 + cells
, no further quantitative analysis could be performed . to assess the cardiac homing of circulating msc towards inflamed hearts and to investigate which chemokines trigger the cardiac homing in patients with cmi , the migratory potential of msc was determined towards conditioned medium of tnf- stimulated hl-1 cardiomyocytes , to mimic the inflamed condition , in the presence or absence of a sdf-1- or mcp-1 antibody .
medium of tnf--stimulated murine hl-1 cardiomyocytes increased the migration of msc by 10% ( p < 0.005 ) compared to basal conditioned medium of hl-1 .
this effect was impaired in the presence of an sdf-1-antibody or in the presence of an mcp-1 antibody , but not in the presence of their respective igg isotype controls ( figure 4 ) .
the salient findings of this study are that endogenous msc migrate into the heart of patients with virus negative cmi depending on the grade of inflammation and that the number of retained cardiac msc is related to the expression of sdf-1. the increased number of msc in the myocardium of patients with cmi is , at least in part , due to a constant recruitment of these cells .
several studies in patients with heart failure have demonstrated the presence of humoral and cellular immunity activation , thus suggesting a possible relationship between dilated cardiomyopathy and inflammation . in heart failure patients , inflammation is a strong predictor of negative outcome .
the nature of msc with their immunomodulatory potential has moved these cells into the focus of novel therapeutic strategies for the treatment of heart failure .
recent data in experimental models of cmi [ 8 , 13 ] underscore the potential of i.v .
application of msc to treat cmi . we and others have shown reduced cardiomyocytes injury in the setting of virus - induced acute myocarditis through paracrine and immunomodulatory effects of msc [ 8 , 13 , 20 ] , indicating beneficial effects of msc in cmi .
most likely paracrine actions or modulation of regulatory immune cells account for the action of this admittedly small amount of msc homed to the heart .
this is in line with other findings from other progenitor cells present in small numbers in the heart exerting their effect on cardiac regeneration in the setting of ischaemia , advanced cardiomyopathies , and inflammation . given the significance of the cardiosplenic axis in the pathogenesis of cmi [ 13 , 23 ] and heart failure , an important contribution of targeting of msc to the spleen and subsequent immunomodulatory effects should be considered in the final cardioprotective effects of msc after i.v . application . at present , no clinical studies in patients with cmi have yet been performed involving i.v .
administration of msc and a direct proof that these multipotent cells play a physiological role in human cmi is lacking .
we therefore investigated whether endogenous circulating mcs migrate and home into the myocardium in cmi patients . in our study , there was a significant transcardiac reduction of circulating msc in patients with cardiac inflammation .
the association of reduction of circulating msc with increase of cardiac msc is a hint towards homing of msc to the site of injury in cmi . here , we are in line with other studies demonstrating that msc selectively home to sites of injury , irrespective of the type of tissue . among different mechanisms leading to a continuous recruitment of msc into the heart of patients with cmi , sdf-1 [ 25 , 26 ]
our findings are consistent with those results : the homing factor sdf-1 had the strongest association with numbers cardiac of msc , as marker for cardiac retention , in our patients with cmi , whereas inflammation was the strongest determinant for continuous declined numbers of circulating msc after transcardiac passage as indicator for migration .
this could also be confirmed in vitro where sdf-1 was not shown as main contributor to migration .
furthermore , we did not see any proliferation of cardiac msc , which supports our hypothesis that msc are rather constantly recruited . in brief , this study underscores the importance of the sdf-1/cxcr4 axis in the cardiac homing of msc by cmi .
this finding as well as the observation that cxcr4 expression is decreased upon cell culture expansion stresses the relevance to induce cxcr4 expression in msc before injection .
due to the clinical nature of this study , further conclusions as to the major sources and orchestration of chemokines involved in msc homing and retention and further mechanistic insights are precluded .
furthermore , it has to be acknowledged that despite the well - documented cardioprotective effects of msc in experimental models of cmi [ 8 , 13 ] , further studies will have to address the fate and function , repair of cmi or contribution to the pathogenesis of cmi , of endogenous cardiac msc in humans .
we provide evidence that endogenous circulating msc are constantly recruited into the myocardium of patients with cmi . it will be the aim of future studies to analyse the therapeutic potential of msc in this disease .
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### Summary:
: introduction . mesenchymal stromal cells ( msc )
have immunomodulatory features .
the aim of this study was to investigate the migration and homing potential of endogenous circulating msc in virus negative inflammatory cardiomyopathy ( cmi ) .
methods . in 29 patients with (
n = 23 ) or without ( n = 6 ) cmi undergoing endomyocardial biopsies ( emb ) , transcardiac gradients ( tcgs ) of circulating msc were measured by flow cytometry from blood simultaneously sampled from aorta and coronary sinus .
the presence of msc in emb , cardiac inflammation , and sdf-1 mrna expression were detected via immunohistochemistry and real - time pcr .
results .
msc defined as cd45cd34cd11bcd73+cd90 + cells accounted for 0.010 [ 0.00250.048]%/peripheral mononuclear cell ( pmnc ) and as cd45cd34cd11bcd73+cd105 + cells for 0.019 [ 0.00260.067]%/pmnc , both with similar counts in patients with or without cardiac inflammation .
there was a 29.9% ( p < 0.01 ) transcardiac reduction of circulating msc in patients with cmi , correlating with the extent of cardiac inflammation ( p < 0.05 , multivariate analysis ) .
a strong correlation was found between the tcg of circulating msc and numbers of msc ( cd45cd34cd90+cd105 + ) in emb ( r = 0.73 , p < 0.005 ) .
sdf-1 was the strongest predictor for increased msc in emb ( p < 0.005 , multivariate analysis ) .
conclusions .
endogenous msc continuously migrate to the heart in patients with cmi triggered by cardiac inflammation .
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: morphologic small - scale modules or minicolumn structures can be observed frequently in the cerebral cortex .
functional minicolumns have also been identified , but the relationship between morphologic and functional minicolumns is ambiguous . although morphologic minicolumn structures can be observed frequently , there is a marked variability in the definition of minicolumns , as well as in the diagnostic markers used for identifying these minicolumns ( for review see jones , 2000 ; defelipe et al . , 2002 ; rockland and ichinohe , 2004 ) .
dendritic bundles were first discovered using golgi methods , but these structures can today be more easily seen using microtubule - associated protein 2 ( map2 ) immunohistochemistry . myelinated axon bundles
can be visualized using tau immunohistochemistry or conventional myelin staining , and axon bundles of double bouquet cell can be seen using calbindin immunohistochemistry .
the spatial interrelationship between these differently identified morphologic minicolumns is more complex than originally expected , and is neither clear nor unanimously defined . in this review , i will focus on a well - examined small module exiting in layers 1 and 2 of the rat granular retrosplenial ( grs ) cortex .
this modular structure was first described as a module consisting of a combination of prominent apical dendritic bundles from layer 2 pyramidal neurons and thalamocortical patchy inputs , which are spatially matched with the dendritic bundles ( wyss et al . ,
further examination showed more intricate components of this modular structure , which will be reviewed first in this paper .
second , the postnatal development of this structure and potential molecular mechanisms underlying the formation of this module will be reviewed .
thirdly , i will describe the way in which this modular organization in wild - type rodents is transformed in mutant rodents , which have a disorganized layer structure in the cerebral cortex ( i.e. , the reeler mouse and shaking rat kawasaki , srk ) .
( 1990 ) by injecting the retrograde tracer fluoro - gold into the contralateral rat grs .
the well - filled dendrites of callosally projecting layer 2 pyramidal neurons were found to group together in discrete bundles , as they ascend toward the pial surface ( figure 1 ) . following this initial discovery ,
most recently , molecular techniques have been used for visualizing fluorescent protein - filled layer 2 pyramidal neurons ( figure 2a ; miyashita et al . , 2010 ; zgraggen et al . ,
2011 ) . as shown in figure 1 , the dendritic bundles in layer 1b / c are tighter than those in other layers , with a reported width of 30100 m and a distance between bundles of approximately 30200 m ( wyss et al .
, 1990 ; ichinohe and rockland , 2002 ) . near the layer 1b/1a interface ,
the dendritic tufts diverge and spread out in layer 1a to occupy the entire width of the layer ( figure 2a ) .
the extension range of these tufts is about the same range as the distance between dendritic bundles ( i.e. , 30200 m ; wyss et al . , 1990 ; ichinohe and rockland , 2002 ) .
schematic drawing of the modular organization of the layer 1 granular retrosplenial cortex ( grs ) .
( a ) dendritic bundles in layer 1 [ postnatal day ( p ) 10 ] , visualized by electroporation of enhanced green fluorescence protein ( egfp ) at embryonic day ( e ) 18 .
( b d ) confocal micrographs of layer 1 of the rat grs stained by double - immunofluorescence for microtubule - associated protein 2 ( map2 ; green ) and parvalbumin ( pv ; red ) .
scale bar : ( a ) , 50 m ; ( b d ) , 200 m .
immunohistofluorescence for map2 has been a convenient method for visualizing these dendritic modules ( figure 2b ; ichinohe and rockland , 2002 ; ichinohe et al .
2006 ) . using double / triple - immunofluorescence with a combination of appropriate antibodies , including antibodies against map2 ,
the spatial relationship between dendritic modules and other structures labeled by the different antibodies can be easily examined ( summarized in figure 1 ) .
one interesting example is that double - immunofluorescence for map2 and parvalbumin ( pv ) , a marker for a subpopulation of gabaergic neurons , reveals that pv - positive dendrites co - localize with apical dendritic bundles ( figures 1 and 2b d ) .
this intricate structure may be related to feedforward inhibition , as characterized by electrophysiologic studies in other thalamocortical systems ( swadlow and gusev , 2000 ) .
that is , these pv - positive neurons , activated by thalamic inputs , may inhibit layer 2 pyramidal neurons receiving the same thalamic inputs .
another possibility is that , since some pv - positive neurons have laterally widespread axonal fields ( kisvrday et al . , 2002 )
, these pv - positive neurons can inhibit intricate combinations of pyramidal neurons within different modules , which receive thalamic inputs different from inputs to these pv - positive interneurons . this potential organization may work as a substrate for lateral inhibition between modules .
immunohistochemistry using ocam , a cell adhesion molecule , has revealed patchy structures in layer 1 of the grs ( figures 1 and 3a , d ) .
the patches of ocam - positive and map2-positive areas can be seen to interdigitate ( figure 3 ) . to identify ocam - positive structures in layer 1 ,
this shows that ocam - positive structures are composed mostly of dendrites ( ichinohe et al . , 2003b ) .
in situ hybridization for the ocam gene shows that expression of the gene occurs in layer 5/6 pyramidal neurons ( ichinohe et al . , 2008 ) .
thus , the ocam - positive patches in layer 1 appear to constitute an aggregation of apical dendritic tufts of layer 5 pyramidal neurons ( figure 1 ) .
ocam is associated with the fasciculation of subsets of olfactory and vomeronasal axons ( yoshihara et al . , 1997 ) and the accurate segregation of odorant receptor - specific axons ( alenius and bohm , 2003 ) .
moreover , recent studies in olfactory glomeruli have shown that ocam is required for establishing or maintaining the compartmental organization and segregation of axodendritic and dendrodendritic synapses within glomeruli ( walz et al . , 2006 ) , and is important for the synchrony of mitral cell activity in olfactory glomeruli ( borisovska et al . ,
, ocam may be also involved in the maintenance of compartmental organization ( i.e. , segregation of map2-positive dendritic bundles from layer 2 pyramidal neurons and the complementary aggregation of ocam - positive apical dendrites from layer 5 pyramidal neurons ) .
dendritic modules in layer 1 are visualized by ocam - immunoreactive ( ir ) and map2-ir in adults .
the right column shows merged images where patches of ocam - ir and map2-ir are seen to interdigitate .
arrowheads point to corresponding locations in two sets consisting of three figures ( a f ) .
vesicular glutamate transporter 1 ( vglut1 ) and vglut2 are convenient markers for corticocortical and thalamocortical terminals in the cerebral cortex , respectively ( fujiyama et al . , 2001 ) .
double - immunofluorescence for ocam and vglut1 or vglut2 has shown that ocam- and vglut1-positive modules are co - localized and that ocam- and vglut2-positive modules are interdigitated in layer 1 ( figures 1 and 4 ) . these results underscore the notion that ocam - negative ( i.e. , map2-positive ) apical dendritic bundles from layer 2 pyramidal neurons are targeted by thalamocortical terminals and that ocam - positive aggregations of apical dendritic tufts of layer 5 pyramidal neurons are targeted by corticocortical inputs ( shibata , 1993 ; van groen and wyss , 1995 , 2003 ; mir - berni et al . , 2006 ; ichinohe et al . ,
these results indicate that not only different types of dendrites but also different kinds of axon terminals are aggregated and segregated in this module .
that is , specific combinations of dendritic modules ( recipients ) and axon terminal modules ( inputs ) are co - localized . this type of co - localization of recipient and input modules has previously been described in other cortical areas and layers ( e.g. , the rodent barrel cortex and the honeycomb - like structure at the border of layers 1 and 2 of the cerebral cortex ; datwani et al .
architectonics of the rat grs , visualized by immunohistochemistry for ocam and vesicular glutamate transporter 1 ( vglut2 ; presumptive thalamocortical terminations ) or vglut1 ( presumptive corticocortical terminations ) .
ocam - ir in the wild - type rat ( a ) is bistratified , with one superficial band in layers 1b and c and another , deeper band in layers 5 and 6 .
similarly , vglut2 concentrates are seen in two bands , but these correspond to layer 1a and layers 3 and 4 ( b ) .
double - immunofluorescence for ocam and vglut2 directly demonstrates this complementary relationship ( c ) .
the developmental time - course of the dendritic bundles in the grs has been investigated using immunohistochemistry for map2 and glutamate receptor subunits 2/3 ( glur2/3 ; ichinohe et al . , 2003b ) .
bundles in layer 1 are apparent as early as postnatal day ( p ) 5 , first using glur2/3 immunohistochemistry and then , from p14 , using map2 immunohistochemistry . as a step toward understanding the mechanisms underlying dendritic aggregation , we further investigated the ontogeny of expression of the cell adhesion molecule ocam .
ocam exhibits a patchy distribution in layer 1 from p3 to adulthood , and the regions of weak ocam immunoreactivity selectively correspond to the dendritic bundles ( using glur2/3 and map2 immunohistochemistry ) . the periodic geometry of ocam - positive regions , the time - course of their appearance , and their distinct localization , complementary to the bundles , support the possibility that ocam significantly contributes to the establishment and maintenance of dendritic modules .
more specifically , the interdigitating relationship between regions of high ocam immunoreactivity and the dendritic bundles in layer 1 suggests that ocam may have a repellent influence on the formation of these bundles ( see also above section ) . in order to identify molecules other than ocam that are involved in the formation of the grs layer 1 bundles from layer 2 pyramidal neurons ,
several genes , including that for neurotrophin-3 ( nt-3 ) , have been found to be highly and specifically expressed in grs layer 2 at p3 versus p12 ( i.e. , before and after bundle formation ) .
specificity was inferred by comparisons with grs layer 5 at p3 and with barrel cortex layer 2 at p3 . in barrel cortex ( with low nt-3 expression ) , layer 2 pyramidal neurons do not form prominent apical dendritic bundles . to examine whether nt-3-mediated events are causally involved in bundle formation , we used in utero electroporation to overexpress nt-3 in other cortical areas .
this overexpression succeeded in producing prominent bundles of dendrites originating from layer 2 neurons in the barrel field cortex , where layer 2 bundles are normally absent ( figure 5 ) .
the controlled ectopic induction of dendritic bundles identifies a new role for nt-3 and a new in vivo model for investigating dendritic bundles and their formation .
( a ) egfp - expressing layer 2 pyramidal neurons at p20 , after electroporation of egfp alone at e18 .
( b ) electroporation of egfp and nt-3 at e18 induces distinct dendritic bundles in the barrel cortex .
to further investigate the distinctive compartmental organization in the grs , we examined reelin - deficient mutant rodents ; namely , the reeler mouse and srk . in these animals ,
the normal grs lamination is conspicuously disrupted , and dendrites are malpositioned ( lambert de rouvroit and goffinet , 1998 ; kikkawa et al . , 2003 ) .
to understand these abnormalities in more detailed level , it is necessary to examine how the highly organized laminar and modular architecture of the grs in the wild - type rodent is transformed in these mutant rodents ( ichinohe et al . , 2008 ) . in
both the srk and reeler grs , immunohistochemistry for ocam revealed a patch and matrix - like mosaic , with large ocam - negative patches , in the middle of the cortical thickness , embedded in an ocam - positive matrix ( figure 6 ) .
1994 ) also reported a similar patch - matrix pattern in the reeler visual cortex using acetylcholinesterase staining ; however , the visual cortex described in their study may actually have been the grs , as discussed by ichinohe et al .
it is difficult to conclude that the patch - matrix organization in mutant rodents is comparable to the micromodularity of layer 1 in wild - type rodents .
nevertheless , it may be significant that the discontinuous appearance of both features is strikingly similar between mutant and wild - type rodents .
moreover , the thalamic and cortical afferents in mutant rodents maintain the same relationship in the patch - matrix configuration as in wild - type rodents ( figure 4 ) ; namely , ocam - positive areas match vglut1 ( corticocortical input)-rich areas and ocam - negative areas match vglut2 ( thalamocortical input)-rich areas . further , by filling neurons with lucifer yellow in fixed slices of the reeler grs , we ascertained that these neurons can be grouped into two populations , with dendrites showing preference to either ocam - negative patches ( figure 7a ) or the ocam - positive matrix ( figures 7b e ; ichinohe et al . , 2008 ) . from additional in situ hybridization and electron microscopy results ,
we conclude that the ocam - positive matrix in mutant rodents is filled with aggregated dendrites of neurons , comparable to layer 5 neurons in wild - type , and ocma - negative patch in mutant rodents with aggregated dendrites of layer 2 neurons .
thus , even in the disrupted laminar cortex of the reeler mouse and srk , ocam may exert dendritic population - dependent homophilic or repellent effects .
further , these results suggest that , even though layer formation ( and subsequently the position of the cell bodies ) is disorganized in mutant rodents , recipient dendrites , and specific inputs aggregate appropriately and probably maintain proper synaptic connectivity , sufficient for maintaining relatively normal cortical function in these mutant animals ( simmons and pearlman , 1983 ) .
architectonics of mutant grs , visualized by immunohistochemistry for ocam and vglut2 ( presumptive thalamocortical terminations ) or vglut1 ( presumptive corticocortical terminations ) .
( a c ) coronal sections reacted for ocam and vglut2 from shaking rat kawasaki .
i ) , 300 m ; ( d f ) , 600 m . pyramidal cell dendrites preferentially arborize in either patch or matrix compartments in reeler grs .
( a ) coronal section reacted for vglut2 ( red ) , with a lucifer yellow ( ly)-filled neuron ( green ) .
this ly - filled neuron has a soma located in a zone of low vglut2-ir ( presumably equivalent to the ocam - positive matrix ) and many dendrite branches within a vglut2-dense patch ( presumably equivalent to an ocam - negative patch ) .
these dendritic portions within vglut2-dense patches have spines [ arrowheads in ( a ) ] , but not the portions outside the vglut2-dense region ( a ) . insets in ( a ) [ i.e. , ( a,a ) ] show a higher magnification of the images in the white boxes [ ( a ) from left box and ( a ) from right box ] . ( b
e ) serial sections of a ly - filled neuron ( green ) , double reacted for ocam ( red ) .
an apical dendrite - like process gives off an oblique dendrite proximally , before entering an ocam - negative patch .
an apical tuft branches just at the border between patch and matrix compartments ( c ) .
the basal dendrites tend , like the cell body , to stay within the ocam - dense matrix .
scale bar : ( a e ) , 50 m ; ( a,a ) , 20 m .
the grs in rats is implicated in a wide range of behaviors , including visual and vestibular integration , path integration , and spatial navigation , as well as certain aspects of learning and memory ( cooper et al . , 2001 ; garden et al . , 2009
the grs is part of a heavily interconnected limbic circuit , including the anterior thalamic nuclei and subiculum .
the underlying substrates involved in grs functioning and the true significance of upper layer modular organization are undoubtedly complex .
more anatomical and physiological studies will obviously be necessary ( see recent anatomical study by odagiri et al . , 2011 ) .
prominent characteristics of the modular organization of the rat grs in layer 1 include ( 1 ) the aggregation or segregation of apical dendrites ( recipients ) of the same or different types of pyramidal neurons , respectively , and ( 2 ) the fact that certain types of terminals ( inputs ) either match or interdigitate with a particular type of dendritic aggregation . as mentioned above
, this type of recipient and input matching also occurs in other small - scale modular organizations in the neocortex ( i.e. , honeycomb - like organization in the uppermost layers : ichinohe et al .
modular aggregations consisting of appropriate types of recipients and inputs , such as those seen in the rat grs , may help to achieve efficient and quick synaptic wiring changes , such as occur in the context of learning and memory .
the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
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### Summary:
: structures associated with the small - scale module called minicolumn can be observed frequently in the cerebral cortex .
however , the description of functional characteristics remains obscure .
a significant confounding factor is the marked variability both in the definition of a minicolumn and in the diagnostic markers for identifying a minicolumn ( see for review , jones , 2000 ; defelipe et al . , 2002 ; rockland and ichinohe , 2004 ) . within a minicolumn
, cell columns are easily visualized by conventional nissl staining .
dendritic bundles were first discovered with golgi methods , but are more easily seen with microtubule - associated protein 2 immunohistochemistry .
myelinated axon bundles can be seen by tau immunohistochemistry or myelin staining .
axon bundles of double bouquet cell can be seen by calbindin immunohistochemistry .
the spatial interrelationship among these morphological elements is more complex than expected and is neither clear nor unanimously agreed upon . in this review ,
i would like to focus first on the minicolumnar structure found in layers 1 and 2 of the rat granular retrosplenial cortex .
this modular structure was first discovered as a combination of prominent apical dendritic bundles from layer 2 pyramidal neurons and spatially matched thalamocortical patchy inputs ( wyss et al . ,
1990 ) .
further examination showed more intricate components of this modular structure , which will be reviewed in this paper .
second , the postnatal development of this structure and potential molecular players for its formation will be reviewed .
thirdly , i will discuss how this modular organization is transformed in mutant rodents with a disorganized layer structure in the cerebral cortex ( i.e. , reeler mouse and shaking rat kawasaki ) .
lastly , the potential significance of this type of module will be discussed .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: lung , large intestine , and oral cavity carcinomas in males and breast carcinoma in females are the most frequent cause of cutaneous metastases .
nodular , inflammatory , telangiectatic , and bullous are various forms of clinical presentations of skin metastasis .
nodular cutaneous metastasis is most commonly caused by lymphatic dissemination . in a review of 4,020 patients with metastatic squamous cell carcinoma ( scc ) , cutaneous lesions occurred in 10.4% .
the morphology of these metastases includes nodules , ulcers , inflammatory areas , sclerotic areas , bullae , and vesicles .
a 65-year - old male smoker patient diagnosed to have scc of larynx in year 2002 presented with complaints of change in voice , significant weight loss , difficulty in swallowing , reduced appetite , and gradual progressive random appearance of nodular cutaneous lesions .
laryngoscopy in 2002 revealed a 1.5-cm mass arising from the undersurface of epiglottis on the left side .
the patient did not take any standard treatment and remained on self medication with homemade remedies .
this patient reported to our hospital when he developed progressive and generalized skin lesion over the body .
he had multiple nodular lesions of varying sizes over trunk , chest , back , face , scalp , and extremities ; some of these lesions were erythematosus and crusted [ figure 1a and b ] .
indirect laryngoscopy was done , which revealed a proliferative growth on the laryngeal surface of epiglottis .
18f - fluorodeoxyglucose positron emission tomography computed tomography ( fdg pet / ct ) was done that showed an irregular soft tissue thickening in the epiglottis , multiple fdg avid cutaneous deposits of varying sizes involving all extremities , trunk , neck , scalp , and face , multiple fdg avid pleural - based nodules fdg avid abdominal lymph nodes , and a solitary skeletal lesion in left scapula [ figures 2 and 3 ] .
a representative lesion was excised and histopathology as well as immunohistochemistry confirmed the deposits of poorly differentiated carcinoma consistent with metastasis in a known case of carcinoma of larynx .
( a ) random distribution of nodular lesion and some erythematous lesion with crusting in the head , trunk , back , and upper as well as lower extremities ( b ) random distribution of nodular lesion of varying sizes in the head , trunk , back and upper as well as lower extremities .
all these lesions were non tender and did not bleed on touch f-18 fdg pet / ct coronal section mip image ( a ) showing random distribution of metabolically active cutaneous lesion all over the body ( b ) sagittal section showing fdg avid lesion in the laryngeal side of epiglottis f-18 fdg pet / ct images ( a ) axial section in lung window showing a subpleural nodular deposit on the left side ( b ) axial section showing fdg avid subcutaneous deposits and fdg avid abdominal lymph node , and ( c ) axial section showing fdg avid lesion involving the epiglottis
there is a wide variety of morphological spectrum for the clinical presentation of cutaneous metastases .
scc is responsible for 95% of carcinoma of the larynx in adults and is the most common tumor in upper respiratory tract .
this tumor originates from glottis ( 59% ) , supraglottis ( 40% ) , or infraglottis ( 1% ) and generally spreads to regional lymph nodes or through blood to the pulmonary system .
the most common sites for scc of head and neck are lung ( 70 - 75% ) , liver ( 17 - 38% ) , and bone ( 23 - 44% ) .
skin metastasis has been reported to occur in 1 - 2% and is solitary or multiple .
cancers arising in the oral cavity are the commonest head and neck cancers metastasizing to skin .
other malignancies associated with skin metastases include carcinoma of bronchus , breast , colon , and kidney .
the site of skin metastases include neck , chest , scalp , face , lips , axilla , areola , back , arms , and digits , with the most common being the neck and chest .
the skin metastases may evolve through three possible mechanisms , direct spread via tissue planes , local spread through dermal lymphatic 's , and distant spread as a result of hematogenous spread .
cutaneous metastases from laryngeal carcinoma may present as non - tender firm nodules , as sclerodermoid lesions , or may mimic an inflammatory process .
the diagnosis should be confirmed by cytology or histopathological examination of the lesions , and , in this case , it was confirmed with a positive cytology report .
krunic et al . , reported a case of laryngeal scc with infradiaphragmatic metastasis that is a very rare presentation .
multiple skin metastatic tumors was reported by bhandarkar such skin metastatic tumor has a poor prognosis and he observed that such skin metaststatic tumors have a poor prognosis .
veraldi reported a case with metastatic laryngeal tumor in the form of localized nodules in frontal area and arm in a patient with laryngeal tumor .
bottoni reported a patient with metastatic laryngeal carcinoma in the form of infiltrate erythema in supra and infra clavicular regions after 4 years of primary surgical treatment .
as cutaneous metastases in cases of carcinoma larynx can be solitary or multiple , therefore fdg pet ct has an added benefit in knowing the extent of disease as well as sites of metastases .
skin metastasis from laryngeal cancer is rare and may alter disease staging , management , and hence prognosis .
fdg pet / ct imaging has been widely used in the staging and management of the patients of head and neck cancers .
fdg pet / ct has an added benefit of being a potential modality for diagnosing advanced disease by providing whole - body cancer involvement information ( i.e. , n and m staging ) that might not be clinically apparent as was in the above mentioned case .
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### Summary:
: distant metastases in squamous cell carcinoma of the larynx have an incidence of 6.5 - 7.2% and most commonly involves the lungs , liver , and bone .
metastases to the skin are very rare , but , when present , they are usually considered a poor prognostic sign .
this most often affect the supradiaphragmatic area , i.e. , the head , neck , thorax , or upper extremities .
we have reported 18f - fluorodeoxyglucose positron emission tomography computed tomography ( fdg pet / ct ) scan of a patient with squamous cell carcinoma of the larynx showing multiple subcutaneous nodules all over the body , which was helpful in the assessment as well as staging of the disease .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the incidence of chiari i malformation ( cm - i ) by neuroimaging techniques range from 0.1 to 1% with the average age of presentation between 25 and 40 years .
these patients manifest with headache , neck pain , progressive scoliosis and cerebellar dysfunction due to cervico - medullary compression .
we describe the presentation of a patient with occult cm - i in an undiagnosed obstructive sleep apnea ( osa ) patient who had hypercapnic respiratory failure in the post - anaesthetic care unit necessitating endotracheal intubation and unanticipated intensive care unit ( icu ) admission after an uneventful elective knee surgery under subarachnoid block .
a 60 year old asa iii female patient ( bmi : 40 kg / sq .
she was evaluated for syncope while coughing 3 months back but her holter monitoring and bilateral carotid doppler studies were negative .
moderate concentric left ventricular hypertrophy with inferior wall motion abnormality with ejection fraction of 56% was documented by transthoracic echocardiogram .
anaesthetic concerns were discussed and patient was consented for regional anaesthesia , subarachnoid block ( sab ) along with left femoral nerve block . in the operating room , baseline monitors ( pulsoximetry , non - invasive blood pressure and electrocardiogram ) were established . to avoid anxiety , 2 mg of i.v
sab was performed with 12.5 mg of bupivacaine and 100 mcg of morphine using 27 g atraumatic spinal needle .
she had an adequate surgical block with the sensory blockade to the level of t10 dermatome level .
no further sedatives were given since she was drowsy with the initial dose of midazolam .
the rest of the intraoperative period was unremarkable and transferred to post - anaesthetic care unit ( pacu ) subsequently . in the pacu , she continued to be very drowsy , with worsening upper airway obstruction .
arterial blood gas analysis done 2 hours later showed hypercapnic respiratory failure with ph of 7.28 , paco2 65 mmhg and pao2 84 mmhg .
patient 's trachea was intubated and lungs were ventilated in view of gradual deterioration of consciousness , airway protection and to facilitate ventilatory support .
oxygenation and ventilation were maintained easily after intubation ( ph 7.34 , paco2 38 mmhg , pao2 148 mmhg , inspired o2 40% and peep 5 cm h2o ) .
ophthalmologist , neurologist and otolaryngologist consultations were done and magnetic resonance imaging ( mri ) of the brain was done .
mri brain showed cm - i with 17 mm cerebellar tonsillar herniation below the foramen magnum compressing lower medulla without hydrocephalus [ figure 1 ] .
the sleep study performed 2 months later was consistent with moderate - severe osa and continuous positive airway pressure ( cpap ) therapy was instituted .
cm - i is a congenital anomaly seen in adult population and associated with craniocervical abnormalities .
these patients with cm - i are more likely to manifest their symptoms when the cerebellar tonsillar herniation is greater than 5 mm and are invariably symptomatic when it is more than 12 mm .
dysphagia , blurred vision and syncope was described in 15.7% , 17% and 3.3% symptomatic cm - i patients , respectively . however , our patient had preoperative syncope , mild dysphagia without major neurological or cardiorespiratory symptoms despite occult cerebellar tonsillar herniation of 17 mm below foramen magnum . our patient developed delayed postoperative symptoms probably due to slow leak of csf through puncture site with the compression of vagus nerve and subsequent changes in cranio - caudal csf flow dynamics .
in a retrospective review involving 109 osa patients receiving 100 - 300 mcg of intrathecal morphine for total joint arthroplasty experienced more transient desaturations , defined as sao2 < 92% ( 11.2% vs 2.9% ,
patients with cm - i have decreased ventilatory response to carbon dioxide and insensitivity to hypoxia .
it is precipitated by the administration of benzodiazepines which further decrease the arousal response to hypoxia and hypercarbia and increase the duration of apnoea in osa patients .
firstly , the local edema compressing medulla on the clivus or to the vasospasm causing brainstem ischemia due to slow seepage of csf through puncture site .
secondly , the administration of i.v midazolam and intrathecal morphine with underlying osa would have further precipitated her respiratory depression .
there are no consensus guidelines on the anesthetic management of patients with cm - i .
acute deterioration of occult cm - i has been described in parturients . on the contrary ,
the safe use of general anaesthesia ( ga ) and spinal anesthesia has been documented with known cm - i in parturients .
uneventful spinal anaesthesia with narcotics added to local anaesthetic has been described in a known cm - i parturient for cesarean delivery .
there is limited data on the use of neuraxial techniques in patients with surgically corrected chiari malformation .
though successful spinal anaesthesia for caesarean delivery in a woman with a surgically corrected cm - i has been described but the authors did advise a word of caution . in a recent systematic review on the effect of sedatives and anaesthetics in osa patients , the authors emphasized temporary oxygen desaturation intraoperatively with the use of midazolam and fentanyl and those patients were retrospectively diagnosed with osa .
use of screening questionnaire for the diagnosis of osa as well as a thorough neurological evaluation including mri scan would have diagnosed osa and cm - i , respectively .
if diagnosed early , anaesthetic techniques in the management of this patient could have included graded epidural anaesthesia or general anaesthesia with awake fibreoptic intubation and controlled ventilation .
patients with occult chiari malformation are at considerable risk of respiratory depression and bulbar dysfunction in the perioperative period with underlying osa .
a thorough literature search did not reveal any such other reported case of occult chiari i malformation which was diagnosed postoperatively after uneventful knee surgery performed under spinal anaesthesia .
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### Summary:
: chiari i malformation ( cm - i ) manifests with tonsillar herniation below foramen magnum .
these patients are at high risk of respiratory depression and bulbar dysfunction in the perioperative period with underlying obstructive sleep apnea .
however , the safe use of both general and regional anaesthesia has been documented in a known cm - i parturients .
we describe the successful management of a patient who had hypercapnic respiratory failure in the post - anaesthetic care unit following an uneventful subarachnoid block for left knee replacement surgery .
this patient was retrospectively diagnosed with occult cm - i and moderate to severe obstructive sleep apnea in the postoperative period .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the study protocol received institutional review board ( irb ) approval from liberty irb , inc .
the study complied with the american psychological association ethical standards in the treatment of participants and in obtaining informed consent .
all parents signed a consent and a health insurance portability and accountability act form and all received a copy .
children with a diagnosis of autism , asd , and pervasive developmental disorder - not otherwise specified ( pdd - nos ) were prospectively recruited from the community . after explaining the study and obtaining informed consent from the parent(s ) , each child was evaluated by a trained professional using the cars and then the parents completed the atec . neither the professional nor the parent was aware of the scores generated from their respective completed tests
. statistical analysis was then conducted to examine the relationship between the cars and the atec .
a total of 56 participants diagnosed with an asd were prospectively recruited from the community by using fliers and word of mouth .
each child in the asd group had been previously diagnosed by a professional . in the state of texas , the only professionals who are allowed to diagnose asd are either licensed clinical psychologists or medical doctors . to further evaluate each child 's diagnostic accuracy ,
the study was designed to exclude children with fragile x disorder , tuberous sclerosis , phenylketonuria , lesch - nyhan syndrome , seizure disorder , cerebral palsy , fetal alcohol syndrome , or any history of maternal illicit drug use .
detailed information was collected on each participant regarding age , race , gender , and year of birth .
the children who participated in the study were 2 to 16 years of age ( m = 6.5 , sd = 3 ) with a diagnosis of either autism ( n = 34 ) or asd ( n = 22 ) .
there were 49 males and 7 females , and regression was reported in 36 ( 64% ) of the children .
the children were caucasian ( n = 41 ) or of hispanic , black , asian , or mixed ancestry ( n = 15 ) . table 1 summarizes the scores from the atec and the cars .
autistic disorder characteristics ( n = 56 ) cars = childhood autism rating scale ; atec = autism treatment evaluation checklist .
study participants were evaluated using a cars conducted only by a single study investigator ( jkk ) who observed the participants and interviewed the parent(s ) .
the investigator who completed the cars has been formally trained in the administration of the cars .
the cars is suitable for use with any child over 2 years of age and studies show that it is a reliable and stable indicator of autism in adolescents ( garfin , mccallon & cox , 1988 ) .
the cars is a 15-item behavioral rating scale developed to identify autism as well as to quantitatively describe the severity of the disorder ( schopler et al . , 1994 ) .
taste , smell , and touch response and use ; x. fear or nervousness ; xi . verbal communication ; xii .
each item is scored from 1 ( no pathology ) to 4 ( severe pathology ) in 0.5 intervals .
a total score of 1529.5 is considered nonautistic ; a score of 3036.5 is considered mild to moderate autism ; a score of 3760 is considered moderate to severe autism ( these are based on raw scores ) .
these cutoff scores were determined in a study of 537 children enrolled in the treatment and education of autistic and related communication handicapped children ( teacch ) program over a 10-year period ( schopler , reichler , devellis , & daly , 1980 ) .
the internal consistency reliability alpha coefficient is .94 , the interrater reliability correlation coefficient is .71 , and the test - retest correlation coefficient is .88 ( schopler et al . , 1994 ) .
cars scores have high criterion - related validity when compared to clinical ratings during the same diagnostic sessions , with a correlation of .84 ( p < .001 ; schopler et al . , 1994 ) . as with the cutoff scores ,
these psychometrics were determined in a study of 537 children enrolled in the teacch program over a 10-year period by schopler et al .
other comparisons , based on information from records , parent interviews , and nonstructured clinical interviews with the child , report a correlation coefficient of .80 ( p < .001 ) .
eaves and milner ( 1993 ) found that it correctly identified 98% of participants with autism and correlated ( r = .67 ) with the autism behavior checklist ( krug et al .
in a similar study by sevin , matson , coe , fee , and sevin ( 1991 ) , 92% of participants were correctly classified , and the cars correlated with the real life rating scale ( freeman , ritvo , yokota , & ritvo , 1986 ) .
pereira , riesgo , and wagner ( 2008 ) found that the convergent validity , in comparison with the autistic traits assessment scale ( ballabriga , escude , & llaberia , 1994 ) , exhibited a pearson 's correlation coefficient of r = .89 .
perry , condillac , freeman , dunn - geier , and belair ( 2005 ) , for example , studied a sample of 274 preschool children ( ages 26 years ) clinically diagnosed as falling in one of five groups
autistic disorder , pdd - nos , mental retardation ( mr ) , delayed , and other and found that the cars had a high concordance with clinical diagnosis using dsm - iv ( including excellent sensitivity and specificity ) .
similarly , rellini , tortolani , trillo , carbone , & montecchi ( 2004 ) found complete agreement between the dsm - iv and cars .
they also found that the number of false negatives in distinguishing individuals with autistic disorders from other cases of developmental disorders was 0% with cars .
the cars was shown to have good sensitivity and specificity in distinguishing children with autism from trainable children with mental retardation ( teal & wiebe , 1986 ) , distinguishing autistic disorder from pdd - nos , and distinguishing asd from other developmental disorders and typical development ( chlebowski , green , barton , & fein , 2010 ) .
, the participant 's parent completed an atec form ( rimland & edelson , 1999 ) . the atec is a one - page form designed to be completed by parents , teachers , or others who see the individual 's behavior on a regular basis ( rimland & edelson , 1999 ) .
the atec consists of four subtest scales : scale i. speech / language / communication ( 14 items scores can range from 0 to 28 ) , scale ii .
sociability ( 20 items scores can range from 0 to 40 ) , scale iii .
sensory / cognitive awareness ( 18 items scores can range from 0 to 36 ) , and scale iv .
health / physical behavior ( 25 items scores can range from 0 to 75 ) .
the four subscale scores can be used to calculate a total score ( total scores can range from 0 to 180 ) .
the higher the subscale and total score , the more impaired the participant . the lower the subscale and total score , the less impaired the participant . the overall scores in each subscale and the total score can be extrapolated to determine the percentile of severity of the participant in comparison with score distributions provided by the autism research institute .
the atec form was developed by the autism research institute ( rimland & edelson , 1999 ) .
pearson split - half ( internal consistency ) coefficients provided by the autism research institute based upon evaluation of 1,358 participants revealed uncorrected r values as follows : scale i. speech / language / communication ( r = .92 ) , scale ii .
sociability ( r = .84 ) , scale iii . sensory / cognitive awareness ( r = .88 ) , scale iv .
health / physical behavior ( r = .82 ) , and total score ( r = .94 ) . the uncorrected correlation coefficients represent a simple correlation without correcting for other factors between the variables .
the internal consistency reliability of the measure is high ( r = .94 for the total score ) .
the atec has been successfully used to measure treatment effects and progress over time in several studies in asd ( jarusiewicz , 2002 ; lonsdale , shamberger , & audhya , 2002 ; magiati , moss , yates , charman , & howlin , 2011 ) . moreover
, the atec has been found to correlate with physical symptoms ( adams , johansen , powell , quig , & rubin , 2011 ) and biomarkers in asd ( kern , geier , adams , & geier , 2010 ) .
however , the atec is not nationally normed and the reliability and validity evidence is limited .
this study used the statistical package sas jmp 9 . the nonparametric spearman 's rank correlation test statistic ( )
receiver operating characteristic ( roc ) was used through logistic regression to determine the optimal cutoff point for atec total and each domain and also to evaluate the sensitivity , specificity and accuracy between the cars and atec .
the roc curve is a graphical representation of the relationship between 1 specificity ( false - positive ) and sensitivity ( true - positive rates ) .
a standard way to evaluate the relationship is with the area under the curve ( auc ) , shown below the plot . in the plot ,
this marks a good cutoff point under the assumption that false negatives and false positives have similar costs .
sensitivity is defined as the proportion of participants rated severe by the cars and the atec to the number of participants rated severe by cars .
similarly , specificity is defined as the proportion of participants rated mild - moderate by the cars and the atec to the number of participants rated mild - moderate by cars .
children with a diagnosis of autism , asd , and pervasive developmental disorder - not otherwise specified ( pdd - nos ) were prospectively recruited from the community . after explaining the study and obtaining informed consent from the parent(s ) , each child was evaluated by a trained professional using the cars and then the parents completed the atec .
neither the professional nor the parent was aware of the scores generated from their respective completed tests . statistical analysis was then conducted to examine the relationship between the cars and the atec .
a total of 56 participants diagnosed with an asd were prospectively recruited from the community by using fliers and word of mouth .
each child in the asd group had been previously diagnosed by a professional . in the state of texas ,
the only professionals who are allowed to diagnose asd are either licensed clinical psychologists or medical doctors . to further evaluate each child 's diagnostic accuracy ,
the study was designed to exclude children with fragile x disorder , tuberous sclerosis , phenylketonuria , lesch - nyhan syndrome , seizure disorder , cerebral palsy , fetal alcohol syndrome , or any history of maternal illicit drug use .
detailed information was collected on each participant regarding age , race , gender , and year of birth .
the children who participated in the study were 2 to 16 years of age ( m = 6.5 , sd = 3 ) with a diagnosis of either autism ( n = 34 ) or asd ( n = 22 ) .
there were 49 males and 7 females , and regression was reported in 36 ( 64% ) of the children .
the children were caucasian ( n = 41 ) or of hispanic , black , asian , or mixed ancestry ( n = 15 ) . table 1 summarizes the scores from the atec and the cars .
autistic disorder characteristics ( n = 56 ) cars = childhood autism rating scale ; atec = autism treatment evaluation checklist .
study participants were evaluated using a cars conducted only by a single study investigator ( jkk ) who observed the participants and interviewed the parent(s ) .
the investigator who completed the cars has been formally trained in the administration of the cars .
the cars is suitable for use with any child over 2 years of age and studies show that it is a reliable and stable indicator of autism in adolescents ( garfin , mccallon & cox , 1988 ) .
the cars is a 15-item behavioral rating scale developed to identify autism as well as to quantitatively describe the severity of the disorder ( schopler et al . , 1994 ) .
taste , smell , and touch response and use ; x. fear or nervousness ; xi . verbal communication ; xii .
each item is scored from 1 ( no pathology ) to 4 ( severe pathology ) in 0.5 intervals .
a total score of 1529.5 is considered nonautistic ; a score of 3036.5 is considered mild to moderate autism ; a score of 3760 is considered moderate to severe autism ( these are based on raw scores ) .
these cutoff scores were determined in a study of 537 children enrolled in the treatment and education of autistic and related communication handicapped children ( teacch ) program over a 10-year period ( schopler , reichler , devellis , & daly , 1980 ) .
the internal consistency reliability alpha coefficient is .94 , the interrater reliability correlation coefficient is .71 , and the test - retest correlation coefficient is .88 ( schopler et al . , 1994 ) .
cars scores have high criterion - related validity when compared to clinical ratings during the same diagnostic sessions , with a correlation of .84 ( p < .001 ; schopler et al . , 1994 ) . as with the cutoff scores ,
these psychometrics were determined in a study of 537 children enrolled in the teacch program over a 10-year period by schopler et al .
other comparisons , based on information from records , parent interviews , and nonstructured clinical interviews with the child , report a correlation coefficient of .80 ( p < .001 ) .
eaves and milner ( 1993 ) found that it correctly identified 98% of participants with autism and correlated ( r = .67 ) with the autism behavior checklist ( krug et al . , 1980 ) . in a similar study by sevin , matson , coe , fee , and sevin ( 1991 ) ,
92% of participants were correctly classified , and the cars correlated with the real life rating scale ( freeman , ritvo , yokota , & ritvo , 1986 ) .
pereira , riesgo , and wagner ( 2008 ) found that the convergent validity , in comparison with the autistic traits assessment scale ( ballabriga , escude , & llaberia , 1994 ) , exhibited a pearson 's correlation coefficient of r = .89 .
perry , condillac , freeman , dunn - geier , and belair ( 2005 ) , for example , studied a sample of 274 preschool children ( ages 26 years ) clinically diagnosed as falling in one of five groups
autistic disorder , pdd - nos , mental retardation ( mr ) , delayed , and other and found that the cars had a high concordance with clinical diagnosis using dsm - iv ( including excellent sensitivity and specificity ) .
similarly , rellini , tortolani , trillo , carbone , & montecchi ( 2004 ) found complete agreement between the dsm - iv and cars .
they also found that the number of false negatives in distinguishing individuals with autistic disorders from other cases of developmental disorders was 0% with cars .
the cars was shown to have good sensitivity and specificity in distinguishing children with autism from trainable children with mental retardation ( teal & wiebe , 1986 ) , distinguishing autistic disorder from pdd - nos , and distinguishing asd from other developmental disorders and typical development ( chlebowski , green , barton , & fein , 2010 ) .
, the participant 's parent completed an atec form ( rimland & edelson , 1999 ) . the atec is a one - page form designed to be completed by parents , teachers , or others who see the individual 's behavior on a regular basis ( rimland & edelson , 1999 ) .
the atec consists of four subtest scales : scale i. speech / language / communication ( 14 items scores can range from 0 to 28 ) , scale ii .
sociability ( 20 items scores can range from 0 to 40 ) , scale iii . sensory / cognitive awareness ( 18 items scores can range from 0 to 36 ) , and scale iv .
health / physical behavior ( 25 items scores can range from 0 to 75 ) . the four subscale scores can be used to calculate a total score ( total scores can range from 0 to 180 ) .
the higher the subscale and total score , the more impaired the participant . the lower the subscale and total score , the less impaired the participant . the overall scores in each subscale and the total score can be extrapolated to determine the percentile of severity of the participant in comparison with score distributions provided by the autism research institute .
the atec form was developed by the autism research institute ( rimland & edelson , 1999 ) .
pearson split - half ( internal consistency ) coefficients provided by the autism research institute based upon evaluation of 1,358 participants revealed uncorrected r values as follows : scale i. speech / language / communication ( r = .92 ) , scale ii .
sociability ( r = .84 ) , scale iii . sensory / cognitive awareness ( r = .88 ) , scale iv .
health / physical behavior ( r = .82 ) , and total score ( r = .94 ) . the uncorrected correlation coefficients represent a simple correlation without correcting for other factors between the variables .
the internal consistency reliability of the measure is high ( r = .94 for the total score ) .
the atec has been successfully used to measure treatment effects and progress over time in several studies in asd ( jarusiewicz , 2002 ; lonsdale , shamberger , & audhya , 2002 ; magiati , moss , yates , charman , & howlin , 2011 ) .
moreover , the atec has been found to correlate with physical symptoms ( adams , johansen , powell , quig , & rubin , 2011 ) and biomarkers in asd ( kern , geier , adams , & geier , 2010 ) .
however , the atec is not nationally normed and the reliability and validity evidence is limited .
this study used the statistical package sas jmp 9 . the nonparametric spearman 's rank correlation test statistic ( )
receiver operating characteristic ( roc ) was used through logistic regression to determine the optimal cutoff point for atec total and each domain and also to evaluate the sensitivity , specificity and accuracy between the cars and atec .
the roc curve is a graphical representation of the relationship between 1 specificity ( false - positive ) and sensitivity ( true - positive rates ) .
a standard way to evaluate the relationship is with the area under the curve ( auc ) , shown below the plot . in the plot ,
this marks a good cutoff point under the assumption that false negatives and false positives have similar costs .
sensitivity is defined as the proportion of participants rated severe by the cars and the atec to the number of participants rated severe by cars .
similarly , specificity is defined as the proportion of participants rated mild - moderate by the cars and the atec to the number of participants rated mild - moderate by cars .
it was observed that there was a significant ( p < .0001 ) correlation between the total atec and cars scores ( = .71 , p < .0001 ) .
specific domains in the atec evaluation significantly correlated with cars scores as follows : sensory / cognitive awareness ( = .74 , p <
.0001 ) > speech / language / communication ( = .72 , p < .0001 ) > sociability ( = .55 , p <
.0001 ) > health / physical behavior ( = .31 , p < .01 ) .
these results suggest that the highest level of correlation between the cars and the atec was in the sensory / cognitive awareness domain , followed by the speech / language / communication domain , then the sociability domain .
spearman 's rank correlations between cars scores and atec domain scores ( n = 56 ) cars = childhood autism rating scale ; atec = autism treatment evaluation checklist .
table 3 presents the cutoff point , sensitivity , specificity , and accuracy between cars and total atec and each one of the four atec domains .
sensory / cognitive awareness is the best predictor of cars with cutoff point equal to 12 , which means that if the score is greater than 12 the child is considered severely affected , sensitivity equal to 1.00 , specificity is .67 , auc is .89 , and accuracy is .84 .
figure 1 shows the roc analysis of the relationship between sensitivity ( true - positive ) and 1 specificity ( false - positive ) .
autistic disorder : sensitivity , specificity , and accuracy between cars scores and atec domain scores ( n = 55 ) cars = childhood autism rating scale ; atec = autism treatment evaluation checklist .
one participant was rated nonautistic by cars ; this case was excluded from the sensitivity , specificity , receiver operating characteristic , and accuracy analysis .
the results of this study showed a significant association between professionally derived cars scores and parentally derived atec scores using spearman correlation and auc analysis .
it was further observed that there was significant association between specific domains from the atec evaluation and cars scores , supported with the two statistical methods . as mentioned in the introduction ,
many children with autism show in addition to the psychiatric diagnostic triad of ( a ) qualitative impairment in social interaction ; ( b ) qualitative impairments in communication ; and ( c ) restricted repetitive and stereotyped patterns of behavior , interests , and activities , other features that are more physical or systemic in nature .
although there are several measures available to be used in the evaluation of children and adults with asd , there is a paucity of measures that address these associated features of a more physical or systemic nature .
however , atec is unique in that it does address these issues , and this study begins the process of comparing the atec with more well - established asd measures .
as mentioned , the highest auc and correlation between the cars and the atec was in the sensory / cognitive awareness domain , followed by the speech / language / communication domain , then the sociability domain .
these results would be expected because , as mentioned earlier , the cars and most asd measures do not specifically address health and physical issues . because recent research suggests that many children with asd have more physical and health related issues ( schieve et al . ,
2011 ) , the atec has useful attributes to help us study and better understand the physical issues in asd , such as sleep problems , seizures , gastrointestinal issues , and so on .
other advantages of the atec include simple administration , easy to understand , and that it can be completed by a parent usually within 15 min and thus does not create an undue burden upon participants .
the atec , in addition to providing a quantitative overall score of severity , provides quantitative domain - specific scores , and atec scores can be translated to percentiles of severity . finally , the atec is not copyrighted and may be used free of charge by any parent , researcher , or health care provider .
copies are available on request from the autism research institute ( ari ) or the ari website ( http://www.autism.com/ind_atec_survey.asp ) .
the atec form can be instantly scored by entering the responses on the ari website . among the strengths of this study
was the fact that data was collected prospectively on a cohort of children diagnosed with an asd , and so unknown potential biases / confounding regarding noncontinuously collected cohorts of participants should have minimally impacted the present study .
raters of the atec of cars were unaware of the results of the other instrument . further , because a single professional undertook cars evaluations of study participants , subjective differences in scoring methods between different professionals were minimized , and this helped to significantly reduce potential unknown confounding in the data examined . also , cars and atec scores , despite being collected for study purposes , were collected in a similar fashion as would be expected to occur in a clinical setting where patients are examined , so that data collection methods should not be unique to the study methods employed but should yield similar results in a standard clinical setting where patients are examined .
another strength of this study was the demographics of the cohort of participants diagnosed with an asd examined in the study appear to be similar to the recognized demographics of the general population diagnosed with an asd , so that the results observed should be expected to be extendible beyond the cohort of participants diagnosed with an asd examined in this study .
in addition , because the participants diagnosed with an asd examined in this study were wide - ranging with respect to age , gender , racial composition , and severity , potential outlier skewing of the data should not have significantly impacted the results observed .
an additional strength of this study was the consistency and magnitude of the correlations observed between atec and cars scores and the limited number of statistical tests performed .
as a result , it is unlikely that the results observed in this study were the result of statistical chance . among the limitations of the study
is that participants examined were assumed to be on the autism spectrum based upon the fact that they were previously diagnosed with an asd and a subsequent professional cars evaluation .
it is possible that other tests such as autism diagnostic observation schedule ( lord et al . , 2000 )
further , other tests metrics may have revealed different potential relationships with the parent - completed atec evaluations examined in this study . despite this potential limitation ,
cars evaluations are a well - recognized metric of helping to establish an asd diagnosis , provide important quantitative measurements of asd severity , and yield significant correlations with parent - completed atec evaluations .
future studies should further explore the potential correlations between other metrics of asd symptoms with atec testing .
another potential limitation of this study was that participants were examined a single point in time using atec and cars evaluations .
it is not clear how the presently observed correlations between atec and cars evaluations would vary over the course of multiple examinations at multiple time points .
future studies should further the consistency of the correlation between atec and cars over multiple examinations at different times .
, the results of this study revealed a significant correlation between total atec and cars scores .
it was also observed that there were significant correlations between the atec domains and the cars total score .
the findings from the study validate the parent - completed atec in comparison with the cars , an established , professional - related measure of autism .
furthermore , integrating atec testing into health care practice in the quantitative evaluation of participants diagnosed with an asd would allow for the examination and quantification of the symptoms in asd that are more physical and health related in nature .
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### Summary:
: the purpose of this study was to evaluate scores generated from the autism treatment evaluation checklist ( atec ) , a parent - rated measure , and those derived from professionally completed childhood autism rating scale ( cars ) evaluations .
a cohort of 56 participants diagnosed with an autism spectrum disorder was used for the study , and each child was evaluated independently by the parent using the atec and a health care professional using the cars .
the spearman 's rank correlation statistic was used to evaluate the correlation between atec and cars scores .
it was observed that there was a significant correlation between total atec and cars scores ( = .71 ) .
specific domains in the atec evaluation significantly correlated with cars scores .
sensitivity , specificity , and receiver operating characteristic confirmed the association between cars and atec domains .
the results help to validate the utility of the parentally completed atec in comparison with an established , professional - related measure of autism .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: 62.4 million indians were reported to have type 2 diabetes mellitus ( t2 dm ) putting india on the forefront of diabetic epidemic across globe .
fear of hypoglycaemia and gain in body weight are barriers for initiation of insulin therapy .
modern insulin analogues are a convenient new approach or tool to glycaemic control , associated with low number of hypoglycaemia and favourable weight change .
a1chieve , a multinational , 24-week , non - interventional study , assessed the safety and effectiveness of insulin analogues in people with t2 dm ( n = 66,726 ) in routine clinical care .
please refer to editorial titled : the a1chieve study : mapping the ibn battuta trail .
the patient characteristics for the entire cohort divided as insulin - nave and insulin users is shown in the table 1 .
the majority of patients ( 72.4% ) started on or switched to biphasic insulin aspart .
other groups were insulin detemir ( n = 70 ) , insulin aspart ( n = 55 ) , basal insulin plus insulin aspart ( n = 19 ) and other insulin combinations ( n = 15 ) . overall demographic data after 24 weeks of treatment , overall hypoglycaemic events increased in both insulin nave ( from 0.0 events / patient - year to 0.7 events / patient - year ) and insulin user ( from 0.0 events / patient - year to 1.2 events / patient - year ) groups .
blood pressure decreased from baseline , while overall lipid profile improved at week 24 in the total cohort [ tables 2 and 3 ] .
mean hba1c and fpg values improved from baseline to study end in the total cohort [ table 4 ] .
overall efficacy data of the total cohort , 417 patients started on biphasic insulin aspart ogld , of which 332 ( 79.6% ) were insulin nave and 85 ( 20.4% ) were insulin users .
after 24 weeks of starting or switching to biphasic insulin aspart , hypoglycaemic events increased in both insulin nave ( from 0.0 events / patient - year to 0.8 events / patient - year ) and insulin user ( from 0.0 events / patient - year to 1.4 events / patient - year ) groups [ tables 5 and 6 ] .
biphasic insulin aspartoral glucose - lowering drug safety data mean hba1c and fpg values improved from baseline to study end in those who started on or were switched to biphasic insulin aspart for both insulin nave and insulin user groups [ table 7 ] .
biphasic insulin aspartoral glucose - lowering drug efficacy data of the total cohort , 19 patients started on basal + insulin aspart ogld , of which 11 ( 57.9% ) were insulin nave and 8 ( 42.1% ) were insulin users .
after 24 weeks of starting or switching to basal + insulin aspart , hypoglycaemia was nil , similar to baseline in both the groups [ tables 8 and 9 ] .
basal+insulin aspartoral glucose - lowering drug safety data mean hba1c and fpg values improved from baseline to study end in those who started on or were switched to basal + insulin aspart oglds for both insulin nave and insulin user groups [ table 10 ] .
basal+insulin aspartoral glucose - lowering drug efficacy data of the total cohort , 70 patients started on insulin detemir ogld was 70 , of which 60 ( 85.7% ) were insulin nave and 10 ( 14.3% ) were insulin users .
after 24 weeks of starting or switching to insulin detemir , hypoglycaemic events increased from 0.0 events / patient - year to 0.5 events / patient - year in insulin nave group while hypoglycaemia was nil in insulin users group , similar to baseline [ tables 11 and 12 ] .
insulin detemiroral glucose - lowering drug safety data mean hba1c and fpg values improved from baseline to study end in those who started on or were switched to insulin detemir oglds for both insulin - nave and insulin user groups [ table 13 ] .
insulin detemiroral glucose - lowering drug efficacy data of the total cohort , 55 patients started on insulin aspart ogld was 55 , of which 54 ( 98.1% ) were insulin nave and 1 ( 1.9% ) was insulin user .
after 24 weeks of starting or switching to insulin aspart , hypoglycaemic events increased from 0.0 events / patient - year to 0.3 events / patient - year in insulin nave group whereas hypoglycaemia was nil in insulin user , similar to baseline [ tables 14 and 15 ] .
insulin aspartoral glucose - lowering drug safety data mean hba1c and fpg values improved from baseline to study end in those who started on or were switched to insulin aspart oglds for insulin - nave group [ table 16 ] .
of the total cohort , 417 patients started on biphasic insulin aspart ogld , of which 332 ( 79.6% ) were insulin nave and 85 ( 20.4% ) were insulin users .
after 24 weeks of starting or switching to biphasic insulin aspart , hypoglycaemic events increased in both insulin nave ( from 0.0 events / patient - year to 0.8 events / patient - year ) and insulin user ( from 0.0 events / patient - year to 1.4 events / patient - year ) groups [ tables 5 and 6 ] .
biphasic insulin aspartoral glucose - lowering drug safety data mean hba1c and fpg values improved from baseline to study end in those who started on or were switched to biphasic insulin aspart for both insulin nave and insulin user groups [ table 7 ] .
of the total cohort , 19 patients started on basal + insulin aspart ogld , of which 11 ( 57.9% ) were insulin nave and 8 ( 42.1% ) were insulin users .
after 24 weeks of starting or switching to basal + insulin aspart , hypoglycaemia was nil , similar to baseline in both the groups [ tables 8 and 9 ] .
basal+insulin aspartoral glucose - lowering drug safety data mean hba1c and fpg values improved from baseline to study end in those who started on or were switched to basal + insulin aspart oglds for both insulin nave and insulin user groups [ table 10 ] .
of the total cohort , 70 patients started on insulin detemir ogld was 70 , of which 60 ( 85.7% ) were insulin nave and 10 ( 14.3% ) were insulin users .
after 24 weeks of starting or switching to insulin detemir , hypoglycaemic events increased from 0.0 events / patient - year to 0.5 events / patient - year in insulin nave group while hypoglycaemia was nil in insulin users group , similar to baseline [ tables 11 and 12 ] .
insulin detemiroral glucose - lowering drug safety data mean hba1c and fpg values improved from baseline to study end in those who started on or were switched to insulin detemir oglds for both insulin - nave and insulin user groups [ table 13 ] .
of the total cohort , 55 patients started on insulin aspart ogld was 55 , of which 54 ( 98.1% ) were insulin nave and 1 ( 1.9% ) was insulin user .
after 24 weeks of starting or switching to insulin aspart , hypoglycaemic events increased from 0.0 events / patient - year to 0.3 events / patient - year in insulin nave group whereas hypoglycaemia was nil in insulin user , similar to baseline [ tables 14 and 15 ] .
insulin aspartoral glucose - lowering drug safety data mean hba1c and fpg values improved from baseline to study end in those who started on or were switched to insulin aspart oglds for insulin - nave group [ table 16 ] .
our study reports improved glycaemic control ( hba1c , fpg ) following 24 weeks of treatment with any of the insulin analogues ( biphasic insulin aspart ; basal + insulin aspart ; insulin detemir ; insulin aspart ) with or without ogld . a small increase in body weight was observed for the total cohort .
though the findings are limited by number of patients , still the trend indicates that insulin analogues can be considered effective and possess a safe profile for treating type 2 diabetes in kolkata , india .
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### Summary:
: background : the a1chieve , a multicentric ( 28 countries ) , 24-week , non - interventional study evaluated the safety and effectiveness of insulin detemir , biphasic insulin aspart and insulin aspart in people with t2 dm ( n = 66,726 ) in routine clinical care across four continents.materials and methods : data was collected at baseline , at 12 weeks and at 24 weeks . this short communication presents the results for patients enrolled from kolkata , india.results:a total of 576 patients were enrolled in the study .
four different insulin analogue regimens were used in the study .
patients had started on or were switched to biphasic insulin aspart ( n = 417 ) , insulin detemir ( n = 70 ) , insulin aspart ( n = 55 ) , basal insulin plus insulin aspart ( n = 19 ) and other insulin combinations ( n = 15 ) . at baseline ,
glycaemic control was poor for both insulin nave ( mean hba1c : 8.3% ) and insulin user ( mean hba1c : 8.6% ) groups .
after 24 weeks of treatment , both the groups showed improvement in hba1c ( insulin nave : 1.3% , insulin users : 1.4% ) .
sadrs including major hypoglycaemic events or episodes did not occur in any of the study patients.conclusion:starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: dentin dysplasia ( dd ) is an extremely rare , autosomal - dominant condition , primarily characterized by defective dentin formation affecting both the deciduous and permanent dentitions .
dentinal dysplasia. depending on the parts of the teeth affected , witkop has broadly classified dd into two categories , type i radicular dentin dysplasia and type ii coronal dentin dysplasia , where type i dd is characterized by the presence of primary and permanent teeth with a normal appearance of the crown portions , but absent or rudimentary root development , incomplete or total obliteration of the pulp chamber , and periapical radiolucent areas or cysts .
type 1a showed absence of the pulp chamber and root formation and frequent periradicular radiolucencies ; type 1b exhibited a single , small , horizontally oriented , and crescent - shaped pulp with roots extending only a few millimeters in length , associated with frequent periapical radiolucencies ; in type 1c , two horizontal or vertical crescent - shaped pulpal remnants surrounding a central island of dentin are seen , with significant , but shortened root length , and variable periapical radiolucencies ; in type 1d , there is a visible pulp chamber and canal with near normal root length and large pulp stones that are located in the coronal portion of the canal , which create a localized bulging in the canal as well as root constriction of the pulp canal apical to the stone and few periapical radiolucencies .
the first type presented with total pulp chamber obliteration , no root development , and multiple periapical radiolucencies , the second and third types depicted less obliterated pulp chambers , crescent - shaped radiolucent areas , and minimal root formation , with less frequent periapical radiolucencies , and the fourth subtype presented radiographically visible and delimited chambers , with pulpal nodules found in the coronal third of the canal and the roots had significant development , but few or no radiolucencies .
this case report of type i dentin dysplasia highlights the radiographic findings that are unique and diverse from the classical findings of various subtypes of this disease reported to date .
the article also presents the implant - based oral rehabilitation of this young patient diagnosed with the variant model of dentin dysplasia type i.
a 17-year - old female patient reported to the department of periodontology and oral implantology with a chief complaint of severe mobility of her upper and lower front teeth .
she had started noticing the mobility since the past two years and it was noticed that the mobility had increased progressively over the years .
this was the first dental visit for the patient and the past medical and social histories were noncontributory .
there was no relevant familial history of the disease and hence the patient was considered to be a first generation sufferer .
the clinical intraoral examination revealed the presence of normal color and morphology of the crowns of all teeth .
stable gingival and periodontal health was confirmed by a thorough intraoral assessment , which demonstrated a clinical absence of gingival inflammatory changes , absence of bleeding on probing , as well as , loss of clinical attachment .
however , assessment of mobility revealed grade iii mobility of the upper and lower anterior teeth and all the four first premolars .
the patient demonstrated good oral hygiene and there were no other relevant intraoral findings noted .
an orthopantamogram of the patient revealed rudimentary and nearly absent root structures in relation to the upper and lower anterior teeth , the premolars , and molars [ figure 1 ] .
the intraoral periapical radiographs revealed a defective morphology with a strikingly flared , inverted , crescent - shaped appearance of the roots of the mandibular first molar teeth [ figure 2 ] .
there was a generalized total obliteration of the pulp tissues within the pulp chambers and root canals [ figures 13 ] .
based on the clinical and radiographic findings of the disease , the diagnosis was established as dentin dysplasia type i. however , the findings of this case did not fit into any subtypes of the existing classification systems of the disease .
the observations of an absence of familial hereditary pattern , the absence of periradicular radiolucent lesions and osseous pathologies , and the variant morphological defects of the molar roots were diverse from the classical findings of the various subtypes of dentin dysplasia type i reported to date . orthopantamogram revealing the pathological changes . note the generalized rudimentary or nearly absent root structures . also note the absence of periapical radiolucencies and osseous pathologies
intraoral periapical radiographs revealing the unusual morphology of the mandibular right and left first molar teeth .
note the strikingly flared , inverted , crescent - shaped appearance of the roots intraoral periapical radiographs revealing generalized complete obliteration of the pulp tissues within the pulp chambers and root canals of the teeth the treatment plan was formulated based on the age of the patient , the expected esthetic outcome , and the long - term prognosis of the therapy . the patient had completed the craniofacial growth phase and was highly concerned about the esthetic outcome of the treatment . as the patient was 17 years old at the time of the visit to the dental office , a major period of growth and growth spurts was completed .
hence , no further changes in the craniofacial structure that might cause gross future occlusal derangement were deemed to occur and no further growth investigations were carried out . taking all these multiple factors into consideration , an implant - based oral rehabilitation was finalized as the treatment for this patient .
the treatment plan was explained in detail to the patient and her family and a written informed consent was obtained from the patient as well as the guardian of the patient .
the surgical sites extending bilaterally between the first premolar regions in the maxilla and mandible were anesthetized using local administration of 2% lignocaine hydrochloride ( lox , neon laboratories ltd . , mumbai , india ) with 1 : 200,000 adrenaline . all the grade iii mobile teeth were extracted and the osteotomy site preparations were carried out under copious irrigation with sterile isotonic saline solution . after establishing proper depth and direction , a total of 10 self - threaded titanium implant fixtures , including six in the maxillary and four in the mandibular regions were placed [ figure 4 ] .
postoperative care included a prescription of 8 mg of betamethasone and 2 g/ day dosage of amoxicillin , for 10 days .
the patient was advised to rinse with warm saline solution for the first two weeks to promote flap healing without disturbing the surgical sites .
the patient was also instructed to use 0.12% chlorhexidine gluconate mouthwash ( peridex , zila pharmaceuticals , phoenix , az , usa ) , twice daily , to facilitate plaque control .
the surgical sites were checked every two weeks for a period of two months . following six months of healing , the second surgical procedure to uncover the implants
was performed , the abutments were placed , and the final prostheses were delivered [ figures 6 and 7 ] . the patient and family members expressed a positive response toward the superior esthetic and functional outcome of the treatment .
the patient has been put on a strict maintenance program with a first year recall interval of three months , followed by a review once in six months to one year , based on the home care performance and assessment of the intraoral health status .
implants placed in position in the maxillary and mandibular arches maxillary and mandibular temporary partial removable prostheses in position maxillary and mandibular occlusal view of the final fixed prostheses frontal view after placement of final fixed restorations in the maxilla and mandible
the surgical sites extending bilaterally between the first premolar regions in the maxilla and mandible were anesthetized using local administration of 2% lignocaine hydrochloride ( lox , neon laboratories ltd . , mumbai , india ) with 1 : 200,000 adrenaline .
all the grade iii mobile teeth were extracted and the osteotomy site preparations were carried out under copious irrigation with sterile isotonic saline solution . after establishing proper depth and direction , a total of 10 self - threaded titanium implant fixtures , including six in the maxillary and four in the mandibular regions were placed [ figure 4 ] .
postoperative care included a prescription of 8 mg of betamethasone and 2 g/ day dosage of amoxicillin , for 10 days .
the patient was advised to rinse with warm saline solution for the first two weeks to promote flap healing without disturbing the surgical sites .
the patient was also instructed to use 0.12% chlorhexidine gluconate mouthwash ( peridex , zila pharmaceuticals , phoenix , az , usa ) , twice daily , to facilitate plaque control .
the surgical sites were checked every two weeks for a period of two months . following six months of healing , the second surgical procedure to uncover the implants
was performed , the abutments were placed , and the final prostheses were delivered [ figures 6 and 7 ] .
the patient and family members expressed a positive response toward the superior esthetic and functional outcome of the treatment .
the patient has been put on a strict maintenance program with a first year recall interval of three months , followed by a review once in six months to one year , based on the home care performance and assessment of the intraoral health status .
implants placed in position in the maxillary and mandibular arches maxillary and mandibular temporary partial removable prostheses in position maxillary and mandibular occlusal view of the final fixed prostheses frontal view after placement of final fixed restorations in the maxilla and mandible
the etiopathogenesis of dentinal dysplasia remains unknown despite the numerous hypotheses put forward by different authors .
hypothesized that abnormal degeneration and calcification would occur in the dental papilla , resulting in reduced growth and final obliteration of the pulpal space .
it was also assumed that the occurrence of an earlier ingrowth of the radicular epithelial sheath resulted in ectopic dentin formation .
witkop proposed that the internal cells of the developing dental organ would be displaced and proliferate in the dental papilla producing ectopic dentin formation . according to wesley et al .
, a failure in the interactions between odontoblasts and ameloblasts would occur , causing differentiation and / or abnormal function of the odontoblasts .
however , to date , there is no consensus in the dental literature regarding the etiology of dd .
dd is an extremely rare autosomal - dominant hereditary disturbance , primarily characterized by defective dentin formation , affecting both the deciduous and permanent dentitions in approximately one in every 100,000 patients .
however , in the present case report , there are many variations from the typical features of type i dd .
first , the patient showed no signs of family heritage and these findings are in concurrence with three other reports .
also , in this patient , there was no report of formation of any painful , spontaneous abscesses or cysts , and a radiograph confirmed the absence of periapical radiolucencies , which was consistent with the findings of only one other recent case report .
an association was also noted between dentin dysplasia and osseous changes including sclerotic bone deposition in a case report , but the present case had no signs of any bone - related pathologies .
all these diversities in the radiographic presentation make this case report a unique one , challenging the already existing classification systems of type i dd .
type i dd is an extremely rare disease , yet of high concern to dental practitioners , due to the tooth loss affecting patients at an early age on account of unknown and unidentified etiological factors leading to severe esthetic and functional deficits .
implant - based oral rehabilitation provides a long - term esthetic and fixed replacement therapy for young patients diagnosed with this disease condition . to date
also , considering the rarity of this disease , we can safely conclude that case reports can serve as useful tools to elucidate and understand the different aspects of this condition .
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### Summary:
: dentin dysplasia is an exceptionally rare , autosomal - dominant , hereditary condition , primarily characterized by defective dentin formation affecting both the deciduous and permanent dentitions .
the etiology remains imprecise to date , in spite of the numerous hypotheses put forward and the constant updates on this condition .
this case report of type i dentin dysplasia exhibits radiographic findings that are unique and diverse from the classical findings of various subtypes of this disease reported to date . this article also depicts the implant - based oral rehabilitation of the young patient diagnosed with this variant model of dentin dysplasia type i. early diagnosis and implementation of this preventive and curative therapy is vital for avoiding premature exfoliation of deciduous and permanent dentition and the associated residual ridge resorption , thereby overcoming functional and esthetic deficits and ensuring protection of the remaining dentition from further harm .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: india is uniquely positioned with regard to schistosomes and schistosomiasis discovering seven new schistosome species , namely , schistosoma indicum , s. spindalis , s. bomfordi ( montgomery , 1906 ) , s. incognitum ( chandler,1926 ) , s. nasalis ( rao , 1933 ) , s. nairi ( mudaliar and ramanujachari , 1945 ) , and orientobilharzia dattai ( dutt and srivastava , 1955 ) .
additionally , prevalence of o. turkestanicum in srinagar has been confirmed by dutt and srivastava , while presence of o. harinasutai in buffaloes has been suspected long back .
this is the country where an endemic area may harbor as many as five schistosome species , leading to its own complexities .
in contrast to african schistosomes , the life cycle of these blood flukes involves snails inhabiting no big rivers but stagnant water bodies , that is , ponds , tanks , marshy land , agricultural fields , and so forth .
even with presence of nine schistosome species , existence of human schistosomiasis is marred with controversies despite confirming an endemic focus of urinary schistosomiasis ( probably by a new schistosome species ) in gimvi village of ratnagiri district , maharashtra [ 4 , 5 ] .
there are interesting differences in schistosomes and schistosomiasis of india with regards to conventional schistosomes and schistosomiasis . in this paper , we have attempted to discuss a few features which require attention of international scientific community for better understanding indian as well as global schistosomiasis .
schistosomiasis is considered only next to malaria among parasitic diseases of man . obviously , those schistosome species , namely , s. haematobium , s. mansoni , s. intercalatum , and s. japonicum , which cause clinical syndrome in man have attracted almost all the attention of the scientists as well as our scientific organizations , neglecting other schistosome species . in the beginning of twentieth century , india also attracted attention of the scientists on the subject as this was the period of new discoveries on the schistosomes and also because of reporting of several cases of human schistosomiasis from different parts of the country .
soon , it was realized that schistosomiasis can not establish on the indian soil as the known intermediaries of human schistosomes are not prevalent ; further , trials of infecting local snails with miracidia of s. haematobium or s. japonicum did not succeed .
notwithstanding the above facts , a confirmed endemic focus of urinary schistosomiasis was demonstrated in gimvi village of ratnagiri district , maharashtra state of the country . as the eggs were oval shaped and were present in the urine of the patients , the parasite was termed as schistosoma haematobium .
but no species of bulinus snail , the intermediate host of s. haematobium , is existing in indian continent ; hence a search for its local snail host was extensively made with experimental infection trials with the miracidia .
much later , a who team , in collaboration with government of india was able to eliminate the infection from gimvi village and now it is a dead infection . however , there are many questions which have remained unanswered in this case [ 5 , 7 ] .
the basic question is about the species of schistosome capable of infecting human beings in gimvi and also why we have considered it confined only to gimvi or adjacent villages .
the main objection of considering it as s. haematobium is that schistosome speciation is still a loose arrangement where egg morphology , snail species , and geographies are taken into consideration while deciding its species .
thus s. haematobium is the name given to the african schistosome whose snail host is a bulinus species .
therefore , it will be confusing to call the parasite as s. haematobium as neither it is utilizing bulinus species nor existing in known geographies . for this reason ,
we have suggested to call it a new schistosome species , that is , schistosoma gimvicum .
there is no reason to consider this blood - fluke to be confined only to gimvi village , as ferrissia tenuis snails , so widely prevalent in india , were not screened at other places of the country for furcocercous cercariae .
it may be emphasized that so far only gastropods have been incriminated as snail hosts of the schistosomes and no where ferrissia or its related cousin , except in gimvi village , has ever been incriminated as schistosomes ' intermediaries .
if ferrissia species is reconfirmed as snail host for any schistosome species from any part of the geography , it will lead to basic changes in our understanding in life cycle of the blood flukes .
we have no information if ever comprehensive surveillance of remote areas for urinary schistosomiasis has ever been made in india .
this no - reporting does not confirm absence of the infection at other places but may reflect lack of scientific interest in the subject .
even schistosome infections responsible for hepatic form have been reported from human beings from the country .
a confirmed infection of s. incognitum was reported from two human cases by chandler supporting the view of milton ( 1919 ) that a fourth human schistosome is existing in the country .
another support of hepatic infection came forward by reporting schistosome eggs in human stools in punjab state and also from a village of andhra pradesh .
but these reports failed to identify new endemic areas of human schistosomiasis , thereby failing to generate interest in the subject by any scientific agency .
the later work on the subject has also not ruled out the probability of occurring human schistosomiasis in india .
however , this work was not restricted to examining human stools or urine but was extended to search for cercarial dermatitis . as indian schistosomes
have not developed in line with river system but are using snails inhabiting stagnant waters , the search was made in human beings located near to the ponds and tanks and using them for their routine domestic work including recreational activities .
surprisingly , this surveillance resulted in finding cercarial dermatitis in high proportion in rural / tribal population of assam , chhattisgarh , madhya pradesh , and even in suburbs of jabalpur .
in considerable cases and particularly with avian schistosomes , the schistosomulae are destroyed in the skin of man itself . in other cases , at least some schistosomulae are able to traverse to lung or liver where they may be trapped . still , there is a parasite like s. japonicum which causes cercarial dermatitis but able to develop to maturity with laying of eggs in human beings .
it is difficult to predict the same with conformity but positivity of the cases by chr diagnostic test suggested presence of circulating antibodies hence presence of alive schistosomes in the body of the concerned person . additionally , five cases turned positive for presence of schistosome antigen in urine when it was tested by a single step diagnostic kit developed by the netherland laboratory .
nevertheless , the above bird - view confirms one fact that man is not suffering from schistosomiasis as widely or as acutely by any of the existing indian schistosomes as is happening with s. japonicum or s. mansoni or s. haematobium . what may be the reasons for this difference ?
we may get some clue from the hypothesis of combes who opined that man received schistosome infection by lateral rout and not ventrally .
the important argument put by him in support of this hypothesis is absence of any schistosome species in the primates thereby negating its descending to man through primates .
the schistosomes have developed either in the ungulates ( s. haematobium group ) or in the rodents ( s. mansoni group ) , and it is only in the later part of their evolution when man was incriminated as its host . in line , it may be argued that indian schistosomes have evolved from original clone and are not descendants of african schistosomes ( if we consider origin of s. indicum group from african clad of s. mansoni or s. haematobium , it is difficult to explain exclusion of humans in india as their ancestors , african schistosomes , had developed the ability to infect human beings , by that time ) , and man escaped from its fury mainly because human population was not concentrated to the infection sites . in developing host - parasite relationship , host immune system has played a great role and it might be possible that immune system of indians is more capable to fight the schistosomes than human beings of other continents .
no comparative studies of this type have been made to suggest differences in immunological system of various human populations .
nevertheless , this innate immune system does not appear a simple phenomenon as it does not hold identical for all the schistosome species existing in an endemic area .
the best example is of indian pigs which is resistant to all the schistosome species except s. incognitum which thrives well in this host system .
another example may be of sheep which develops three important schistosome species , that is , s. indicum , s. spindale , and s. incognitum .
even the former species has been responsible for out breaks with considerable mortality in the states like rajasthan , haryana , and southern states .
yet s. nasale is found to remain only in the liver of sheep , sheep were negative for s. nasale in endemic areas , or only 2 - 3% sheep were excreting the eggs in certain areas without any harm .
perhaps , immunological studies of these host species with regards to different schistosome species will be able to throw some light on how host 's immune system reacts to different schistosome species it encounters in nature .
india may prove a correct place to study the interplay among different schistosome species , occurring in same final or intermediate hosts .
here , we will like to cite an example of goats which harbor s. indicum , s. spindale , and s. incognitum at jabalpur , india .
along with monospecies infection , sympatric infections are also common ( this is so in all the ruminants ) ; heterologous infections with s. indicum and s. spindale or with s. spindale and s. incognitum are observed but with absence of sympatric infections of s. incognitum and s. indicum suggesting a strong heterologous immunity between the two .
in contrast to the general belief , the absolute number of schistosomes was always high in sympatric infections in comparison to the monospecies infections .
though s. spindale and s. incognitum were cohabiting in same goats in nature , our experiments revealed another facet of their survival . in one experiment , seven goat kids were infected simultaneously with equal number of cercariae ( 2000 each ) of s. spindale and s. incognitum following a new developed polythene - pinna method .
the faeces of goats were examined continuously for more than six months ; eggs of s. incognitum were first to appear and later joined with presence of s. spindale eggs .
however , when the goats were sacrificed at different time intervals , the number of s. incognitum flukes was just half to that of s. spindale a situation difficult to assess by egg concentration in the faeces .
it is also difficult to explain while female s. incognitum possesses only a single egg in its uterus whereas several eggs is the rule in female s. spindale , suggesting higher egg laying capacity of the latter .
then why excreting egg numbers of the two species were not differing markedly ? at the end of the experiment , when a goat died on 605 dpi , it yielded only male s. spindale worms ( n = 505 ) with total absence of any s. incognitum flukes .
this experiment clearly suggested that s. spindale was able to knock out all s. incognitum flukes from the goats although both parasites got entry in the host at same time , with same number of the cercariae hence with equal opportunity of survival .
heterologous mating among schistosome species is also not uncommon in the ruminants . we were able to identify mating of s. indicum female with male s. spindale and vice versa .
this heterologous mating could be recognized because of gross morphological differences of the two fluke species .
it is difficult to identify heterologous mating between tuberculated blood flukes ( s. indicum s. nasale s. incognitum ) or two atuberculated flukes ( s. spindale orientobilharzia dattai ) because of difficulty of differentiating the two species in alive condition .
the sequel of this heterologous mating has yet not been determined whether it is able to produce natural hybrids as has been confirmed in african countries .
for example , a seasonal variation in schistosomiasis cases ( as determined by faecal examination ) , when the blood flukes are known to survive more than 2 - 3 years .
a well - known phenomenon is change in prevalence rate of schistosome cercariae emerging from the snails as per season .
however , it is worth investigating if reduced number of positive snails in summer season is because of lower number of miracidia available in nature or infectivity of the snails is influenced as per season .
so far , studies on indian schistosomes and schistosomiasis have been made using conventional techniques .
but further studies on the subject require application of modern techniques like pcr , iso - enzyme , electron microscopy , recombinant techniques , otherwise there are all chances of the studies being remained inconclusive
. it will be rewarding if joint studies are made by indian scientists with international scientific communities and international laboratories working on schistosomiasis .
this joint international study is also important since asia witness existence of two types of schistosome species . on the one hand
, we are having indian schistosomes which are least pathogenic while on the other hand , there is s. japonicum which is most pathogenic with widest host rang , including human beings in its spectrum .
there is also a need to establish international laboratory in india which is uniquely positioned with regards to schistosomes and schistosomiasis .
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### Summary:
: india is uniquely positioned with regard to schistosomes and schistosomiasis discovering seven new mammalian species with the existence of three more schistosome species : orientobilharzia turkestanicum , o. harinasutai , and schistosoma haematobium ( ? ) .
an endemic focus of urinary schistosomiasis was reported from gimvi village of ratnagiri , maharashtra with infrequent occurrence of schistosome eggs in human stools .
cercarial dermatitis has been reported to be more abundant in rural population using ponds , tanks , and so forth , for their domestic purposes .
few dermatitis cases were tested positive by chr .
schistosome antigen was also detected in urine of five cases suggesting existence of active schistosomiasis in india .
nevertheless , human kind does not appear to be the usual host for indian schistosomes in contrast to s. haematobium , s. mansoni , or s. japonicum .
various reasons for this phenomenon are discussed including evolution of indian schistosomes , immune mechanisms , and environmental conditions .
these and other aspects such as seasonal effect on the prevalence , snail infectivity , heterologous mating , existence of hybrids , and number of schistosomes in heterologous infections need further investigations with application of molecular techniques .
joint efforts by the national as well as international scientific community would be much more rewarding for better understanding of the parasite and the infection .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: argy wormwood leaf , named ai - ye in chinese , is a traditional and widely - used chinese medicine .
this medicinal material , as shown in figure 1 , is produced in all parts of china , collected in summer before flowering , foreign matter removed , and dried in the sun or in the shade before use .
as its special medical effectiveness , many chinese people like bath with argy wormwood leaf water to relieve skin itching or expel cold .
in this paper , we report an accidental chemical burn affecting 7% of her total body surface area resulted from hot wormwood leaf water when bathing .
by pregnancy at 40 weeks , a 29-year - old woman delivered her baby under natural mode .
it is a traditional custom in china that a puerpera should have a steam bath 315 days after delivery .
sauna equipments are always expensive and unaffordable to most of chinese people and it is inconvenient for a puerpera to go to a public sauna bathroom in the street .
therefore , the puerperae always take steam bath by using a simple household device , as shown in figure 2 .
a bathtub is set inside a vapour hood and the boiled water is poured into it .
then , the woman sits on a stool above the bathtub for bath . due to the effect of haemostasis and cold - dispersion
, the argy wormwood leaf is always added into the water for boiling to produce steam .
after the boiled water was poured into the bathtub , people sat on a stool to undergo steam bath .
after the boiled water was poured into the bathtub , people sat on a stool to undergo steam bath .
the patient was victim of an accident that occurred at the bath on the 13 day after delivery .
however , the plastic stool became soft and weak when it met hot water and steam .
when sitting on the stool , she fell into the boiled water with argy wormwood leaf inside due to the negligence .
cleansing of the lesions and topical mebo ( moist exposed burn ointment ) application were carried out at a small community medical unit . after a period of 3 h , the patient was transferred to our burn centre . at admission
, there were superficial partial - thickness burned areas on both buttocks and left thigh ( figure 3 ) .
conservative treatment with jianshuneng ( a kind of chitosan ) was performed on the wounds . around the 14th day ,
epithelialization began when the patient was discharged and the process was almost complete on the 20 day .
superficial partial - thickness burn was found on both buttocks and left thigh .
at admission .
its stem and leaves have a unique scent and taste a little bitter . in chinese traditional medicine
besides topical use , the drug can be made into wool , put on the acupoints and ignited to treat arthralgia due to cold .
it can also be used to treat metrorrhagia , irregular menstruation , etc , which are of cold deficiency type in chinese medical science .
second , it has anti - infection effect and can relieve itch . according to the results of modern pharmacology , argy wormwood leaf has multiple anti - bacteria and anti - viral properties .
. therefore , many chinese puerperae are accustomed to taking steam bath with hot argy wormwood leaf water . to our knowledge , this is the first reported individual case of burn by hot argy wormwood leaf water . in our case ,
chemical analysis study showed that the main pharmacological ingredients of argy wormwood leaf were eupatilin , jaceosidin , 2-hydrobenzoie acid , octacoanic acid , linarin , and so on . due to its acid component
the hot argy wormwood leaf water , the cause of thermal injury in this case , was in weak acidity .
accordingly , this kind of burn wound was invariably deeper than first appearance and the healing process was slightly delayed . the wound healing was delayed .
until the 20 day postburn , the epithelialization process of superficial partial thickness burn was just complete . with the increasing use of this chinese traditional medicine ,
this case highlights potential thermal injury danger of the people underwent household steam bath with hot wormwood leaf water .
the following methods , we think , can bring down the incidence of this burn injury significantly .
first , also the most important , the plastic stool should be replaced by a wooden or metal one , which does not become soft and deform when meets heat .
second , people who undergo the simple household steam bath should take care not to overturn the bathtub .
third , another factor of some significance to lessen the incidence is to lower the temperature of bath water .
early , copious lavage is important to reduce the extent and depth of chemical burn wound .
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### Summary:
: an unusual burn case caused by hot wormwood leaf water was discussed .
a 29-year - old woman sustained a 7% second - degree burn on both buttocks and left thigh .
this case report highlights a rare cause of a chemical burn that may become more common with increasing use of this chinese traditional medicine .
the prevention measures of this burn injury were also presented .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: a 83-year - old woman was admitted to the emergency department for abdominal pain . at physical examination , she had fever and a hypogastric pain with tenderness and guarding .
a blood analysis showed 15,000 leukocytes / mm and elevated c - reactive protein ( 340 mg / l ) .
the abdominal computed tomography ( ct ) revealed a pelvic abscess ( figure 1 ) and discovered a solid tumour of the caudal pancreas with splenic vein thrombosis and segmental portal hypertension ( figure 2 ) .
a radiological drainage of the abscess was performed , as well as a biopsy of the pancreatic mass , revealing a pancreatic adenocarcinoma .
the clinical evolution was fair and a surgical management was decided both for the colon and the pancreas .
an abdominal ct - scan showed a pneumoperitoneum with diffuse fluid within the abdomen ( figure 3 ) .
an emergent laparotomy was performed , finding a perforated pseudotumoral sigmoid with diffuse fecal peritonitis and two nodules of carcinomatosis in the major omentum .
the pathological examination revealed a peritoneal metastasis from the pancreatic cancer involving the sigmoid and causing the perforation .
tissular tumor of the caudal pancreas ( long arrow ) with a splenic vein thrombosis and a segmental portal hypertension ( short arrow ) .
tissular tumor of the caudal pancreas ( long arrow ) with a splenic vein thrombosis and a segmental portal hypertension ( short arrow ) .
pancreatic adenocarcinoma is the third cause of non gynaecological carcinomatosis , after colonic and gastric cancer .
it may present as clinically evident ascitis , but it is more frequently discovered at preoperative imaging or during surgery .
bowel perforation is well known as a complication of colon cancer or colonic wall haematogenous metastases , by the growing of the tumour from the inside to the outside .
inversely , in this case the mechanism was the growing of the peritoneal nodule from the serosa through the colonic wall layer until the mucosa leading to perforation .
this is an atypical presentation of peritoneal carcinomatosis from pancreatic origin , revealing the neoplasm .
when the carcinomatosis is already known , physicians must keep in mind these complications for an early management despite a very bad prognosis .
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### Summary:
: we report the case of a patient with a pelvic abscess and a malignant pancreatic tumor .
the management of this complicated diverticulitis included radiological drainage and surgery .
this abscess was due to a peritoneal carcinomatosis originating from the pancreas , which is an extremely rare cause of intestinal perforation .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: dental bleaching carried out with an unstable chemical oxidant agent has been , for a long time , a conservative alternative to the recovery of vital aesthetic and chromatic aberrations in teeth with endodontic treatment .
however , all bleaching therapies known and practised today have several limitations and complications that can and must be recognised , so that they can be avoided
.
the definition of the aetiology and its diagnosis is important to establish an appropriate treatment plan , evaluating the absolute necessity of intervention or , on the other hand , its simple resolution with prophylactic procedures .
the technique of home external bleaching is extremely popular considering it is practical , simple , and of low cost
.
these characteristics have turned the technique easily marketable , being now available in free - sale kits for whitening treatments , which include whitening products and universal trays from pharmacies or over the internet
.
such free - sale kits for tooth whitening treatments may have a whitening product with two kinds of active ingredient , or hydrogen peroxide or carbamide peroxide , at different concentrations depending on the brand
.
changes in oral tissues can occur if an excessive amount of bleach is used , or if the set protocol is not carried out
.
the use of hydrogen peroxide generally involves a greater risk to soft tissues when compared to carbamide peroxide .
it is caustic and can cause chemical burns and gingival necrosis if the adequate protection of these tissues is not carried out
.
the bleaching treatments performed with over - the - counter ( otc ) products were due to the use of universal trays with poor adaptation to dental arches , which may increase the risk of gingival erosions and ulcers in the oral mucosa , especially when there is severe dental misalignment
.
the various bleaching techniques have different degrees of risk and side effects for patients depending on the techniques used and on the regularity of controls made by the dentist
.
there are also different concentrations of active ingredients used , particularly with higher hydrogen peroxide concentrations
.
the actual effect of these higher concentrations on oral , oesophageal , gastric , and intestinal mucosa has not been thoroughly studied yet . when performing this therapy , it is critical to have the clinical history of the patient , since the presence of any pathology of the digestive system may be considered a contraindication , representing an increase in the risk of worsening this condition regardless of the amount of product swallowed ( at the very least , it could aggravate the clinical condition of such patients )
.
this clinical situation has not been studied and is not referenced in studies of this therapy .
given this gap in the research of whitening products , it seemed important to start the testing in animals that have had gastrointestinal pathology induced . in this experimental work ,
6% of hydrogen peroxide was used , since this product is less studied than carbamide peroxide . in most studies ,
the hydrogen peroxide has side - effects , considering that , until recently , it was only used in clinical medical practice and , therefore , it was always manipulated by a dentist .
now with the existence of the new home formulae that can be used by patients , there is a higher risk of potential side effects in patients
.
this experimental study intended to observe the effects of a tooth whitening product , whose active agent is 6% hydrogen peroxide , on the gastric mucosa of healthy and with no gastric tumour pathology animals .
this experimental study was evaluated by an advisory committee for the protection of animals used for experimental and/or other scientific purposes , ( paragraph b of number 49 of the decree 1005/92 of 23 october ) , having been authorized for its realization .
similarly , authorization was also given by the general direction of veterinary services , direction of health defence services , welfare and animal food . during the experimental period ,
the animals were kept in standard laboratory conditions , according to the legislation in force ( decree 113/2013 of 7 august ) .
records of animal weight were made weekly and daily records of any visible behavioural change .
all animals were subjected to normal conditions of maintenance and nutrition , with an ambient temperature of 22c and cycles of 12 h/12 h light / dark .
all animals were housed in cages appropriate to their species ( 2 - 3 animals per cage ) . the diet consisted of a complete ration of granules , standard for laboratory rodents and acidified water ad libitum in a system subject to the same environmental conditions . for this study , we used 50 rats of the strain wistar - han of 8 weeks of age , with about 250 grams in weight . in week 1 , all animals were quarantined . in periods ii and iii , which took place in the 2 and 3 weeks
, the animals were subjected to different test protocols , and divided into 5 groups with 10 animals each .
the group i was the negative control , in which the animals were not manipulated , while the groups ii and v were the positive control groups in which the animals were subjected to the administration of a bleaching agent ( group ii ) and to an non - tumour gastric pathology induction protocol by administering a chemical compound ( group v ) .
these groups were divided into two subgroups to control all other test groups . in group
iii , which is the test group that expresses the goal of the study , the animals were subjected to a non - tumour gastric pathology induction protocol by administering a chemical compound in the 2 week and the administration of a bleaching agent in the 3 week . in the group
( q - quarantine , p - hydrogen peroxide administration ; g - non - tumoral gastric pathology induced )
for the induction of non - tumour gastric pathology , a single administration of 1ml / kg dose of 50% ethanol was performed by gavage ; after 6 more subsequent days it was performed with 5% ethanol in drinking water . as the bleaching agent was used in a commercial preparation of hydrogen peroxide 6% ( colgate oral colgate visible white- pharmaceuticals inc , new york , usa ) administered in a dose of 1 g / kg during for 7 days , by gavage . during the first 3 hours after the administration of the bleaching product ,
, the bleaching product doses were administered differently according to the weight of each animal , and were adjusted every 3 days , according to new animal weight . by the end of the 3 week
, all animals were euthanized . after confirming the absence of vital signs , all macroscopic changes in the external appearance of each animal
after dissection , each animal was observed in detail and an exhaustive study was made with the intention of identifying any macroscopic lesions in organs ( colour , consistency , inspection , and palpation ) .
the spleen was taken , weighed and measured in three dimensions ( length , height , and width ) .
samples were taken from the stomach and fixed in 10% of neutral buffered formaldehyde from 24 to 36 hours depending on the fragment s thickness .
after fixation , they were processed according to the guidance that had been programmed , leaving the mucosa plane perpendicular to the cutting plane .
the processing was carried out in the conventional manner , after dehydration in increasing concentrations of ethanol and subsequently embedded in paraffin .
the influence of time and treatment parameters in body and spleen weight at the time of the euthanasia were evaluated by analysis of variance ( anova ) and an student t test was conducted in the presence of significant differences in multiple comparisons of pairs of means .
statistical analysis was performed using the statistical software program jmp ( jmp version 7 , sas institute , inc .
, nc , usa ) . differences were considered significant at a probability of 95% ( p<0.05 ) .
the evolution of animal weights in percentage was analyzed using the t test for paired samples to a 0.05 significance level , and the significance of differences between groups was assessed by kruskal - wallis test .
gastric mucosa was examined macroscopically and each lesion was graded and scored based on its incidence and severity according to an arbitrary grading system .
the grade of severity was attributed differently in each parameter : hemorrhagic areas ( rated 0 to 5 ) ; loss of mucosal folds ( rated 0 to 5 ) ; necrotic areas / ulcers ( rated from 0 to 3 ) ; perforation ( 0 , 10 ) . the ulcer index ( ui ) for each stomach was the sum of scores of all lesions .
the ui for each experimental group was reported as median ( minimum - maximum ) .
the staining routine performed on each of the samples was the haematoxylin - eosin ( he ) .
the microscopic observation of these histological sections was performed by light microscopy by an independent observer .
this experimental study was evaluated by an advisory committee for the protection of animals used for experimental and/or other scientific purposes , ( paragraph b of number 49 of the decree 1005/92 of 23 october ) , having been authorized for its realization .
similarly , authorization was also given by the general direction of veterinary services , direction of health defence services , welfare and animal food . during the experimental period ,
the animals were kept in standard laboratory conditions , according to the legislation in force ( decree 113/2013 of 7 august ) .
records of animal weight were made weekly and daily records of any visible behavioural change .
all animals were subjected to normal conditions of maintenance and nutrition , with an ambient temperature of 22c and cycles of 12 h/12 h light / dark .
all animals were housed in cages appropriate to their species ( 2 - 3 animals per cage ) . the diet consisted of a complete ration of granules , standard for laboratory rodents and acidified water ad libitum in a system subject to the same environmental conditions .
for this study , we used 50 rats of the strain wistar - han of 8 weeks of age , with about 250 grams in weight . in week 1 , all animals were quarantined . in periods ii and iii , which took place in the 2 and 3 weeks
, the animals were subjected to different test protocols , and divided into 5 groups with 10 animals each .
the group i was the negative control , in which the animals were not manipulated , while the groups ii and v were the positive control groups in which the animals were subjected to the administration of a bleaching agent ( group ii ) and to an non - tumour gastric pathology induction protocol by administering a chemical compound ( group v ) .
these groups were divided into two subgroups to control all other test groups . in group iii , which is the test group that expresses the goal of the study
, the animals were subjected to a non - tumour gastric pathology induction protocol by administering a chemical compound in the 2 week and the administration of a bleaching agent in the 3 week . in the group
( q - quarantine , p - hydrogen peroxide administration ; g - non - tumoral gastric pathology induced )
for the induction of non - tumour gastric pathology , a single administration of 1ml / kg dose of 50% ethanol was performed by gavage ; after 6 more subsequent days it was performed with 5% ethanol in drinking water . as the bleaching agent was used in a commercial preparation of hydrogen peroxide 6% ( colgate oral colgate visible white- pharmaceuticals inc , new york , usa ) administered in a dose of 1 g / kg during for 7 days , by gavage . during the first 3 hours after the administration of the bleaching product ,
, the bleaching product doses were administered differently according to the weight of each animal , and were adjusted every 3 days , according to new animal weight .
by the end of the 3 week , all animals were euthanized . after confirming the absence of vital signs , all macroscopic changes in the external appearance of each animal
after dissection , each animal was observed in detail and an exhaustive study was made with the intention of identifying any macroscopic lesions in organs ( colour , consistency , inspection , and palpation ) .
the spleen was taken , weighed and measured in three dimensions ( length , height , and width ) .
samples were taken from the stomach and fixed in 10% of neutral buffered formaldehyde from 24 to 36 hours depending on the fragment s thickness .
after fixation , they were processed according to the guidance that had been programmed , leaving the mucosa plane perpendicular to the cutting plane .
the processing was carried out in the conventional manner , after dehydration in increasing concentrations of ethanol and subsequently embedded in paraffin .
the influence of time and treatment parameters in body and spleen weight at the time of the euthanasia were evaluated by analysis of variance ( anova ) and an student t test was conducted in the presence of significant differences in multiple comparisons of pairs of means .
statistical analysis was performed using the statistical software program jmp ( jmp version 7 , sas institute , inc .
the evolution of animal weights in percentage was analyzed using the t test for paired samples to a 0.05 significance level , and the significance of differences between groups was assessed by kruskal - wallis test .
gastric mucosa was examined macroscopically and each lesion was graded and scored based on its incidence and severity according to an arbitrary grading system .
the grade of severity was attributed differently in each parameter : hemorrhagic areas ( rated 0 to 5 ) ; loss of mucosal folds ( rated 0 to 5 ) ; necrotic areas / ulcers ( rated from 0 to 3 ) ; perforation ( 0 , 10 ) . the ulcer index ( ui ) for each stomach was the sum of scores of all lesions .
the ui for each experimental group was reported as median ( minimum - maximum ) .
the staining routine performed on each of the samples was the haematoxylin - eosin ( he ) .
the microscopic observation of these histological sections was performed by light microscopy by an independent observer .
during the study period , most animals showed a healthy appearance with motor activity and normal breathing .
however , few animals of all groups ( except control negative group ) presented occasionally respiratory symptoms , including wheezing , without specific patterning . hair loss and its rough appearance was also one of the characteristics common in some animals , once again without there being any specific standardization . during the study period , two animals died : one from the va group by the 9 day of experimental work , one day after 50% ethanol was administered ; and another from the iiib group by the day 18 , two days after starting the administration of hydrogen peroxide . in almost all groups there
was an increase in weight , by comparing the beginning and end of the experimental work .
table 1statistical results with mean valuesse of the animal weights of the various experimental groups over study time and paired mean comparison ( p < 0.0001 ) .
the letters a , b and c correspond to significant differences between the values of the same column between groups .
same letters mean no significant differences between values of the same columnstudy timegroupleast sq meanstd errorpaired mean comparison ( student s t ) p<0.0001day 7gr i351.45.46a gr ii - a298.47.72b gr ii - b285.87.72b gr iii287.25.75b gr iv288.55.46b gr v - a295.47.72b gr v - b296.58.63bday 10gr i353.855.54a gr ii - a313.07.84b c gr ii - b314.27.84b gr iii293.45.84c gr iv300.05.54b c gr v - a299.647.84b c gr v - b301.758.76b cday 15gr i365.45.97a gr ii - a322.08.44b gr ii - b319.88.44b gr iii296.776.29c gr iv306.45.97b c gr v - a311.08.44b c gr v - b313.289.44b cday 18gr i375.197.94a gr ii - a329.811.22b gr ii - b319.211.22b c gr iii304.08.37b c gr iv298.67.94c gr v - a327.3711.22b gr v - b297.9812.55b cday 22gr i381.368.49a gr ii - a337.4412.00b gr ii - b322.9612.00b c gr iii326.668.95b gr iv299.628.49c gr v - a342.8512.00b gr v - b310.0513.42b c
the negative control group had a constant weight increase in animals through the entire duration of the experimental work .
the evolution of the mean weight gains of all other groups are compared with this group , as show in figure 2 .
figure 2results of the analysis of variance of animal weight in all experimental groups over study time .
the results are presented as meanstandard error ( se ) for all conditions tested
the analysis of the figure shows group ii did not gained weight constantly .
the subgroup b , early in the 2 week of study , has gained weight faster than subgroup a. at the beginning of the 3 week , subgroup a described a curve similar to control group , while subgroup b remained with the same weight , only slightly increasing by the end of that week .
group iii had a very slight increase in weight during the entire study , a considerable difference in the control group , only revealing a significant increase in the last three days of the study . in group iv , the weight increase was moderate in the first two weeks , reversing the slope of increase in the 3 week of the study with weight loss . in group
v , the va subgroup had a constant weight increase , with a similar curve to the control group .
however , the vb group had a similar trend to group iv considering weight , showing slight signs of weight recovery in the last three days of the study .
the evolution of animal weights in percentage was showed in figure 3 , which compares the fraction of weight change from the beginning to the end of the study .
there are statistical significant differences between the groups : control , iii , va ( < 0.0001 ) , and iib ( < 0.05 ) , when compared with the group that have the lowest weight gain ( group iv ) .
figure 3results of the analysis of evolution of animal weights in percentage , which is the fraction of weight change from the beginning to the end of study .
the results are presented as meanstandard error ( se ) with a level of significance of ( * ) < 0.05 ; ( * * ) < 0.01 ; ( * * * ) < 0.001
the results of the spleen weight were compared with the weight of the respective animals in the different groups .
table 2 shows the statistical analysis for the percentage change of animal and spleen weight and the relationship between these two parameters for each group and subgroup . in table 2
, it can be seen that there are statistically significant differences , marked with different letters , between the experimental groups studied . between the control group and the manipulated groups ,
there are some significant differences , particularly with groups va , iib and iv . between manipulated groups
there are statistically significant differences , but only between the group vb and groups iii and iv . in groups with subgroups ( group ii and v )
, no statistically significant differences were found between subgroups a and b.
table 2results of statistical analysis for comparison of animal and spleen weights .
the letters a , b and c correspond to significant differences between the values of the same column between groups .
same letters mean no significant differences between values of the same columnparameteranimal weight ( gr)s1spleen weight ( gr)s2animal weight variance ( % ) s3spleen weight variance ( % ) s4spleen weight / animal weight ( % ) s5i group ( control)381.36a0.81a-0.33a-2.52a0.21aii - a group337.44b0.69abc-13.52bc-19.12abc0.2abii - b group322.96bc0.67bc-19.4bcd-23.55bc0.21abiii group326.66b0.76ab-16.99bc-9.04ab0.23aiv group299.62c0.61c-27.94d-39c0.2abv - a group342.85b0.65bc-11.46ab-25.92bc0.19bv - b group310.06bc0.72abc-25.98cd-13.44ab0.24a
in the groups in which only one type of substance was administered , as groups ii and v , no statistically significant differences were found when compared with the control group that was observed . concerning the groups that administered two different substances ( bleaching product and 50% ethanol ) , as groups iii and iv , only the group iv showed highly significant differences from the control group .
the differences between the control groups and manipulated groups are all negative , which means spleen weight is always higher in the control group when compared to the other groups .
figure 4 compares the variations of spleen weight relative to animal weight , based on the results of table 2 . only the va group shows statistically significant differences compared with the control group .
however , the va group also presents statistically significant differences compared with the two manipulated groups , groups vb and iii .
figure 4results of the comparison as a percentage of the ratio of animal and spleen weight .
the results are presented as mean with a level of significance of ( * ) < 0.001
although we collected , analysed , and weighed various organs , some of them that required special attention during the autopsy .
a more careful analysis of organs , particularly of lungs , spleen , oesophagus , and stomach was performed to determine the probability of systemic toxicity .
after the full cleaning of the gastric mucosa , lesions were observed in several different areas , thus classifying them according to the methodology of the macroscopic analysis .
statistical analysis was performed based on a frequency analysis , since the variables are discrete and not continuous .
the microscopic observation for the histological analysis of the study group can be seen in figure 5 .
a group ii , mucosal changes with foci of necrosis and sloughing can be observed ; b group iii , loss of the surface layer of the mucosal epithelium can be observed ; c group iv , the presence of inflammatory infiltrate and edema may be observed ; d group v , loss of superficial epithelial layer of the mucosa may be observed
the first parameter examined is related to the normal appearance of the mucosa , which was only found in the control group and in one animal of group va and two animals of group vb , as shown in figure 6 .
figure 6macroscopic observation of the gastric mucosa in relation to parameter - normal appearance of the mucosa in its entire length
for the analysis of figure 7 , we can observe that all manipulated groups have macroscopic areas corresponding to inflammation , which is more pronounced in groups ii , iv , and va . in group iii , despite the fact that the highest frequency values corresponding to macroscopically inflammation areas are not present , over 50% of the animals of this group present high frequency values for this parameter . in group
iv , both situations occur , presenting the highest frequency values and greater percentage of animals with gastric inflammation .
figure 7macroscopic observation of the gastric mucosa in relation to parameter - macroscopically corresponding to inflammation areas
the erasing of the folds of the mucosa parameter does not show a generalized pattern , because a large percentage of animals of various manipulated groups have frequency zero of this parameter . only in groups
iia , iv , and va this feature is scored as the ones with most occurrence . however , in groups iii , iv and va , this parameter presents higher frequency ( figure 8) .
figure 8macroscopic observation of the gastric mucosa in relation to parameter - erasing of the mucosa folds
all manipulated groups have macroscopic areas corresponding to bleeding .
groups iii , iv , and va have a large number of animals with this type of alteration , while the group va has the highest frequency .
group ii presents more than 50% of the animals with low frequencies of this parameter , which is still less pronounced in subgroup b. the control group shows no animals with this type of injury ( figure 9 ) .
figure 9macroscopic observation of the gastric mucosa in relation to parameter macroscopically corresponding to bleeding areas
the frequency of macroscopic areas corresponding to necrosis or ulcer is low in all manipulated groups .
this parameter is only evident at a low frequency in group ii ( subgroup a and b ) , and in groups iii and iv . among these , the groups with the largest number of animals with this type of injury are the groups iia and iii .
groups i , control , and v show no animal with this type of injury ( figure 10 ) .
figure 10macroscopic observation of the gastric mucosa in relation to parameter macroscopically corresponding to necrosis / ulcers
the inflammation and the bleeding parameters showed statistical significant differences between some groups . in the inflammation parameter , there are significant differences between the control group and the groups iia ( 0.015 ) , iii ( 0.003 ) , and iv ( < 0.001 ) . in the bleeding parameter
, there are significant differences between the control group and the groups iii ( 0.002 ) , iv ( 0.001 ) and va ( 0.011 ) .
in this experimental work , a therapy study in an animal model was chosen , since this type of testing can be performed to predict the biocompatibility of a particular product .
these tests are much more reliable because they mimic better the clinical use of the products tested , including time , location , and application techniques .
the rat model was chosen as described in several studies in the literature regarding the induction of gastric pathology and biocompatibility evaluation of various products in animal models
. to reduce the risk of developing gastric pathologies associated with old animals ,
the administration of 50% ethanol , bleaching product , hydrogen peroxide 6% was performed by gavage to ease the manipulation that allows this methodology .
a large number of studies on non - tumour induction of gastric pathologies use this method of administration
.
the ease of handling and of the certification of the receipt of the product at the desired location without loss of the administered dose are considered reasons for the choice . with regard to the bleaching product , using it in a similar way to clinical practice was not possible with these animals .
the maintenance of a tray in the dental arch without the manipulation of anaesthesia would be an impossible task to accomplish .
however , with the administration of chemical compounds by gavage , the objective of the study is maintained , since these compounds are placed in the desired location .
the induction of non - tumour gastric damage is widely performed in several studies with experimental models , such as the use of intragastric indomethacin
, cold stress method
, the induction by helicobacter pylori infection , and the administration of iodoacetamide
or ethanol . the experimental model of ethanol can have some variables , but , in this study , it was chosen the administration of 50% ethanol in 1 ml single dose by gavage , keeping the drinking water with 5% ethanol for 6 days
.
this experimental model is effective ; it is coordinated by the administration of the bleaching product and avoids the recovery of the induced lesions in the mucosa , which occurs in single - dose models
.
the use of 6% hydrogen peroxide in this study required the analysis of the probable dose administration with the balance of several factors , contributing to this issue .
some authors reported that during an hour of use of a tray with whitening product , about 50% of the product escaped from the tray .
moreover , another factor to take into account is the presence of carbopol in these products of .
this substance prolongs the time release of oxygen peroxide , thereby contributing to higher levels of toxicity
.
as mentioned above , the experimental design of the study should be the best mimic for the clinical use of the product . in this case
, the manufacturer indicates 1 hour of use twice a day for 30 minutes in a treatment of 3 to 7 days ( colgate visible white - colgate oral pharmaceuticals inc , new york , usa ) .
the determination of the dose administered to the animals as well as the time of study was based on the clinical protocol recommended by the manufacturer and in several experimental and clinical studies on therapeutic bleaching .
most of these clinical studies concluded that the treatment with carbamide or hydrogen peroxide , depending on the concentrations ( 10% to 20% ) of the active ingredient should be performed from 15 to 30 days , according to the type of stains . in vivo
animal experimental studies are scarce , and , generally , call for proposals of single daily doses or manipulations of 1 week . regarding the administered dose , 1 g / kg
body weight was chosen , since studies suggest that this is closest to the clinical dose . moreover , this dose is in accordance with the requirements of outpatient therapy for the same type of product made by some authors
. during the experimental study ,
drinking water was not restricted to the animals manipulated with hydrogen peroxide , but their diet was restricted for 3 hours after the administration of the product . according to some studies , the diet should be restricted during the first 3 hours after the administration of the bleaching product , so that it is not diluted by food , diminishing its action
.
the statistical analysis of the data on the increase in animal weight throughout the study indicates that there is a decrease in weight gain in all manipulated experimental groups when compared with the weight increase of the control group . in spite of remaining constant
, such increase is slight in all groups , except in groups iv and vb . in these groups ,
weight loss occurs after the administration of ethanol 50% , indicating transient systemic toxicity . on the other hand ,
the administration of hydrogen peroxide does not induce weight loss , but marked decrease in weight gain .
these data reveal the presence of systemic toxicity less severe than that induced by the administration of ethanol . regarding the spleen weight of all study groups ,
there were statistically significant differences detected in the manipulated groups compared with the control group .
, an increase in the weight of the organ would be expected in a situation of systemic toxicity .
these differences appear to be negative and also explainable by the decrease in weight gain observed in these animals , thus reducing their body weight in general .
the change in spleen weight compared to the weight of the respective animal could be important for the evaluation of the presence of systemic toxicity .
values higher than those from the control group would allow us to consider an increase in spleen weight and , consequently , in the presence of splenomegaly .
however , there is only one significant statistical change compared to the control group in the negative direction , indicating a lower spleen weight .
however , it seems to be a positive variation in groups iii and vb , which may indicate the presence of splenomegaly despite of the fact that such difference is not statistically significant .
these parameters were chosen to characterize the type of changes induced by the various chemical compounds used in conjunction with their severity and frequency .
all animal groups showed higher or lower frequency except for the last type of changes that was translated into macroscopically areas corresponding to ulcers .
thus , for the parameters with the presence of macroscopic areas of inflammation , haemorrhage , and erasing of mucosal folds , all groups manipulated had positive frequencies .
these results were expected since substances that may cause lesions to the gastric mucosa were administered in all groups .
the parameters corresponding to inflammation and bleeding areas have higher incidence in the groups mentioned , particularly in the groups iii and iv .
both parameters are more frequent in group iv , with the most relevant one corresponding to macroscopic areas of inflammation and bleeding . however , in group iii , the presence of lesions can be observed in a larger number of animals , despite being less frequent . the bleaching product administered to rats with the presence of non - tumour gastric damage contributes to the maintenance of these same lesions and thus , some favourable clinical evolution may occur .
the results suggest an aggravation of gastric lesions caused by the bleaching product in the group iv , when in the presence of 50% ethanol and drinking water with 5% ethanol . in the groups
ii and v , in which it was administered only a single type of chemical compound , such parameters are referred to as positive , but there seems to be a standard set of most common type of lesions . corroborating these results , the presence of ulcers is also more frequent in the groups iii and iv .
the combination of these two chemicals appears to have a synergy , enhancing the appearance of lesions and keeping it active , despite being less evident when the bleach product is given in the last week of the study .
the erasure of the mucosal folds does not seem to be related with any type of pattern , despite being more common in the groups iii , iv , and va .
although this parameter is evident in some animals , it can occur in limited areas of the mucosa and/or in slight anatomical variations .
both products administered have caused gastric injury , which was already expected to ethanol considering it is an inductor model of gastric injury .
the intensity and the severity of these lesions is greater with the simultaneous administration of the products , without having a pattern or differences in the administration order .
thus , further studies are needed to evaluate the impact of some individual variants of the clinical application of the technique such as long therapies and the increase of the dose or of the concentration of bleaching products .
the systemic toxicity seems to be induced either by the bleaching product , hydrogen peroxide 6% or by 50% ethanol , but the severity of the systemic toxicity is greater when both are administered .
thus , the bleaching therapy that is carried out with this product should be well monitored by a dentist to avoid the excess of product and of applications , with the careful removal of excesses , avoiding its intake .
the trays should always be individualized for better containment of the product and the treatment must be made individually in each dental arch .
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### Summary:
: the value of aesthetic dentistry has precipitated several developments in the investigation of dental materials related to this field .
the free marketing of these products is a problem and it is subject to various interpretations regarding its legality .
there are several techniques for tooth whitening , the most used one being the external bleaching .
it is the later version of such technique that poses the greatest danger of ingesting the product .
the present study analysed the systemic effect of these products when they are swallowed .
objective this experimental study aimed to observe the effects of a tooth whitening product , whose active agent is 6% hydrogen peroxide , on the gastric mucosa of healthy and non - tumour gastric pathology animals.material and methods fifty wistar - han rats were used and then distributed into 5 groups , one for control and four test groups in which the bleaching product was administered in animals with and without non - tumour gastric pathology ( induced by the administration of 1 sample of 50% ethanol and 5% of drinking water during 6 days ) at different times of study by gavage .
there was a decrease in body weight in animals of groups handled during the study period , which was most pronounced in iv and va groups .
changes in spleen weight relative to body weight revealed no statistically significant changes .
an analysis of the frequency was performed on the results of macroscopic observation of the gastric mucosa.results the gastric mucosa revealed lesions in all manipulated groups , being more frequent in groups iii and iv .
it appears that there is a synergism when using hydrogen peroxide and 50% ethanol in the same group.conclusion therefore , it seems that there are some signs of toxicity 3 to 4 days after administration of 6% hydrogen peroxide .
the prescription of these therapies must be controlled by the clinician and the risks must be minimized .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: technical advances in molecular biology over the past 20 years , including the advent of polymerase chain reaction ( pcr ) , the discovery of snps as a class of highly variable polymorphisms , and the use of multi - well format plates and associated instrumentation for many genetic analyses have provided essential building blocks for high - throughput genome - wide association studies . however , identifying , consenting and gathering relevant clinical information for thousands of individuals are challenging . distributing human genetic materials and associated clinical information poses legal challenges and issues related to protection of human subjects .
therefore , collection and distribution of human biomaterials for genetic research is not an area into which traditional us commercial entities have ventured , and the supply of large numbers of genomic dna samples represents a bottleneck .
evidence of the value of readily accessible and abundant human dna comes from the study of the heritability of schizophrenia in iceland .
the relative isolation and proximity of icelandic families with schizophrenia , together with their remarkable cooperation and consent , allowed decode genetics to perform a genome - wide linkage scan that identified neuregulin i ( nrg1 ) as a candidate gene for schizophrenia ( stefansson et al 2002 ) .
however , the specific conditions that facilitated this population - based study in the icelandic community , and thus the efforts associated with this study are not readily reproducible in other populations .
in addition , the samples used in those and most other population - based studies are not publicly available .
limited access to such biomaterials and the associated clinical data is a large impediment to progress in genome - wide analyses of complex diseases , including neuropsychiatric disease .
the national institutes of health and other contracting agencies have addressed the need for such biomaterials by funding non - profit repositories to receive , manage and distribute human biomaterials .
repositories that generate and store human cell lines , and the genomic dna derived from these cell lines , rely on an approach that was developed over 30 years ago in which epstein - barr virus ( ebv ) infects and transforms b lymphocytes present in whole blood ( yata et al 1975 ) .
both the lymphoblasts and the dna can be distributed to investigators , and in the case of public repositories , these materials are a valuable resource for the biomedical research community at large .
additionally , in some cases the availability of cell lines with associated genotypic and phenotypic information represents a second - generation resource for mrna- and protein - expression analyses and other cell - based studies aimed at follow - up of genetic hits .
this strategy employs biomaterials for gene discovery , ie , the transformed lymphoblasts from which subject dna is extracted , as a tool for further investigating the biological significance of candidate gene variation .
the first critical step in designing a successful genome - wide association study involves the collection of human biomaterial , most often a peripheral blood specimen .
this step requires oversight by an institutional review board ( irb ) and creation and use of an informed consent document .
when developing such a document for a genetic study there are three primary ethical issues related to the use of specimens and associated private medical information ( pmi ) in research .
the first is the protection of individuals who have contributed their samples or data from research risks and to weigh these risks with the potential benefits .
the principal risk to subjects is the potential breach of privacy and confidentiality , with additional risks being psychosocial harms from research or research findings , and physical risks from procedures for collecting specimens , such as biopsies or blood draws .
the relative benefits to society need to be considered explicitly when establishing population - based genetic research studies that are unlikely to lead to direct benefit for any individual human subject .
the second major ethical issue is respect for persons ; this includes respect for individuals and groups of individuals and the autonomy of these individuals to make decisions about the use and disposition of their samples and data . attending to respect for persons should be considered independently of the need to evaluate and minimize risks ; subjects may have values or beliefs in relation to uses of samples and data that are not directly linked to concerns about risk .
the third ethical issue is the importance of ensuring the responsible use of valuable research resources to advance scientific knowledge about human health for the benefit of society .
the research community must engage in an open and continual dialog regarding the responsible use of human genetic materials .
it is wise to create an infrastructure by which biomaterials can be collected and distributed responsibly , with minimal barriers to research or inordinate costs that prevent societal investment in research from yielding benefits to human health . in some cases there
may be risks to social groups or communities due to the release of aggregate research findings that can cause anxiety , stigma , or economic consequences , even when no individually identifiable information has been revealed .
for example , it may be appropriate to include a community representative on an advisory or oversight board for the repository , or other extensive consultations may be undertaken in advance of initiating a research project that focuses on a particular population . in all cases
the collection , storage , distribution and use of human specimens and data should be conducted in accordance with all applicable regulations .
these include 45 code of federal regulation ( cfr ) part 46 , the food and drug administration human subjects regulations 21 cfr part 50 and 56 , and 812 ; the health insurance portability and accountability act ( hipaa ) privacy and security rules ( 45 cfr parts 160 and 164 ) .
there are also state and local laws , such as laws governing genetic testing , regulating genetic information and medical records privacy that must be considered when designing a genetic study of human subjects .
it is noteworthy that under 45 cfr 46 , research use of specimens and data that are not readily identifiable , and for which there are no links to individually identifying information , is not considered to be human subjects research .
additionally , some repositories , such as those funded by the national institutes of health , are contracts to non - billable entities , ie , entities that do not provide clinical care , and in those cases , the hipaa privacy rule does not apply . nonetheless , hipaa compliance is worthwhile , as most of the specimens are likely to originate at sites that are billable entities .
repositories should consider how the hipaa privacy rule may apply to the collection and use of any individually identifiable information that is particular to their repository operations [ for further information , see : nih : research repositories , databases and the hipaa privacy rule issued july 2 , 2004 ( http://privacyru-leandresearch.nih.gov/research_repositories.asp ) and ohrp : guidance on research involving coded private information or biological specimens
the answer to that question depends on several factors , including the genetic architecture ( number of genes , their effects , and interactions with other genes and environmental risk factors ) , potential disease heterogeneity ( genetic and environmental ) , and proposed study design . because we do not know the number of loci involved in most neuropsychiatric disease etiology , nor
do we know their population prevalence and penetrance , the number of subjects needed can not be precisely predicted .
many diseases , including neuropsychiatric disease , have multiple clinical profiles that may reflect differences in underlying pathogenesis .
sub - populations or strata defined by gender , age of onset , race , ethnicity , are all potentially valuable classification variables .
however , the more stratified a population of samples , the larger the sample size needed for study ( wang et al 2005 ) . in the case of parkinson s disease ( pd ) , there are examples of disease - causing alleles that are inherited in a mendelian fashion ( simon - sanchez et al 2005 ; mizuno et al 2006 ) , but these do not represent the majority of cases ( see reviews ( gwinn - hardy 2002 , wood - kaczmar et al 2006 ) .
substantial statistical genetic and empirical data suggest that 5,000 pd cases would be sufficient for discovery of individual gene effects underlying risk of complex human disease under most genetic models with 80% statistical power .
banking specimens from a minimum of 2,000 cases allows identification of snps with approximately a 1.5-fold or greater relative risk . for common snps
( with minor allele frequency > 10% ) , this represents an allele frequency difference of at least 10% .
in addition , replication of the experimental findings depends upon the availability of populations independent of the original cohort . to design a study capable of detecting gene - gene or gene - environment interactions , the sample size required to maintain power would be increased by at least 4-fold .
public availability of such biomaterials is vital for accelerating the rate at which large - scale genetic studies can reach sufficient power to detect disease - causing genes and interacting loci .
the quality of genotype - phenotype characterizations involving many thousands of samples acquired over a period of years depends on the quality of phenotypic definitions , uniform data acquisition , and rigorous data management .
standardized clinical criteria are essential to a large - scale sample comparison within and across clinical collection sites .
furthermore , use of these criteria can allow stratification by associated traits ( endophenotypes or sub - phenotypes ) .
fortunately , in the neuropsychiatric disease community , a large number of clinical trials have accustomed many clinicians to standardized clinical criteria , thus facilitating collection of large , well - characterized populations .
also , the strong clinical tradition in neuropsychiatric disease sets a foundation for pharmacogenetic studies , and , when possible , pharmacological response or significant exposure should be included in clinical datasets .
additionally , well - designed collections of control subjects are crucial and in some cases may allow for the use of control subjects for multiple neuropsychiatric disorders .
this is particularly important because most genome - wide association studies ( gwas ) use the case / control paradigm .
identifying and enrolling large numbers of control subjects in these studies requires significant dedication and application by a collaborative team .
neurologically normal individuals , who would be suitable for use as control subjects , are not likely to be seen in clinical neurology and clinical neuropsychiatric settings .
some case / control studies utilize unaffected spouses as control subjects in part due to their accessibility and to the fact that they are likely to share some environmental exposure history .
it is unlikely that individual researchers are capable of enrolling the large number of subjects necessary for gwas of complex diseases .
in addition , the most appropriate subjects for genetic studies are sometimes those who are the most difficult to enroll .
typical sporadic cases of a disease are often desirable in gwas , yet these are the cases that are least likely to present in a subspecialty clinic . therefore , a major collaborative effort involving a large number of clinicians is often required to enroll sufficient subjects for successful gwas .
an approach that has been used successfully in the cancer research community is one in which private practitioners that enroll subjects maintain an academic interest and involvement in the collaborative project ( kaluzny et al 1993 ) .
this approach has catalyzed the expansion of cancer clinical trials to include a much broader and larger collection of patients . in 2003 ,
the national cancer institute proposed a framework for nci - funded large - scale biospecimen and data collection and distribution entitled , the national biospecimen network blueprint ( http://prostatenbnpilot.nci.nih.gov/final_nbn_blueprint.pdf ) . using the experiences gained from the structure of nih - funded cancer clinical trials networks , the clinical research collaboration ( crc ) at the national institute of neurological disorders and stroke ( ninds )
has undertaken a project to develop of an infrastructure to efficiently execute ninds - sponsored clinical research ( see http://www.ninds.nih.gov/news_and_events/proceedings/2002_clinical_research_workshop.htm ) .
the crc was established to expedite subject recruitment ; it involves a wide spectrum of investigators , including practicing physicians .
the involvement of the clinic - based neurologist has the additional benefit of making participation in ninds - sponsored clinical research more accessible to patients .
one of the projects that utilizes the crc initiative enrolls subjects and collects specimens to build a sizeable , well - characterized cohort with which to perform gwas of neuropsychiatric disorders .
additionally , the crc at ninds aims to engender a tradition of participation in clinical research and to educate primary physicians regarding neurogenetics research .
the ninds human genetics repository ( http://ccr.coriell.org/ninds ) , established in 2002 , benefits from the crc sample collection and submission study .
the repository , located at the coriell institute for medical research , currently has specimens from over 14,000 subjects , over 4,000 of which are already publicly available , including those with parkinson s disease , epilepsy , cerebro - vascular disease and motor neuron diseases .
in addition , the ninds repository is similar in framework and management of processes , quality and data to the large - scale system of biospecimen and data collection and distribution proposed in the nbnb .
the utility of a sample biorepository used for gwas is maximized by a scalable and extensible informatics infrastructure .
the information management system should meet the requirements of real - time data capture , collection site management , chain of custody handling , and operational efficiency for a large number of samples , each of which is linked to individual data .
moreover , as an integrated solution , the system must manage the genotypic and phenotypic data associated with biospecimens under compliance with all relevant privacy laws .
the information systems design must not only consider the quality but also the accessibility of the biospecimens and associated data .
the system should have the ability to integrate with other databases as both a source and a recipient of data .
for example , the informatics infrastructure of the ninds human genetics repository provides open , internet - based access to both phenotypic and genotypic data in several data formats , such as comma - separated values text , excel , and xml .
additionally , curated links to external data sources such as the dbsnp ( http://www.ncbi.nlm.nih.gov/snp ) and gene expression omnibus ( http://www.ncbi.nlm.nih.gov/geo ) supplements the information available about the biospecimens .
the scale of gwas in complex human disorders demands that the data management system be secure , robust , and flexible in order to accommodate the complex and collaborative nature of such projects .
the cost of high - throughput genome - wide snp genotyping is approaching less than 1 cent per genotype , and public application of genome - wide snp analysis has begun in earnest .
biorepositories that can supply large numbers of human specimens and associated clinical datasets are becoming increasingly important to the advancement of translational research and to the achievement of improved medical care .
for example , one of the oldest nih - funded repositories , the national institute of general medical sciences ( nigms ) repository ( http://ccr.coriell.org/nigms ) , collects biomaterials from subjects with a large number of genetic conditions , many of them displaying mendelian inheritance .
structurally , this type of repository tends to be built from many non - interacting individual collection sites , rather than from multiple interacting sites and to have a small number of specimens from each of a large number of disorders .
collections such as these continue to be integral to the success of research aimed at identifying disease - causing mutations for mendelian disorders ( eg , kapetanaki et al 2006 ; matsuura et al 2006 ; rivolta et al 2006 ) .
most recently , the national human genome research institute ( nhgri ) established a cell repository ( http://ccr.coriell.org/nhgri ) aimed at banking nhgri - sponsored projects , including the international hapmap project specimens .
these samples are being collected from distinct populations for studies of human genetic variation and are associated with no clinical information .
additionally , other nih - funded repositories are collecting samples for large - scale studies aimed at identifying genes that have a complex non - mendelian influence on susceptibility .
included in this group are those dedicated to banking samples for the study of a number of neurological disorders ( http://neuroscienceblueprint.nih.gov/neuroscience_resources/cell_tissue.htm ) .
the national heart lung and blood institute ( nhlbi)-sponsored framingham heart study , established 50 years ago to investigate cardiovascular disease by collecting general medical information on a population of individuals from framingham , massachusetts ( namboodiri 1984 ) expanded its goals in recent years to include genetic studies and offers dna from individuals with associated medical information to researchers .
one of the first biorepositories to make genome - wide genotyping data completely and publicly accessible , in combination with detailed clinical data , is the ninds human genetics repository in collaboration with researchers at the nia ( see fung et al 2006 ) .
this genotype / phenotype dataset ( https://queue.coriell.org/q/snp_index.asp ) , initially posted in march 2006 , has generated considerable interest in the scientific community , having been accessed by researchers from across the globe more than 560 times .
the wellcome trust case control consortium ( wtccc ) , made up of 24 united kingdom(uk)-based geneticists , is performing high - density snp genotyping on 2000 cases for each of 7 diseases along with a common set of 3000 controls ( 1500 from the 1958 british birth cohort and 1500 uk blood donors ) ; similar analyses in four additional disease groups are planned .
access to data and materials will be considered by an independent access committee 6 months after completion of the study ( http://www.wtccc.org.uk/info/overview.shtml ) . in 2006 , the nih launched two large gwas initiatives with open access to genotype data at their core .
the first , genetic association information network or gain , was established in 2006 through a public / private partnership between the foundation of the national institutes of health , pfizer global research and development , perlegen sciences , affymetrix inc . and the broad institute ; currently , it funds six studies aimed at determining the genetic factors that influence susceptibility to psoriasis , attention deficit hyperactivity disorder , schizophrenia , bipolar disorder , major depression and type 1 diabetes in a total of 18,000 individuals .
high - density snp genotype information is housed in a database managed by the national center for biotechnology information ( ncbi ) and is available to the research community ( http://www.ncbi.nlm.nih.gov/wga/programs/gain ) .
the second , cancer genetic markers of susceptibility or cgems , is funded by the national cancer institute , and is aimed at determining the genetic factors that influence susceptibility to breast and prostate cancer ( http://cgems.cancer.gov ) .
the data generated is made publicly available at the cancer biomedical informatics grid ( cabig ) ( http://caintegrator.nci.nih.gov/cgems ) .
the first significant finding of this initiative is the identification of a new prostate cancer susceptibility locus as well as confirmation of a previously identified locus , both on chromosome 8 ( yeager et al 2007 ) .
the role of gene dosage has been shown to be an important causal factor in neurological disorders , including alzheimer s and parkinson s disease ( eg , martins et al 2005 , bonifati et al 2005 ) .
also , there is renewed interest in copy number variation and its influence on human disease ( khaja et al 2006 ; redon et al 2006 ; white and den dunnen 2006 ) including neuropsychiatric disease ( eg , eriksen et al 2005 ; nishioka et al 2006 ) as well as its role in pharmacogenomics ( eg , ouahchi et al 2006 ) .
this work is supported by new approaches for measuring such variation ( fiegler et al 2006 ; ragoussis et al 2006 ; tchinda and lee 2006 ) .
recently , the use of genome - wide snp genotyping has been shown to increase the potential to augment or replace current methods aimed at defining chromosomal abnormalities ( simon - sanchez et al 2006 ) .
public availability of genome - wide snp genotyping will greatly facilitate the rapid accumulation of equivalent data to produce an encyclopedia of normal and abnormal structural genomic variation , similar to previous efforts for gross chromosomal abnormalities ( mitelman 1998 ) , in addition to enabling standardized cross - comparison among laboratories .
in summary , the field of neuropsychiatric disease has entered an era of complex gene discovery research . as with all genome - wide approaches to complex disease , there are continued challenges regarding determination of optimal sample sizes for affected and control populations .
such repositories , involved in the collection and dissemination of specimens and associated data , must supply high quality biomaterials and implement powerful data management and bioinformatics tools to meet the needs of a complex collaborative network of collection sites and scientists .
currently , this niche is being filled in large part by federally - sponsored repositories with distinct scientific missions , but a shared interest in supporting collaborative research and public availability of data .
there is the potential for participation by the commercial sector , specifically the pharmaceutical industry , in such large - scale efforts aimed at improving human health .
however , the societal investment in population - based studies of complex disease , including neuropsychiatric disease , is best served by repositories that offer broad access to results and material that can propel these efforts from bench to bedside .
|
### Summary:
: family history , which includes both common environmental and genetic effects , is associated with an increased risk for many neuropsychiatric diseases .
investigators have identified several disease - causing mutations for specific neuropsychiatric disorders that display mendelian segregation .
such discoveries can lead to more rational drug design and improved intervention from a better understanding of the underlying biological mechanisms .
however , a key challenge of genetic discovery in human complex diseases , including neuropsychiatric disorders , is that most diseases with genetic components display non - mendelian patterns of inheritance .
recent advances in human population genetics include high - density genome - wide analyses of single nucleotide polymorphisms ( snps ) that make it possible to study complex genetic contributions to human disease .
this approach is currently the most powerful strategy for analyzing the genetics of complex diseases .
genome - wide snp analyses often require a large collaborative effort to collect , manage , and disseminate the numerous samples and corresponding clinical data . in this review
we discuss the use of publicly available biorepositories for the collection and distribution of human genetic material , associated phenotypic information , and their use in genome - wide investigations of human neuropsychiatric diseases .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: as in other asian countries , there is an increasing trend of overweight in the thai
population .
this trend may primarily be attributed to rapid changes in lifestyle and
sedentary behavior .
the results of the national health survey indicate that the average body
mass index ( bmi ) of the thai population over the age of 18 increased from
22.0 kg / m in 1991 to 23.2 kg / m in 20041 .
the increased prevalence of overweight and obesity has
socio - economic consequences , due to the cost of treatments for overweight and
obesity - related diseases , such as cardiovascular disease , stroke , diabetes type ii , and
hypertension2 , 3 . accumulated evidence indicates that being overweight is linked to a
reduction in lower - limb muscle strength and the alteration several gait parameters ,
including maximum walking speed4 .
decreasing muscle power and a decline in the level of physical activity
divided 8 to 10-year - old boys into normal weight and overweight groups using a body mass
index cut - off point and reported that overweight boys had greater sway velocity in the
sit - to - stand test , a shorter time of one leg stance in the balance beam test , and fewer
correct steps in the heel - to - toe test6 .
bmi and postural stability have been shown to be negatively correlated in single- and
double- leg standing7 , 8 .
these results suggest that the balance ability of overweight
subjects is lower than that of normal weight subjects .
also , teasdale et al . reported that
decreasing body weight improved the balance ability of obese and morbidly obese men9 .
the nintendo wii fit , a computer game console , is an interesting example of a
new exercise choice that could be used for improving strength , flexibility , fitness ,
postural stability , and general well - being . using this device ,
players receive visual and
auditory feedback that provides useful information that helps them to adapt their postural
stability .
graves et al . demonstrated that playing with a wii fit increased
energy expenditure and physical activity .
they also reported that wii fit
appears to be an enjoyable exergame for adolescents and adults that stimulates light- to
moderate - intensity activity through the modification of typically sedentary leisure
behavior10 .
previous studies have
demonstrated that the wii fit significantly improves lower - limb muscle
activities , strength , and the balance performance of healthy adults11 , 12 and
elderly13 .
there have been many studies of wii fit that have used the wii balance board
as an input device , and it can be used as a modern exercise program for improving physical
activity and muscle strength
. however , there has been little discussion about the effect of
wii fit exercise on the balance and muscle strength of overweight
individuals .
a within - subject repeated measures design was used to determine whether wii balance board
exercise could improve the balance and lower - limb muscle strength of overweight young adults
of both genders .
sixteen overweight young adults ( aged 21.87 1.23 years , weight 64.03
7.79 kg , height 1.63 0.09 m , bmi 24.15 0.50 kg / m , 6 males and 10 females )
from chulalongkorn university were recruited ( table
1table 1.characteristics of the participants ( n = 16)characteristicsmean sdrangeage ( years ) 21.87 1.232024weight ( kg)64.03 7.7954.9078.70height ( m)1.63 0.091.521.79bmi ( kg / m)24.15 0.5023.0224.85male : female6 : 10 ) . in this study ,
overweight was defined as a person with a body mass index
( bmi ) between 23.0 and 24.9 kg / m , according to the asian bmi cut - off points14 .
prior to participation in this study , all
the study procedures were explained by the researcher . written informed consent was obtained
from the subjects using forms approved by the institutional ethics committee .
a
questionnaire was used to obtain demographic data and screening for the inclusion and
exclusion criteria .
the inclusion criteria were : 1 ) bmi between 23.0 and
24.9 kg / m ; 2 ) normal visual field and acuity ( the subjects able to wear eye
glasses ) ; 3 ) normal hearing ; 4 ) the ability to stand in a bipedal position with the eyes
closed and without help for 1 minute or more ; and 5 ) the ability to stand on one leg for 30
seconds or more .
the exclusion criteria were : 1 ) a history of musculoskeletal disorders ; 2 )
a history of neurological disorders ; 3 ) a history of back or lower limb surgery ; or 4 ) the
presence of any joint diseases , such as osteoarthritis , gout , or rheumatoid arthritis .
all
of the study procedures were approved by the ethics review committee for research involving
human research subjects , health science group , chulalongkorn university ( project # :
032.2/55 ) .
the subjects exercised on a wii balance board for 30 minutes per day , twice a week , for 8
weeks . the exercise program included 6 yoga exercises ( i.e. , warrior pose , tree pose ,
standing knee pose , palm tree pose , chair pose , and dance pose ) and 5 strength exercises
( i.e. , single - leg extension , lunge , rowing squat , single - leg twist , and sideways leg lift ) .
the subjects were asked to write in exercise dairies if they performed any other exercise
during the 8 weeks of this study .
no subject
performed other exercise of more than 20 minutes / session / week during this study .
a neurocom balance master ( neurocom , or , usa ) was used to assess static and dynamic
postural stability .
this equipment consists of a double force plate that is connected to a
computer and is controlled by the balance master program .
the static and dynamic postural
stability were measured using the unilateral stance test and a limit of stability test ,
respectively . in each assessment
all of the tests were performed in the neurological treatment room , health sciences
service unit , faculty of allied health sciences , chulalongkorn university .
the limit of stability ( los ) is the dynamic standing balance test that measures the maximum
distance a subject can lean without losing balance in 8 directions ( i.e. , forward ,
forward - right , right , backward - right , backward , backward - left , left and forward - left ) .
the
tested parameters were the reaction time ( the time between the start - to - move signal and the
initiation of the center of gravity ( cog ) movement ) , the cog movement velocity ( the average
speed of cog movement ) , the endpoint excursion ( the distance of the cog movement toward the
target in the first attempt ) and the maximum excursion ( the maximum distance of cog movement
from the center point during the trial ) . the unilateral stance test is a static balance test that measures cog sway velocity while
standing on one leg on the force plate for 10 sec under 4 conditions ( i.e. , standing on the
left leg with eyes open , standing on the left leg with eyes closed , standing on the right
leg with eyes open and standing on the right leg with eyes closed ) .
each test was repeated 3
times ; therefore , a total of 12 tests were performed . a hand - held dynamometer (
the lafayette manual muscle test system model 01163 ; lafayette
instrument , usa ) was used to assess the lower limb muscle strength pre- and post - training .
the tested muscle groups were the hip flexor , hip extensor , hip abductor , hip adductor , knee
extensor , knee flexor , ankle dorsiflexor and ankle plantarflexor .
we used the starting
positions and location of the dynamometer as described in a previous study15 ( table 2table 2.positions of the lower limb muscle strength assessment using a hand - held
dynamometer15muscle groupssubject positionsextremity and joint positionslocation of dynamometer applicationhip flexorsupine lyinghip and knee flexed 90 , contralateral hip
neutraljust proximal to femoral condyleship extensorprone lyinghips neutral , knees extendedjust proximal to femoral condyleship abductorside lying , measured side is upperhips and knees extendedjust proximal to lateral joint line of kneehip adductorside lying on measured sidehip and knee extended , contralateral hip and knee
flexed with foot placed on bed anteriorly to measured sidejust proximal to medial joint line of kneeknee extensorsitting with straight backhips and knees flexed 90just proximal to malleoliknee flexorprone lying , feet out of bedhips and knees extendedjust proximal to malleoliankle dorsiflexorsupine lyinghips and knees fully extended , ankles perpendicular to
legsjust proximal to metatarsophalangeal joint lineankle plantarflexorprone lying , feet out of bedhips and knees extended , ankles perpendicular to
legsjust proximal to metatarsophalangeal joint line ) . to avoid frequent changes of position , the testing sequence was begun in
sitting and progressed to supine lying , side lying and prone lying . in order to familiarize
the subjects with the test , they were allowed to practice before data acquisition trials .
the maximum muscle strength was assessed in 2 trials with 120 seconds rest between trials .
statistical analyses were conducted using graphpad prism version 6.0 ( graphpad software ,
ca , usa ) .
the paired
t - test was used to compare pre- and post- training results .
to assess the static balance ability , the los test was performed on the balance master .
table 3table 3.mean sd of reaction time , cog movement velocity , end point excursion and
maximum excursion in each directiondirectionsreaction time ( second)cog movement velocity ( degree / sec)end point excursion ( percent of
los)maximum excursion ( percent of los)pre - trainingpost - trainingpre - trainingpost - trainingpre - trainingpost - trainingpre - trainingpost - trainingforward0.87 0.360.75 0.344.76 2.144.79 1.9983.8 22.791.6 18.1 * 97.2 11.5104.0 9.69*forward right0.78 0.400.56 0.17 * 3.60 4.704.60 6.6098.4 15.4110.0 10.6 * 103.0 12.9112.0 8.92*right0.62 0.170.62 0.232.70 4.753.80 6.4086.9 10.586.6 12.498.8 8.6498.2 7.29backward right0.73 0.400.60 0.235.09 1.814.71 1.4278.0 17.772.8 22.586.2 14.286.1 15.7backward0.67 0.330.65 0.203.10 1.354.09 1.53 * 58.3 12.856.4 11.773.6 12.279.0
15.3backward left0.80 0.310.63 0.26 * 6.20 2.086.34 1.0785.1 18.690.2 25.790.1 19.0100.0 18.9*left0.69 0.280.63 0.247.09 2.138.01 2.8093.3 9.7197.2 10.198.0 6.6103.0
6.4*forward left0.74 0.250.63 0.256.87 2.897.81 2.8999.8 14.8105.0 15.4105.0 116110.0 10.6cog , center of gravity ; los , limit of stability ; * significant difference , p <
0.05 , compared to pre - training shows the results of pre- and post- training of four los parameters : the
reaction time , the cog movement velocity , the endpoint excursion and the maximum excursion .
there was a significant decrease in the reaction time in the forward right ( p = 0.0383 ) and
backward left directions ( p = 0.0224 ) ; a significant increase of the average speed of cog
movement ( cog movement velocity ) in the backward direction ( p = 0.0147 ) ; a significant
increase in the endpoint excursion and the measurement of the distance of cog movement
toward the target in the first attempt in forward ( p = 0.0320 ) and forward right ( p =
0.0213 ) ; and a significant increase in the maximum excursion , the measurement of the maximum
distance of the cog movement from the center point during the trial , in the forward ( p =
0.0154 ) , forward right ( p = 0.0279 ) , backward left ( p = 0.0361 ) , and left direction ( p =
0.0100 ) .
cog , center of gravity ; los , limit of stability ; * significant difference , p <
0.05 , compared to pre - training the unilateral stance test was used to quantify postural sway velocity during quiet
standing on one foot on the force plate with eyes closed ( ec ) and eyes open ( eo ) .
there were
no significant differences between pre- and post - training in any condition ( table 4table 4.mean sd of cog sway velocity during the unilateral stance testcog sway velocity during unilateral stance
with eye closed ( ec ) ( degree / sec)cog sway velocity during unilateral stance
with eye open ( eo ) ( degree / sec)pre - trainingpost - trainingpre - trainingpost - trainingright leg1.60 0.901.40 0.590.57 0.130.61
0.16left leg1.79 0.661.55 0.520.73 0.200.81 0.33cog , center of gravity ; no significant differences were found , p
> 0.05 , compared to pre - training ) .
cog , center of gravity ; no significant differences were found , p
> 0.05 , compared to pre - training the subjects lower - limb muscle strength of 8 muscle groups ( hip extensor , hip flexor , hip
abductor , hip adductor , knee flexor , knee extensor , ankle dorsiflexor , and ankle
plantarflexor ) was measured in kilograms ( kg ) by the same researcher with a handheld
dynamometer , pre- and post - training .
the comparisons of lower - limb muscle strength between
pre- and post - training are shown in table
5table 5.mean sd of lower limb muscle strengths between pre- and post - trainingright leg muscle strength ( kg)left leg muscle strength ( kg)pre - trainingpost - trainingpre - trainingpost - traininghip extensor28.70 8.0729.90 6.90 27.50 6.69 30.10 7.00 hip flexor15.30 4.50 17.60 4.36 * 15.20 4.83 17.70 4.39 * hip abductor26.50 7.47 26.10 6.18 26.40 6.89 26.10 5.98 hip adductor19.20 5.05 21.20 5.03 19.60 5.03 20.40 5.28knee extensor27.30 5.9325.60 5.25 25.30 6.7724.90 5.01 knee flexor12.60 3.55 14.70 2.70 * 13.10 3.15 14.80 2.98 *
ankle dorsiflexor19.00 4.48 23.80 4.28 * 18.10 5.13 23.80 4.40 * ankle plantarflexor28.70 4.33 33.80 5.46 * 28.10 3.50 34.90 5.92 * * significance at p < 0.05 compared to pre - training .
four groups , the hip flexor ( left leg , p = 0.0013 ; right leg p = 0.0005 ) ,
knee flexor ( left leg , p = 0.0105 ; right leg , p = 0.0033 ) , ankle dorsiflexor ( left leg , p =
0.0005 ; right leg , p = 0.0001 ) and ankle plantarflexor ( left leg , p = 0.0015 ; right leg , p =
0.0103 ) , showed significant improvement . *
the post - test results , after the subjects had exercised on a wii balance board , showed
significantly better los than the pre - test results .
the reaction time of the post - test
subjects was significantly faster in the forward right and backward left directions .
reaction time is represents the time lag between the prompt to move and the start of
movement16 .
this result means the
subjects were able to respond to prompts faster and spend less time processing information
than in the pretest . these results may be explained by an increased level of concentration
which wound have allowed the subjects to keep their body in the correct or best position .
such awareness would have affected subjects motor systems , nervous systems and
proprioceptive systems by enabling them to learn how to respond to the prompt17 .
a previous study found that exercises
with the nintendo wii fit improved muscle strength and the speed of the
cognitive timed up and go test18 , because
nintendo wii fit training involves considerable single - limb balance
requirements and body - weight resistance workouts that intuitively produce these results .
the movement velocity is the average speed of the center of gravity ( cog ) movement that
occurred between 5% and 95% of the endpoint of the excursion16 .
in other words , the subjects were able to more rapidly move their
cog .
this may be a result of practice and repetition because the subjects learned the
self - perceived cognitive response in order to implement a safer strategy ( i.e. , when they
moved their cog , they did not experience the fear of falling ) and achieve higher
biomechanical efficiency19 .
the maximum excursion is a feedback movement control that helps subjects to correct the
direction of movement , while the endpoint excursion is the ability to pre - plan ( feed forward
control ) the magnitude of the movement16 .
the maximum excursion showed significant increases in forward , forward right , backward left
and left direction , and the endpoint excursion showed similar increases in the forward and
forward right directions .
a possible explanation for these results is that the wii balance
board detects the cog of the subject and displays feedback on the monitor , which may promote
the motor learning of the subject20 .
another possible explanation is that the subjects learned how to shift their body weights
and how to coordinate their bodies in order to maintain balance , execute smooth movement ,
and reach different target positions through practice21 .
a previous study found that postural stability decreased while weight - bearing asymmetry
increased22 , which means that subjects
require greater postural control in a single - leg stance than in a double - leg stance23 .
the pre- and post - training results of the
present study were not significantly different in the unilateral stance test .
however , the
findings of the current study are not supported by previous research24 .
these differences can be explained in part by the
difference in the amount of exercise ( 2 30 min / week for 10 weeks in the previous study vs.
2 30 min / week for 8 weeks in the present study ) and the type of wii balance board
exercises ( yoga , balance , aerobic and strength activities in the previous study vs. yoga and
strength in the present study ) .
the results of a recent study , which researched the effects of playing on a nintendo wii
balance board on lower - limb muscle strength , showed that it could significantly strengthen
the muscles of the lower limbs12 . in the
video games , players have to follow fixed - movement patterns during the game .
all of the
movement patterns or positions would challenge players muscles to contract as they would
during exercise .
our results show that lower - limb muscle strength can be improved by wii
balance board exercise .
however , only four muscle groups were significantly improved in this
study ( hip flexor , knee flexor , ankle dorsiflexor and ankle plantarflexor ) . in a previous
study ,
the hip and knee extensor muscles of young adults24 , high body weight subjects and healthy subjects25 were shown to have high strength without
exercise , compared to the hip and knee flexors , which have low strength .
this outcome may be because activities in daily life often affect
the hip and knee extensor muscles more often than the hip and knee flexor muscles .
a
previous study established that stepping significantly improves the strengths of only the
hip abductor and knee extensor muscles27 .
the results also showed that the knee extensor muscles were already strong through
performing the activities that people often do on a daily basis .
in addition , exercise to
strengthen the lower - limb muscles elicited more improvement in the hip and knee flexor
muscles than in the hip and knee extensor muscles27 .
this result indicates that low - strength muscles may be more
challenged and show more improvement than high - strength muscles .
there were 11 positions in
our present study s exercise program . from our analysis of muscle contraction
, the hip and
knee flexors were mostly used together with the hip and knee extensors in the same
contraction .
the results of the present study show that muscle strength was significantly
improved in the hip and knee flexors but not in the hip and knee extensors by the same
intervention , as a previous study indicated .
the hip abductor muscles were used the same in
all positions of the exercise program , but they showed no significant improvement , possibly
because the exercise program s positions only challenged them a little .
the ankle
dorsiflexor and ankle plantarflexor muscles were heavily challenged to support the whole
body weight to achieve the goal in almost all positions .
a previous study concluded that the
ankle plantarflexor and ankle dorsiflexor muscles are directly associated with the ability
to control posture28 .
the present study
required the subjects to heavily contract their ankle plantarflexor and ankle dosiflexor in
order to participate in the wii fit exercise program . a recent study demonstrated that decreased muscle power
. showed that greater lower - limb muscle strength was associated with better
balance29 .
it is possible that wii
balance board exercise not only improves muscle strength while promoting enjoyment through
the game , as our results indicate , but it may also improve balance at the same time .
, wii balance board exercise can improve the balance ability and lower - limb
muscle strength of overweight young adults .
in addition , the nintendo wii balance board
enhanced physical activity of the overweight subjects , which may have improved their quality
of life .
first , these
findings are limited by the use of a within - subject repeated measures design
thus , further study is needed to investigate the effect of other factors such as
muscle mass and fat mass .
finally , the subjects of this study were young adults , and the
findings might not be transferable to other populations .
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### Summary:
: [ purpose ] the potential health benefits of the nintendo wii balance board exercise have
been widely investigated .
however , no study has been conducted to examine the benefits of
wii exercise for overweight young adults .
the aim of this study was to investigate the
effect of exercise performed on a nintendo wii balance board on the balance and lower limb
muscle strength in overweight young adults .
[ subjects and methods ] within - subject repeated
measures analysis was used . sixteen young adults ( aged 21.871.13 years , body mass index
24.15 0.50
kg / m2 ) were recruited .
all subjects performed an exercise program
on a wii balance board for 8 weeks ( 30 min / session , twice a week for 8 weeks ) .
a neurocom
balance master and a hand - held dynamometer were used to measure balance performance and
lower limb muscle strength .
[ results ] according to the comparison of pre- and
post - intervention measurements , the wii balance board exercise program significantly
improved the limit of stability parameters .
there was also a significant increase in
strength of four lower - limb muscle groups : the hip flexor , knee flexor , ankle dorsiflexor
and ankle plantarflexor .
[ conclusion ] these findings suggest that a wii balance board
exercise program can be used to improve the balance and lower limb muscle strength of
overweight young adults .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: tooth preparation in fixed partial denture is more critical and crucial phase in fixed prosthodontics . improper clearance will lead to fracture of the restoration and jeopardize the structural durability of the prosthesis .
improper tooth reduction such as excessive occlusal clearance than the recommended amount will lead to failure in the retention and resistance property of the prosthesis and will cause irreversible pulpal damage and affects the biological principles of tooth preparation .
varying methods and techniques were used to determine the occlusal reduction , this article describes the use of arti - spot coated on color coded fleximeter strips to determine the amount of occlusal clearance during tooth preparation .
color coded fleximeter strips are placed on the occlusal surface of the prepared tooth .
the color coded strips are available in 3 colors , pink , green , and blue ( bausch flexi strips - germany ) [ figure 1]the colors indicate the thickness of the strips .
pink ( 1 mm 1 mm ) , green ( 1 mm 1.5 mm ) , blue ( 1 mm 2 mm)the surface of the strips is painted or coated with arti - spot and placed on the occlusal surface of the prepared tooth [ figure 2]after evaporation of the arti - spot solvent , it leaves a thin film of color .
every contact of the opposing teeth on the dry color will partially remove the pigment , making the basic material shine through the interferences can be easily detected [ figure 3]any interference or lack of clearance will be indicated on the paint on the flexi strips .
each color strips indicate the amount of clearance to be given , and the coated arti - spot indicate the interference area to be reduced to give proper tooth clearance [ figure 4 ] .
the color coded strips are available in 3 colors , pink , green , and blue ( bausch flexi strips - germany ) [ figure 1 ] the colors indicate the thickness of the strips .
pink ( 1 mm 1 mm ) , green ( 1 mm 1.5 mm ) , blue ( 1 mm 2 mm ) the surface of the strips is painted or coated with arti - spot and placed on the occlusal surface of the prepared tooth [ figure 2 ] after evaporation of the arti - spot solvent , it leaves a thin film of color .
every contact of the opposing teeth on the dry color will partially remove the pigment , making the basic material shine through the interferences can be easily detected [ figure 3 ] any interference or lack of clearance will be indicated on the paint on the flexi strips .
each color strips indicate the amount of clearance to be given , and the coated arti - spot indicate the interference area to be reduced to give proper tooth clearance [ figure 4 ] . color coded fleximeter strips strips coated with arti - spot arti - spot marks on prepared tooth arti - spot marking on opposing cusps
during tooth preparation for fixed partial denture occlusal clearance is more crucial to ensure long - term success of the restoration .
improper tooth reduction such as excessive occlusal clearance than the recommended amount will lead to failure in the retention and resistance property of the prosthesis and will cause irreversible pulpal damage and affects the biological principles of tooth preparation .
varying methods were used such as the use of a piece of folded blotting - paper , wax guide , periodontal probes .
fleximeter strips are also used to measure the amount of clearance by placing on the prepared tooth , but this will give only the clearance but does not show the area of interference and area of insufficient reduction .
arti - spot is a new easy use contact color for testing occlusal surfaces and for the inside of castings [ figure 5 ] .
arti - spot was formulated to identify contact interferences that prevent accurate seating of the dental restorations .
arti - spot film is resistant to saliva , and the thickness of the dry film is only 510 microns . in this technique , using an arti - spot spray coated on the flexi strips will give the amount of interference and the area of insufficient reduction .
hence , the area of interference can be easily removed , and adequate clearance will be there for the prepared tooth .
the amount of occlusal clearance during tooth preparation can be accurately determined using arti - spot coated with fleximeter strips .
the fleximeter strips gives the amount of clearance and arti - sport gives the areas of interference to be reduced .
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### Summary:
: the amount of occlusal clearance during tooth preparation for fixed partial denture is more crucial and critical phase of fixed prosthodontics . improper tooth reduction leads to compromise in structural durability and failure of the restoration . over reduction affects the biological principles of tooth preparation .
this article uses color coded fleximeter strips coated with arti - spot to determine the amount of clearance during tooth preparation in fixed partial denture .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: weak acids , such as acetic , propionic , benzoic and sorbic acids , are commonly used as preservatives to limit unwanted microbial growth in the food and beverage industry ( teixeira , mira and s - correia 2011 ) . the inhibitory effect imposed by weak acids on microorganisms
accordingly , at low ph , weak acids prevail in undissociated form , being more hydrophobic and prone to crossing the membrane by simple passive diffusion .
once inside the cell , weak acids will dissociate in the near - neutral cytosol and release protons , which can potentially acidify the cell and cause dissipation of the proton - motive force ( kotyk and georghiou 1991 ; imai and ohno 1995 ; guldfeldt and arneborg 1998 ) .
in addition , the anion of the weak acid accumulates in the cell and may reach a toxic level and affect the metabolic functions of the cell ( stratford and anslow 1998 ; bauer et al .
the antimicrobial effects of weak acids are determined by the chemical properties of the acid , in particular by the hydrophobicity and pka of the acid ( mira , teixeira and s - correia 2010 ) .
the resistance mechanisms that microorganisms develop to counteract the impact of weak acids have been intensively studied ( as reviewed in brul , kallemeijn and smits 2008 ; mira and teixeira 2013 ) .
it has been demonstrated that acid - challenged saccharomyces cerevisiae maintained intracellular ph homeostasis by atp - dependent efflux of the protons via plasma membrane h - atpase pma1p ( carmelo , santos and s - correia 1997 ) .
extrusion of anions accumulated in the cell has been reported to take place by atp - binding cassette ( abc ) transporter through an atp - driven process in s. cerevisiae ( holyoak et al .
2003 ) . however , the actions of h - atpase and pdr12 ( an atp - binding cassette transporter ) in response to acid stress result in significant increase in energy ( atp ) demand , thereby leaving less atp for cell growth ( holyoak et al .
hydrolysate fermentations , inhibitory compounds such as furan derivatives , weak acids and phenolics often hamper the fermentation ability of s. cerevisiae ( palmqvist and hahn - hgerdal 2000a ) . in order to overcome the impact of inhibitors on yeast metabolism , high initial cell density has often been employed to enhance the detoxification of some inhibitors and achieve a high volumetric fermentation rate ( chung and lee 1984 ) . for instance , enhanced rates of converting furfural and hydroxymethylfurfural to less inhibitory alcohol forms
have been observed in s. cerevisiae by using high initial cell density ( chung and lee 1984 ) .
in addition , detoxification of some phenolic acids is also expected to be enhanced at high initial cell density of s. cerevisiae as this yeast harbors phenylacrylic acid decarboxylase ( pad1 ) , which can convert cinnamic , p - coumaric and ferulic acids to the corresponding vinyl derivatives ( larsson , nilvebrant and jnsson 2001 ) .
it has been reported that the need to elevate ph to alleviate the toxicity of weak acid decreased when a high initial cell density was applied ( palmqvist and hahn - hgerdal 2000a ) . however , in order to better understand the possible effects of using high initial cell density to decrease the effect of weak acid , a detailed physiological study on yeast s. cerevisiae at high initial cell density cultivation in the presence of common weak acids that can be found in lignocellulosic hydrolysate is called for . in our previous study , we investigated the physiological response of s. cerevisiae during aerobic culture , starting from a low cell density ( 0.1 g dry cell weight ( dcw ) l ) under acid stress ( guo and olsson 2014 ) .
we found that the growth of yeast cells on glucose was impaired by the acids .
acids at moderate concentrations can stimulate glycolytic flux , while higher levels of acid slow down the glycolytic flux .
yeast cells under acid stress showed similar energy levels compared with the non - stressed cells in the exponential growth phase .
moreover , slightly higher cellular trehalose content was observed in acid - stressed cells compared with reference cultures .
this study examines s. cerevisiae physiology under acetic , formic , levulinic and cinnamic acid stress in aerobic batch cultures of high initial cell density .
aerobic cultivation conditions were chosen as aerobic production of chemicals and proteins has been commonly used for engineered s. cerevisiae , while they have been less studied than anaerobic cultivation conditions ( abbott et al .
formic acid has a lower pka value ( 3.75 at 20c ) than acetic acid ( pka 4.79 at 20c ) and levulinic acid ( pka 4.66 at 20c ) .
cinnamic acid , a phenolic acid commonly found in hydrolysates ( almeida et al .
2007 ) , is considered to exhibit high anion toxicity due to its high hydrophobicity ( reflected in a log partition octanol / water coefficient of 2.1 ) ( brul , kallemeijn and smits 2008 ) .
the following hypotheses were addressed : ( i ) regardless of initial cell density a specific acid will cause similar physiological responses of yeast cells , ( ii ) each acid will induce general and acid - specific responses of s. cerevisiae , and ( iii ) the increase in phenotypic cell - to - cell heterogeneity in a large inoculum size will improve the tolerance of s. cerevisiae to weak acid stress in high initial cell density cultivations .
the haploid , prototrophic saccharomyces cerevisiae strain cen.pk 1137d ( mata ) was used in this study and stored in 50% glycerol at 80c .
yeast cells taken from frozen stocks were grown on ypd medium containing 10 g l yeast extract , 20 g l peptone and 20 g l glucose .
all the experiments for studying physiological response of yeast to acid stress were performed in defined medium according to verduyn et al .
( 1992 ) containing 25 g l glucose and acids at the indicated concentrations .
the inoculum culture was inoculated with one single colony of yeast from a ypd agar plate that was transferred to 100 ml of defined medium ( as described above ) and cultivated until exponential growth phase in a 500 ml erlenmeyer flask , when the cells were harvested by centrifugation at 6000g for 5 min .
the cell pellet was washed , resuspended in an appropriate volume of defined medium , and then transferred into bioreactors to yield an initial biomass concentration of 1.0 g dcw l , referred to as high initial cell density ( moniruzzaman et al .
batch cultivation was conducted in a 3.0 l dasgip bioreactor ( dasgip biotools , llc , usa ) with a working volume of 2.0 l. the ph was controlled at 5.0 with the automatic addition of 2 m koh .
an aeration of 0.5 vvm was used and the stirring speed was set to 600 rpm to ensure a dissolved oxygen tension of at least 60% of air saturation .
exhaust gas from the fermenter cultures was cooled in a condenser ( 2c ) and dried .
oxygen and carbon dioxide concentrations were determined with a dasgip off - gas analyzer ga4 . to prevent excessive foaming , 0.15 ml l silicone antifoam ( sigma - aldrich ) was added .
samples were taken regularly for later determination of biomass concentration , extracellular metabolites including glucose , ethanol , glycerol , acetate , pyruvate and succinate , intracellular oxidation level , intracellular nucleotides ( atp , adp and amp ) , and the content of trehalose and glycogen . the results are shown as the mean value of three independent experiments .
culture samples ( two of 10 ml each ) were filtered over pre - weighted pes filters ( 0.45 m ; sartorius biolab , germany ) .
the retained biomass on filters was washed , dried in a microwave oven at 150 w for 15 min , and then stored in a desiccator before being weighed .
glucose , glycerol , ethanol , acetate , pyruvate , succinate , formic acid and levulinic acid of the culture broth were analyzed using an aminex hpx87-h column ( bio - rad laboratories , germany ) , with 5 mm h2so4 as the mobile phase at a flow rate of 0.6 ml min .
glucose , glycerol , ethanol and acetic acid were detected with a refractive index detector ( shodex ri-101 ; showa denko , new york , ny , usa ) .
pyruvate , succinate , formic acid and levulinic acid were detected using an uv detector at 210 nm ( dionex , sunnyvale , ca , usa ) .
samples were taken at appropriate intervals during exponential growth to determine the dry weight of yeast cultures , substrate and product concentrations in the supernatant .
values for specific rate of glucose consumption , qglc ( mmol g h ) , were calculated using the following equation : qglc = max / yx / s , where yx / s = dx / ds ( biomass yield coefficient ) was calculated using linear regression of biomass concentration ( x ) vs substrate concentration ( s ) during the exponential growth phase
. the maximum specific growth rate on glucose ( max ; h ) was estimated from the exponential part of a plot of biomass concentration vs time .
similarly , to calculate the specific production rate of ethanol , glycerol , acetate and pyruvate ( qethanol , qglycerol , qacetate , qpyruvate and qsuccinate ) , yx / s was replaced by the yield of each corresponding metabolite .
specific rates of co2 production and o2 consumption during exponential growth were calculated as described previously ( van urk et al . 1998 ) .
the calculations of flux rates and max were based on the viable cell fractions of total cell population as determined by the plate - counting method , and total biomass concentration , respectively .
lag phase was estimated by using dmfit ( www.ifr.ac.uk/safety/dmfit ) as described previously ( rolfe et al .
the product yields of metabolites including ethanol , glycerol , acetate , pyruvate and succinate were obtained as the slope of the linear curve when the metabolite concentration was plotted against the glucose concentration during exponential growth on glucose , unless stated otherwise .
biomass yield was calculated as the final biomass produced divided by the amount of substrate consumed .
ethanol evaporation rate changes with the change in volume of the medium in bioreactors due to sampling . to correct for this ,
ethanol evaporation kinetics were analyzed in bioreactors operated under identical conditions at different working volumes with cell - free medium .
the resulting volume - dependent ethanol evaporation constants ( 0.016 divided by the volume in liters , expressed in h ) were used to correct ethanol concentrations .
all data are presented as mean values of at least three biological replicates standard deviation .
briefly , culture samples were serially diluted ( dilution factors 1010 ) in sterile distilled water and 200 l of each dilution was spread on solid ypd medium .
plates were incubated at 30c for 2 days and colony forming units ( cfu ) in dilutions resulting in the range of 50150 colonies per plate were included for counting . to determine the total cell population , cultures were diluted in sterile distilled water to reach a density of approximately 1.0 10 cells ml and examined under the microscope ( thomas and ingledew 1990 ) .
the measurements of viable cell and total cell numbers were performed for at least five biological replicates to reduce the errors of these methods in the determination of cell numbers in general .
yeast vitality , referring to the yeast activity in sugar utilization , was indicated by glucose - induced proton efflux ( gipe ) and determined by the acidification power ( ap ) test as described previously ( siddique and smart 2000 ) .
the ap test contains two calculated components , water acidification power ( wap ) , which measures spontaneous h efflux sustained solely by endogenous h and energy sources , and glucose acidification power ( gap ) , which measures h efflux closely associated with the utilization of both endogenous and exogenous sources .
quantitative measurement of both processes can thus provide information on the level , availability and utilizability of endogenous energy sources and on the ability of the cells to utilize exogenous substrates .
the gipe value deduced from this assay is an indicator of the overall metabolic state of the cells ( opekarov and sigler 1982 ) .
briefly , yeast cells were harvested , washed and resuspended in distilled water to reach a final cell concentration of approximate 5.0 10 cells ml . for wap
, ph was recorded initially ( wap0 ) after adding 1 ml of cell suspension to 19 ml distilled water .
after 10 min , 5 ml distilled water was added to the cell suspension and ph was measured twice at 10 min interval ( wap10 and wap20 ) .
wap was calculated according to the following equation : wap = wap0 wap20 . for gap ,
a similar procedure was used except that instead of distilled water , 5 ml of 20% ( w / v ) glucose solution was added .
the ph was recorded after addition of cells ( gap0 ) , 10 min ( gap10 ) and 20 min ( gap20 ) after the addition of glucose solution .
consequently , gipe was calculated according to the equation : gipe = gap wap .
samples ( two with a volume of 10 ml each ) were quickly taken from the cultures and immediately placed in liquid nitrogen .
yeast cells were harvested by centrifugation of the samples at 8000 g for 5 min at 4c and the cellular trehalose and glycogen contents were measured as described previously ( parrou and franois 1997 ) , except that 0.1 u ml trehalase ( megazyme int . , bray , ireland ) was used . in this method ,
trehalose and glycogen were extracted from yeast by boiling the cells in 0.25 m na2co3 , and then hydrolyzed to glucose by purified trehalase and amyloglucosidase , respectively .
the released glucose was quantified with an enzymatic kit ( biosis , biotechnological applications ltd , athens , greece ) .
cellular contents of adenosine nucleotides were determined as described previously ( ask et al .
briefly , samples ( two of 5 ml each ) were quenched in 25 ml pure methanol at 40c .
cellular atp , adp and amp were extracted by incubation of cell pellets with 0.5 ml 0.52 m trichloroacetic acid containing 17 mm edta on ice for 15 min .
adenosine nucleotides were separated on a luna 5 m c18(2 ) 100 lc column ( 150 4.6 mm ) ( phenomenex inc . , torrance , ca , usa ) using acetonitrile and tetrabutylammonium buffer ( 0.005 m tetrabutylammonium hydrogensulfate , 0.01 m na2hpo4 , ph 7.0 ) as mobile phase at a flow rate of 1.0 ml min at 20c . the detection was performed with a photodiode array detector ( pda-3000 ; dionex corp . ) at 260 nm .
the energy charge was calculated according to the following equation : energy charge = ( atp + adp)/(atp + adp + amp ) intracellular oxidation level of yeast was estimated by using the oxidant - sensitive probe 2,7-dichlorofluorescin diacetate as described by nomura and takagi ( 2004 ) .
hcl buffer ( 50 mm , ph 7.4 , 3 mm edta and 0.5 mm phenylmethylsulfonyl fluoride ) using an mp fastprep-24 instrument ( mp biomedicals inc . ) .
the homogenate was centrifuged ( 10 000g for 10 min ) and the cell - free extract was obtained and used for the following fluorescence measurement .
fluorescence was measured with ex = 490 nm and em = 524 nm using the safire ii spectrofluorometer ( tecan , austria ) .
intracellular oxidation level was defined as the value of ex = 524 nm divided by the protein concentration in the cell - free extract .
the protein content was determined by a modified biuret method , using bovine serum albumin as a standard ( verduyn et al .
to investigate the effects of different acids on aerobic s. cerevisiae cultures at comparatively high initial cell density ( 1.0 g dcw l ) , yeast was grown on defined medium containing 25 g l glucose at ph 5.0 .
yeast cells grown without acid addition were used for comparison and will in the following be referred to as the reference .
the concentration of each acid required to reduce the biomass yield during growth on glucose by 50% as compared with the reference was determined ( table 1 ) .
the undissociated acid ( concentrations also shown in table 1 ) that can cross the cell membrane by passive diffusion and the anion of weak acids have been shown to be key factors in acid toxicity ( abbott et al .
2007 ;
it was noticed that the amount of acid required to reduce the biomass yield by half was related to the hydrophobicity of acetic acid , levulinic acid and cinnamic acid .
for the most hydrophobic acid , cinnamic acid , the undissociated form at 0.17 mm led to a 50% reduction in biomass yield .
although formic acid is less hydrophobic than acetic and levulinic acids , the amount of undissociated formic acid ( 12.2 mm ) required to decrease the biomass yield by 50% was much lower than that of acetic acid ( 114 mm ) and levulinic acid ( 106 mm ) .
this implied that a unique chemical property of formic acid is the determinant of its toxicity , which has been ascribed to its small molecular size ( palmqvist and hahn - hgerdal 2000b ) . according to our previous results ,
a lower amount of undissociated acetic acid ( 83.9 mm ) , formic acid ( 10 mm ) and levulinic acid ( 76.0 mm ) was required to reduce biomass yield by half when low initial cell density was used ( guo and olsson 2014 ) , compared with the high cell densities applied in the current study . in addition , yeast failed to grow in the presence of 300 mm acetic acid when the culture started with an initial cell density of 0.1 g dcw l. therefore , the acid level in the culture that s. cerevisiae can tolerate increased by increasing the initial cell density .
effect of weak acids on the length of the lag phase and the maximum apparent specific growth rate at ph 5 under aerobic conditions .
the results were calculated from at least three biological replicates , and are given as the mean values standard deviation .
n / a : not available . the lipophilic tendency given by the partition coefficient octanol water ( p ) .
saccharomyces cerevisiae exhibited quite different growth profiles with the imposed acid stress compared with the reference condition ( fig .
the yeast first grew on glucose and produced ethanol , and then grew on ethanol when glucose was depleted .
no obvious lag phase was observed between the two growth phases ( table 1 , fig .
yeast cells exposed to acetic acid or levulinic acid showed a 26 h and a 44 h lag phase on glucose , respectively , whereas addition of formic acid to the culture only resulted in a 4 h lag phase ( fig .
no obvious lag phase was observed for cinnamic acid - stressed cells grown on glucose ( fig .
the cultivation process started at a low initial cell density , a lower amount of acetic acid ( 220 mm ) than the concentration used in the present study resulted in a 36 h lag phase .
yeast cells exposed to the same concentration of formic and levulinic acid exhibited a 72 h and a 69 h lag phase , respectively ( guo and olsson 2014 ) .
comparison of ethanol , biomass production and sugar consumption of s. cerevisiae during aerobic culture with no acid added ( a ) or with addition of 300 mm acetic acid ( b ) , 220 mm formic acid ( c ) , 400 mm levulinic acid ( d ) and 0.8 mm cinnamic acid ( e ) at ph 5.0 .
the cultivation process in the presence of acetic acid , formic acid and levulinic acid was divided by the dashed line into four phases : i , lag phase ( adaptation phase ) ; ii , growth on glucose ; iii , lag phase ; and iv , second growth phase .
the cultivation process in the presence of cinnamic acid only showed phase ii and phase iii .
the results were calculated from biological replicates ( n = 3 ) and are given as the mean value standard deviation .
the observed shorter lag phase when applying high initial cell density may find explanation in a recent publication where 38 s. cerevisiae strains were compared for their tolerance to acetic acid ( swinnen et al .
the duration of the lag phase was primarily determined by the fraction of cells within the population that resume growth in a strain - dependent manner .
the subpopulation that resumes growth after acetic acid exposure was a result of phenotypic cell - to - cell heterogeneity ( swinnen et al .
2014 ) . in our case , the total amount of viable cells in the high initial cell density cultivation was 10-fold that of low initial cell density during the lag phase ( fig .
it is likely that a higher number of viable cells in high initial cell density culture could increase the likelihood of heterogeneity , and therefore , increase the likelihood that the cells resume growth asynchronously during the acid - adaptation phase , which may have contributed to a shorter lag phase than that of cells at low initial density . in support of this , high initial cell density yielded great variation in the length of the lag phase of yeast cells exposed to different amounts of acetic acid , which were all shorter than that of low initial cell density cultivation ( supplementary fig .
s1 ) . vitality ( a ) and viable fractions ( b ) of s. cerevisiae cen.pk 1137d in aerobic cultures without or with addition of 300 mm acetic acid , 220 mm formic acid , 400 mm levulinic acid and 0.8 mm cinnamic acid .
the results were calculated from biological replicates ( n = 3 ) and are given as the mean value standard deviation . in spite of the observed shorter lag phase in high initial cell density cultivations , the actual maximum specific growth rate on glucose ( max - glu ) of yeast cells under acetic , formic , levulinic and cinnamic acid was only 27% , 42% , 36% and 15% , respectively , of that of the reference strain ( 0.26 h ) ( table 1 , fig .
1 ) . however , yeast cells at the same concentration of formic and levulinic acid exhibited less decrease in max - glu ( 50 and 55% , respectively ) , compared with the control ( 0.41 h ) in low initial cell density cultivations ( guo and olsson 2014 ) .
it should be pointed out that because of the presence of dead cells and/or cells in a viable but non - proliferating state , max calculated on the total biomass concentration , referred to as apparent specific growth rate ( app .
max ) ( vrede 1998 ) , was lower than that of the actual max ( supplementary table s1 ) .
no growth could be observed during the ethanol consumption phase in the presence of cinnamic acid ( fig .
the more severe inhibitory effect of the acids on cells during the ethanol growth phase compared with that of cells during the glucose growth phase may have resulted from the low efficiency in energy generation on ethanol compared with that on glucose ( yatp - glucose / yatp - ethanol 2.1 ) ( verduyn et al .
therefore , accumulation of cellular acid and acidification of the cytosol may not be avoided ( stratford and anslow 1998 ; ullah et al .
further analysis of the cellular energy level of the acid stressed cells is needed to confirm this . in order to better understand the influence of increase in initial cell density on acid - adaptation , cell viabilities , indicated by the fraction of viable cells in total cell counts , were determined . as a complement ,
the vitalities of cells , reflected by glucose - induced proton efflux ( gipe ) , were determined by the apt ( see material and methods ) ( fig .
the ap test has been developed by opekarov and sigler ( 1982 ) and it is based on the findings that the ability of yeast cells to excrete protons through the action of membrane h - atpase , h / k exchange , and production of co2 and organic acids is a strictly controlled process that reflects the metabolic activity of the cells ( sigler , knotkov and kotyk 1981a ; sigler et al
1981b ; sigler , pascual and romay 1983 ) . in this assay ,
water acidification power ( wap ) is believed to correlate with the metabolism of endogenous substrates such as glycogen and trehalose , whereas glucose acidification power ( gap ) is related to the ability to utilize intra- and extracellular substrates ( siddique and smart 2000 ) .
the determination of wap and gap allows the calculation of net gipe ( calculated by subtracting the value of wap from gap ) , which reflects the net efflux of proton across the cell membrane induced only by glucose metabolism . in the reference cultivation ,
more than 95% of the yeast cells remained viable during the 20 h cultivation process , and the gipe value increased up to 1.6 for yeast cells grown on glucose , after which it slowly declined after glucose was depleted ( fig .
however , for cultures where the acids were added , gipe values decreased greatly during the lag phase ( fig .
after the yeast cells started to grow , the gipe values increased up to 0.7 and 0.6 for acetic and levulinic acid - stressed cells , respectively .
in contrast to observed low yeast vitalities , cell viability was measured to approximately 85% for the cultures where acetic , formic and levulinic acids were added when glucose was present ( fig .
even though more than 95% of the yeast cells exposed to the same acids remained viable during acid adaptation in low initial cell density cultivations ( guo and olsson 2014 ) , they only account for 10% of the viable cell fractions in high initial cell density cultivations during the same growth period .
therefore , increasing the initial cell density greatly increased the viable cell fractions in acid adaptation , which may have contributed to a shorter lag phase than that of low initial cell density .
however , the viable fractions dropped to 70% as soon as the glucose was exhausted .
this is consistent with the previous observation that yeast cells that do not resume growth die after prolonged exposure to acetic acid ( swinnen et al .
moreover , the inhibitory effects of cinnamic acid on yeast cells were more pronounced , as can be seen from the substantial decline in viable fraction ( as low as 40% ) and vitality ( about 0.2 ) .
it should be noticed that the ap test , even though it has been widely employed for evaluating the metabolic activity of yeast under different conditions such as starvation , acid washing , dehydration and hyper - osmolality ( sigler et al .
2006 ) , has not been used to estimate the changes in cellular physiology caused by acid stress .
comparing the gipe data with the recently developed methylene blue dye reduction test ( li et al .
2011 ) has confirmed the validity of the ap test to study the vitality of yeast under weak acid stress ( supplementary fig .
, we observed that adding acetic acid , formic acid and levulinic acid at concentrations leading to a reduction of the biomass yield by 50% resulted in 24% , 15% and 16% increase , respectively , in the specific rate of glucose consumption compared with the reference ( 16.7 mmol g h ) , while higher levels of acid slowed down the glycolytic flux in aerobic cultivation of s. cerevisiae when using low cell density ( guo and olsson 2014 ) .
here , we studied the effects on carbon flux to investigate the influence of acid on glycolysis in high initial cell density cultivations . in general , yeast cells exposed to different acid stress exhibited significant decrease in the specific rates of glucose uptake and ethanol production , largely dependent on the property of the acid , as compared with the reference ( table 2 ) .
the low specific rates of glucose consumption and ethanol production for the acid - stressed cells can be largely ascribed to the loss of vitality compared with the reference ( as described above ) .
in addition , yeast cells that exhibited higher vitality under acid stress showed higher flux rates .
acetic acid - stressed cells showed a specific glucose uptake rate of 7.9 mmol g h , and ethanol production rate of 13.8 mmol g h , which were similar to that of the levulinic acid - stressed cells ( 8.2 and 14.0 mmol g h , respectively ) , and less than that of the formic acid - stressed cells ( 9.5 and 14.8 mmol g h , respectively ) .
yeast cells exposed to cinnamic acid , exhibited higher vitality than that of the cells under stress of the other acids , and showed the highest specific rates of glucose uptake and ethanol production .
similarly , the specific rates of o2 consumption and co2 production significantly decreased as a response to different acid stress .
in addition , a 60% decrease in the specific glycerol production rate was observed for acetic , formic and cinnamic acid - stressed cells . it should be noticed again that the presence of fractions of dead cells and/or cells persisting in a viable but non - proliferating state significantly influenced the calculations of flux rates as the values of flux rates calculated on the total biomass concentration were much lower than the values obtained only on viable cells ( supplementary table s1 )
. specific production / consumption rate of s. cerevisiae cen.pk 1137d in the presence of weak acids at ph 5 under aerobic conditions .
the results were calculated from at least three biological replicates , and are given as the mean values standard deviation .
, the reference culture showed a specific ethanol consumption rate of 3.9 mmol g h. the specific ethanol consumption rate for formic acid , levulinic acid and cinnamic acid was 1.5 , 1.2 and 2.6 mmol g h , respectively .
in addition , formic acid was co - consumed with ethanol at a specific rate of 1.4 mmol g h. acetic acid was consumed at a specific rate of 0.5 mmol g h after ethanol depletion , while yeast was unable to consume levulinic acid .
the inhibitory effects of weak acids have been ascribed to uncoupling and anion accumulations , and the counteracting responses of the yeast involve export of proton and anion at the expense of atp ( stratford and anslow 1998 ; palmqvist and hahn - hgerdal 2000b ) . as a result
, glucose uptake is enhanced to facilitate the energy generation ( abbott et al .
2007 ) . as we did not observe that acids stimulate glycolysis in high cell density cultivations , the physiological response of yeast cells under acid stress was investigated at cellular energetic level ( fig .
3 ) . we found that yeast cells grown under reference conditions exhibited increased energy charge during growth on glucose compared with growth on ethanol , while the energy charge of acetic , formic and levulinic acid - stressed cells dropped immediately after inoculation ( fig .
the energy charge of yeast cells exposed to levulinic acid was around 0.4 , which was significantly lower than that of acetic acid - stressed cells ( > 0.6 ) .
yeast cells cultured in the presence of formic acid showed higher energy charge than the acetic acid - stressed cells during the glucose lag phase .
however , the energy charge dropped dramatically to as low as 0.1 after the glucose growth phase , which was significantly lower than the charge for the cells exposed to acetic acid and levulinic acid .
therefore , the presence of acid caused significant atp depletion and this effect is more pronounced when the carbon source was depleted .
the energy charge of acetic , formic and levulinic acid - stressed cells increased during the exponential growth phase both on glucose and on ethanol , but these values were still lower than the reference .
intracellular energy level of s. cerevisiae cen.pk 1137d in aerobic cultures without or with addition of 300 mm acetic acid , 220 mm formic acid , 400 mm levulinic acid and 0.8 mm cinnamic acid .
the results were calculated from biological replicates ( n = 3 ) and are given as the mean value standard deviation . in order to investigate acid - specific effects on product formation , the extracellular metabolites were measured during exponential growth phase on glucose . the ethanol yield for yeast cells exposed to formic , levulinic and cinnamic acid increased by 18% , 10% and 25% , respectively , compared with 0.44 c - molc - mol for the reference cultivation ( table 3 ) .
addition of 300 mm acetic acid , however , led to a 34% decrease in ethanol yield as compared with the reference condition .
comparison of growth and product yields of s. cerevisiae cen.pk 1137d during aerobic batch growth in the presence of different acids .
the yields of other metabolites were obtained as the slope of the linear curve when the biomass or metabolite concentration was plotted against the glucose concentration during exponential growth on glucose .
the results were calculated from at least three biological replicates , and are given as the mean value standard deviation .
nd : not detectable . based on glucose and acetate consumed . for the reference culture ,
a biomass yield of 0.35 c - molc - mol was obtained ( table 3 ) . for acetic acid - stressed cells ,
a final biomass yield of 0.14 c - molc - mol was calculated by taking into account acetate that had been consumed in addition to glucose , as acetate can be used for biomass synthesis under aerobic condition ( van den berg et al .
slightly lower biomass yield was obtained for levulinic acid - stressed cells compared with the culture supplemented with acetic acid .
addition of 190 mm formic acid produced a biomass yield around 0.17 c - molc - mol . for cultures to which cinnamic acid was added , the final biomass yield was only 0.05 c - molc - mol , corresponding to only 14% of the reference .
the observed decrease in biomass yield with the addition of weak acids is a physiological response in line with the uncoupling mechanism ( russel 1992 ) .
the impact of acid on biomass production was not relieved until the acid was consumed .
however , no consumption of formic , acetic and levulinic acids was observed when glucose was present in the cultures , while high initial cell density did enhance the conversion yield of cinnamic acid during the adaption phase ( fig .
phenylethyl alcohol and dihydrocinnamic acid were detected as the products of cinnamic acid degradation ( corresponding to 5% conversion yield of cinnamic acid ) .
weak acids have been shown to trigger endogenous production of superoxide free radicals by affecting the function of the mitochondrial respiratory chain of s. cerevisiae , probably by diminishing the proton - motive force of the mitochondria ( kotyk and georghiou 1991 ; piper 1999 ) .
in particular , oxidative stress caused by weak acids is enhanced in aerobic yeast cultures due to the activation of the respiratory chain ( piper 1999 ) .
the intracellular oxidation level ( iol ) of yeast cells grown at reference condition was relatively low ( fig .
however , a sharp increase in iol was observed after inoculation in cultures containing acetic and formic acid , but not for cinnamic and levulinic acid - stressed cells .
after that , a gradual decrease in iol was observed for yeast cells exposed to acetic acid in lag phase and for the cells grown in the presence of formic acid and levulinic acid , respectively ( fig .
yeast cells exposed to formic acid grown on glucose maintained similar iol , but yeast cells exposed to cinnamic acid exhibited much higher iol in comparison with the reference case during the same growth phase .
yeast cells under levulinic acid stress exhibited a higher iol than acetic acid - stressed cells during the lag phase .
subsequently , the iol decreased when yeast cells started to grow on glucose ( fig .
4 ) . in general , iols dramatically increased after glucose was depleted , and reached the highest level at the end of cultivation . intracellular oxidation level of s. cerevisiae cen.pk 1137d in aerobic cultures without or with addition of 300 mm acetic acid , 220 mm formic acid , 400 mm levulinic acid and 0.8 mm cinnamic acid .
the results were calculated from biological replicates ( n = 3 ) and are given as the mean value standard deviation .
the substantial increase in iol reflected that yeast cells exposed to acids suffered from severe oxidative stress .
as trehalose has been shown to protect proteins from oxidative damage and reduce the levels of lipid peroxidation in s. cerevisiae during direct oxidative stress ( benaroudj , lee and goldberg 2001 ; oku et al .
2003 ) , trehalose and glycogen content of the yeast cells were monitored to investigate the response of reserve carbohydrate synthesis to acid stress ( fig .
trehalose and glycogen content for the reference cells were less than 2% of cell weight in the whole process of cultivation ( fig .
exposure of the yeast cells to acids immediately triggered the accumulation of cellular trehalose , especially for acetic acid and levulinic acid - challenged cells , for which the accumulation of trehalose was up to 9% of cell content during the lag phase ( fig .
the cellular trehalose content decreased when yeast cells started to grow on glucose in the presence of acids , and declined to a level similar to the reference when the extracellular carbon source was depleted .
increase in cellular glycogen content was observed only for acetic acid - stressed cells as compared with the reference case .
it remains unclear why acetic acid triggers glycogen accumulation , as no evidence has shown a protective role of glycogen under stress conditions ( fig .
cellular trehalose ( a ) and glycogen ( b ) content of s. cerevisiae cen.pk 1137d in aerobic cultures without or with addition of 300 mm acetic acid , 220 mm formic acid , 400 mm levulinic acid and 0.8 mm cinnamic acid .
the results were calculated from biological replicates ( n = 3 ) and are given as the mean value standard deviation .
in several biological situations , there are indications that both trehalose and glycogen have an energetic function in yeast cells and their mobilization generally occurs at the onset of glucose depletion ( enjalbert et al .
this is different from our observations as degradation of carbohydrate storage happened in the presence of significant amount of glucose .
studies on heat and saline stress on yeast cells have demonstrated mobilization of accumulated trehalose is necessary in growth recovery of the yeast cells ( wera et al .
2000 ) , and their mobilization may be necessary to provide energy to support growth resumption after acid adaptation . this assumption may find evidence in a previous report that showed that the atp surplus produced during the rapid mobilization of reserved carbohydrates supported the budding process ( guillou et al .
interestingly , rapid mobilization of trehalose occurred when the intracellular oxidation levels of the yeast cells increased .
yeast cells with a higher cellular content of trehalose did not show any improvement in the tolerance to acid stress ( data not shown ) .
taken together , these data imply that trehalose may play a role other than protecting yeast cells from acid - induced oxidative stress .
further investigations on the regulatory network of trehalose and glycogen synthesis of the acid - stressed yeast cells are needed to elucidate any significance of accumulation and mobilization of reserve carbon sources for acid tolerance .
fermentation at high initial cell density led to a reduced lag phase and an increased level of acid that the yeast cells could tolerate under acid stress compared with low initial cell density cultivation .
comparison of physiological parameters ( yields , fluxes ) demonstrated that s. cerevisiae responds differently to acetic , formic , levulinic and cinnamic acids , largely determined by the properties of the acid .
all the acids included in our study impaired growth , inhibited glycolytic flux , caused accumulation of trehalose and caused oxidative stress .
trehalose may play a role other than protecting yeast cells from acid - induced oxidative stress . unlike the other acids ,
cinnamic acid did not cause depletion of cellular atp , but exhibited greater inhibitory action on cell function than the other acids even at very low concentration ( 0.8 mm ) .
unlike low initial cell density cultivations , exposure to the acids caused significant loss of viability and vitality .
the low vitality of yeast cells resulted in low specific rates of glucose consumption and metabolite production .
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### Summary:
: high initial cell density is used to increase volumetric productivity and shorten production time in lignocellulosic hydrolysate fermentation .
comparison of physiological parameters in high initial cell density cultivation of saccharomyces cerevisiae in the presence of acetic , formic , levulinic and cinnamic acids demonstrated general and acid - specific responses of cells .
all the acids studied impaired growth and inhibited glycolytic flux , and caused oxidative stress and accumulation of trehalose . however
, trehalose may play a role other than protecting yeast cells from acid - induced oxidative stress . unlike the other acids ,
cinnamic acid did not cause depletion of cellular atp , but abolished the growth of yeast on ethanol . compared with low initial cell density ,
increasing initial cell density reduced the lag phase and improved the bioconversion yield of cinnamic acid during acid adaptation .
in addition , yeast cells were able to grow at elevated concentrations of acid , probable due to the increase in phenotypic cell - to - cell heterogeneity in large inoculum size .
furthermore , the specific growth rate and the specific rates of glucose consumption and metabolite production were significantly lower than at low initial cell density , which was a result of the accumulation of a large fraction of cells that persisted in a viable but non - proliferating state .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: aging in the population is characterized as a worldwide process associated with the reduction of fertility rate and increased longevity .
most elderly have chronic diseases and many individuals present with more than one condition , which can compromise the functional capacity of the aged person and accelerate the fragility syndrome process .
for the most part , the elderly population has an independent and autonomous life , but a part of it becomes vulnerable to adverse events , since increased life expectancy is accompanied by physiological alterations and comorbidities that can compromise functional capacity .
functional incapacity is measured by the report of difficulties or the need for help to carry out daily living activities .
the basic activities of daily living ( adl ) are activities essential for self - care , which may be evaluated by katz index , and the instrumental activities of daily living ( iadl ) are more complex activities , which require an adaptation to the environment and are evaluated by the lawton & brody scale .
within this context , chronic diseases and their external causes configure a growing concern as to functionality of the elderly , since they commonly are associated with increased morbidity , hospitalization , readmission to emergency departments , institutionalization and mortality .
in this way , during hospitalization of the elderly in the emergency department , assessing their functional capacity is necessary , since it provides important data for nursing care and that of other professionals , who can intervene or avoid loss of functional capacity and prevent complications .
additionally , individualized care during hospitalization and patient orientation at discharge may contribute towards a reduction in readmission to emergency departments , as it is associated with a better quality of care .
to evaluate the functional capacity of the elderly admitted to the emergency department as to basic and instrumental activities of daily living .
an epidemiological cross - sectional study carried out at the emergency department of the hospital so paulo , between april and july 2013 .
patients aged 60 years or more , i.e. , considered aged , were included , as per the united nations ( un ) classification for developing countries .
the sample was composed of 200 elderly individuals admitted to the emergency department , of both sexes , non - institutionalized , who agreed to participate in the study and signed the informed consent form .
the research project was approved by the research ethics committee of the universidade federal de so paulo , under protocol number 220.550 , caae : 12704613.0.0000.5505 .
the sociodemographic and clinical variables studied were age , sex , marital status , level of schooling , occupation , family income , and presence of a caregiver , comorbidities , and medications in use .
the functional capacity of the elderly to perform adl and iadl was assessed using the katz index and the lawton & brody scale , respectively .
the katz index measures performance and dependence of the individual in six items of activities of self - care , which are feeding , sphincter control/ continence , transferring , personal hygiene / toileting , dressing , and bathing . scoring varies from 1 to 6 , in which 2 corresponds to the maximal degree of dependence ; from 3 to 5 they are classified as having partial dependence , and a score of 6 , as independent .
the lawton & brody scale , used to identify the degree of dependence for iadl , which are related to participation of the individual within the social context , is constituted by nine questions with three options each : the first indicates independence ; the second , partial dependence ; and the third , total dependence .
once the degrees of independence and dependence are defined , one proceeds to the analysis on three levels ( without help , with partial help , and can not perform ) , and for score calculation , 3 , 2 , and 1 points , respectively , with a maximal score of 27 .
the greater the score , the greater the degree of independence .
completing the form was done with the elderly or , in the case of cognitive compromise diagnosed by the physician , with the caregiver , at one time , with an average duration of 40 minutes . to compare the age with the total score of the katz index and
the lawton & brody scale , variance analysis ( anova ) was used , and for multiple comparisons , bonferroni correction .
comparison of the categorical variables with the total score of the katz index and lawton & brody scale was performed by the test or the likelihood ratio test .
mean age of the elderly was 75.3 years , most were men ( 108 ; 54% ) , retired ( 177 ; 88.5% ) , with a low level of schooling ( 147 ; 73.5% ) , and low income ( 103 ; 51.5% ) .
most of the elderly in this study were independent ( 130 ; 65% ) for the adl and partially dependent ( 154 ; 77% ) for the iadl .
the single and widowed men were more dependent than the married and divorced/ separated men .
the elderly men with jobs showed a greater percentage of independence relative to the rest .
patients with cerebrovascular diseases and dementia were more dependent than those who did not suffer from these conditions .
of the elderly classified with total dependence and independence , most did not use psychotropic medications when compared to those classified as partially independent ( table 1 ) .
table 2 shows that the greater the dependence of the elderly for iadl , the greater their dependence for adl .
this study showed a greater percentage of male elderly individuals , retired , with low level of schooling and income , like other investigations that evaluated the profile of aged patients admitted to the emergency department , seen at an emergency department , and another study that included institutionalized elderly individuals .
however , other national and international studies pointed towards the prevalence of women . the mean age of the elderly was 75.3 years , which was considered high and similar to that of other studies , with elderly people admitted to the emergency department ( 73.8 years ) .
as to the degree of dependence for adl , 65% of the aged of this study were independent , 11% were partially dependent , and 324% dependent .
the percentage of independent elderly was similar to that recorded in literature , such as , for example , an american study with percentage of independence of 56.1% for women and 77.7% for men .
the results of the study carried out among the aged , which assessed the association between functional capacity and the use of healthcare services , who resided in the metropolitan region of belo horizonte , showed that 64.2% of the elderly were independent for performing adl .
as to the categories of dependence for adl , the results obtained in this study differed from those from the literature , which describes less dependent elderly ( 6.7% ) than partially dependent elderly ( 30% ) .
for the iadl , the frequency in the category of independent elderly was lower ( 14.5% ) when compared to the others , and a high percentage of partially dependent patients was noted ( 77% ) . in this study ,
a greater degree of dependence was seen associated with greater age , female sex , being single or widowed , retired and a pensioner , and having cerebrovascular diseases . in agreement with these results , some investigations , including one multicenter study with 760 patients , found an association between greater dependence with more advanced age and female sex .
an american study evaluated the impact of functional capacity on life expectancy of the elderly and showed that the modification to worse functional conditions increased by 10% per year with age , and by 5% in mortality rates .
it was further noted that the impact of the deficiencies was greater in women .
the reduction of work activities due to retirement and the frequent occurrence of chronic conditions that lead to decreased physical capacities in this phase of life is a possible reason for the prevalence of dependence found among the retired persons and pensioners of this study .
a study carried out in the city of cuiab with the elderly also verified that the greatest degree of dependence was associated with the elderly without work - related activities .
some diseases are associated with worse functional conditions , including cardiovascular and cerebrovascular disorders and dementia .
an analysis of 329 elderly individuals from the state of minas gerais showed an association with some diseases , such as diabetes mellitus , stroke and heart diseases , with dependence for adl and iadl . in this study ,
these health conditions result in a higher number of medical visits and longer length of hospital stay .
moreover , after hospital discharge , the patient may present with a decline in functional capacity over time .
data from the emergency department of an australian hospital , where the dependence of patients was evaluated one and three months after discharge from the emergency department , showed that between the discharge and a one - month interval , 26.4% presented a drop in all iadl scores , and up to the third month , this percentage rose to 36.7% .
association between the lawton & brody scale with katz index showed a significant correlation ( p<0.0001 ) for all the domains of the lawton & brody scale , i.e. , the greater the dependence in the domains of this scale , the greater the dependence according to katz index .
the domains that presented with the highest percentage of dependence in iadl were managing medication ( 92.3% ) and use of means of transportation ( 90.3% ) ; they also showed an association with the high dependence for the adl .
a divergent result was noted in another study , in which the activities of housekeeping were the most compromised .
commonly , the decline in functional capacity of the aged individual begins in the iadl , possibly because they are related to activities that require from the individual better physical and cognitive conditions .
the limitation of this study lies in the fact that it was conducted in one single teaching hospital , which delivered care for the public healthcare system and may not represent other populations .
dependence is not considered a permanent state but a dynamic process of which evolution can be modified , prevented , or reduced . for this process to occur , qualified professionals who are committed to helping the elderly are necessary , and they need to recognize potential factors that favor functional impairment , so that prevention and intervention measures might be established to improve autonomy and independence , leading to better quality of life .
it is important to point out the role of the caregiver in cases of dependence , since they should be oriented by healthcare professionals .
the elderly admitted to the emergency department presented with higher ages , and most were men , retired , with low levels of schooling and income .
application of the functional capacity evaluation scales showed that most of the elderly were independent for the basic activities of daily living and partially dependent for the instrumental activities of daily living .
the older female individuals , both single and widowed , and with cerebrovascular diseases and dementia , were related to greater functional dependence .
there was a significant association between the lawton & brody scale and katz index , that is , the greater the dependence of the elderly considering the domains of the lawton & brody scale , the greater was their dependence on the katz index .
the domains with greatest percentages of dependence in the instrumental activities of daily living were managing medication ( 92.3% ) and the use of means of transportation , in addition to association with the high dependence for the basic activities of daily living .
avaliar a capacidade funcional dos idosos internados em um servio de emergncia para as atividades bsicas e instrumentais de vida diria .
estudo transversal com 200 idosos internados no servio de emergncia de um hospital universitrio do municpio de so paulo ( sp ) . a capacidade funcional dos idosos foi avaliada pelas escala de katz e a de lawton e brody .
os testes estatsticos utilizados foram anlise de varincia , correo de bonferroni , ou da razo de verossimilhana .
a maioria dos idosos era independente ( 65% ) , e o grau de dependncia relacionou - se a idade , sexo feminino , ser solteiro e vivo , e apresentar doenas cerebrovasculares e demncias .
os idosos mais dependentes para atividades instrumentais de vida diria apresentaram maior dependncia para as atividades bsicas .
ressalta - se a importncia da avaliao da capacidade funcional do idoso no servio de emergncia , j que esta fornece dados para a assistncia de enfermagem de modo a minimizar ou evitar seu comprometimento funcional .
o envelhecimento populacional caracteriza - se como um processo mundial associado reduo da taxa de fecundidade e ao aumento da longevidade da populao .
( ) a prevalncia de doenas crnicas no transmissveis acompanha o aumento da expectativa de vida .
a maioria dos idosos portadora de doenas crnicas e muitos indivduos apresentam mais de uma afeco , ( ) o que pode comprometer a capacidade funcional do idoso e acelerar o processo da sndrome da fragilidade .
( ) a populao idosa , em sua maioria , tem vida independente e autnoma , porm uma parcela dela torna - se vulnervel a eventos adversos , pois o aumento da expectativa de vida vem acompanhado de alteraes fisiolgicas e comorbidades que podem comprometer sua capacidade funcional .
a incapacidade funcional geralmente mensurada pelo relato de dificuldade ou de necessidade de ajuda para realizar as atividades de vida diria .
as atividades bsicas de vida diria ( abvd ) so atividades essenciais para o autocuidado , que pode ser avaliada pela escala de katz , e as atividades instrumentais de vida diria ( aivd ) so atividades mais complexas , que necessitam de adaptao ao meio ambiente e so avaliadas pela escala de lawton e brody .
nesse contexto , as doenas crnicas e as causas ex ternas configuram uma preocupao crescente , no que concerne funcionalidade dos idosos , uma vez que , comumente eles esto associados ao aumento da morbidade , hospitalizao , readmisso nos servios de emergncia , institucionalizao e mortalidade .
desse modo , durante a internao do idoso no servio de emergncia , a avaliao da sua capacidade funcional faz - se necessria , uma vez que fornece dados importantes para a assistncia de enfermagem e demais profissionais , que podem intervir para minimizar ou evitar a perda da capacidade funcional e prevenir complicaes .
alm disso , o cuidado individualizado , durante a internao e a orientao na alta do paciente , pode contribuir com reduo da readmisso nos servios de emergncia , estando associado melhor qualidade do cuidado .
avaliar a capacidade funcional dos idosos internados no servio de emergncia para as atividades bsicas e instrumentais de vida diria .
estudo epidemiolgico , transversal , realizado no servio de emergncia do hospital so paulo , entre abril e julho de 2013 .
foram includos pacientes com idade a partir de 60 anos que , conforme a classificao da organizao das naes unidas ( onu ) para pases em desenvolvimento , foram considerados idosos .
a amostra comps - se de 200 idosos , internados no servio de emergncia , de ambos os sexo , no institucionalizados , que aceitaram participar do estudo e assinaram o termo de consentimento livre e esclarecido . o projeto de pesquisa foi aprovado pelo comit de tica em pesquisa da universidade federal de so paulo , sob o nmero de protocolo 220.550 , caae : 12704613.0.0000.5505 . as variveis sociodemogrficas e clnicas estudadas foram idade , sexo , estado civil , escolaridade , ocupao , renda familiar , presena de cuidador , comorbidades e medicamentos em uso .
a capacidade funcional dos idosos para realizar as abvd e as aivd foi avaliada pela escala de katz e escala de lawton e brody , respectivamente .
a escala de katz mensura o desempenho e o grau de dependncia do indivduo em seis itens de atividades do autocuidado , que so alimentao , controle de esfncteres , transferncia , higiene pessoal , capacidade para se vestir e tomar banho .
a pontuao varia de 1 a 6 , sendo que 2 correspondem ao grau mximo de dependncia ; de 3 a 5 so classificados com dependncia parcial ; e escore 6 , como independentes .
a escala de lawton e brody , utilizada para conhecer o grau de dependncia para as aivd , relacionadas participao do indivduo no contexto social , constituda por nove questes , com trs opes cada : a primeira indica independncia ; a segunda , dependncia parcial ; e a terceira , dependncia total . definidos os graus de independncia e dependncia , procede - se anlise em trs nveis ( sem ajuda , com ajuda parcial
e no consegue ) e , para o clculo do escore , so atribudos 3 , 2 e 1 pontos , respectivamente , com pontuao mxima de 27 .
o preenchimento do formulrio foi realizado com os idosos ou , no caso de comprometimento cognitivo diagnosticado pelo mdico , com o cuidador , em um nico momento , com durao mdia de 40 minutos .
para comparar a idade com o escore total das escalas de katz e de lawton e brody , foi utilizada a anlise de varincia ( anova ) e , para as comparaes mltiplas , utilizou - se a correo de bonferroni . a comparao das variveis categricas com o escore total das escalas de katz e de lawton e brody foi realizada por meio do teste ou da razo de verossimilhana .
a idade mdia dos idosos foi 75,3 anos , a maioria era homens ( 108 ; 54% ) , aposentados ( 177 ; 88,5% ) , com baixa escolaridade ( 147 ; 73,5% ) e baixa renda ( 103 ; 51,5% ) .
a maioria dos idosos deste estudo apresentava - se independente ( 130 ; 65% ) para as abvd e parcialmente dependente ( 154 ; 77% ) para as aivd .
os idosos com dependncia parcial e total tinham idade maior que os independentes . as idosas apresentaram maior dependncia quando comparadas aos idosos .
pacientes com doenas cerebrovasculares e demncias foram mais dependentes que aqueles que no tinham essas doenas . dos idosos classificados com dependncia total e independncia , a maioria no utilizava medicaes psicotrpicas , quando comparada queles classificados como parcialmente independentes ( tabela 1 ) .
observa - se , na tabela 2 , que quanto maior a dependncia dos idosos para aivd , maior foi a sua dependncia para as abvd .
neste estudo , verificou - se maior percentual de idosos do sexo masculino , aposentados , com baixa escolaridade e renda , semelhante a outros , que avaliaram o perfil dos idosos internados no servio de emergncia , atendidos em um pronto atendimento , e outro que estudou idosos institucionalizados .
no entanto , outros estudos , nacionais e de outros pases , apontaram prevalncia do sexo feminino . , a mdia de idade dos idosos foi de 75,3 anos , considerada elevada e semelhante a de outros trabalhos , com idosos internados no servio de emergncia ( 73,8 anos ) .
em relao ao grau de dependncia para as abvd , 65% dos idosos deste estudo eram independentes , 11% eram parcialmente dependentes e 24% dependentes .
o percentual de idosos independentes foi semelhante ao registrado na literatura , como , por exemplo , em pesquisa americana , na qual os percentuais de independncia foram de 56,1% para mulheres e de 77,7% para homens .
os resultados de estudo realizado entre idosos , que avaliou a associao entre capacidade funcional e a utilizao dos servios de sade , residentes na regio metropolitana de belo horizonte , mostraram que 64,2% do total de idosos eram independentes para realizao das abvd .
quanto s categorias de dependncia para as abvd , os resultados obtidos neste estudo diferiram dos da literatura , segundo a qual a proporo de idosos dependentes ( 6,7% ) foi menor que a dos parcialmente dependentes ( 30% ) .
para as aivd , a frequncia na categoria de idosos independentes foi menor ( 14,5% ) quando comparada a outras , e observou - se elevado percentual de pacientes parcialmente dependentes ( 77% ) .
neste estudo , verificou - se maior grau de dependncia associado a maior idade , sexo feminino , ser solteiro e vivo , aposentado e pensionista , e ter doenas cerebrovasculares .
em concordncia com esses resultados , estudos , inclusive um multicntrico com 760 pa cientes , encontraram associao da maior dependncia com idade mais avanada e ao sexo feminino .
estudo americano avaliou o impacto da capacidade funcional na expectativa de vida de idosos e mostrou que a modificao para piores condies funcionais aumentou em 10% por ano com a idade , sendo que esse aumento foi de 5% nas taxas de mortalidade .
observou - se , ainda , que o impacto das deficincias foi maior nas mulheres .
a reduo das atividades de trabalho , em razo da aposentadoria e da ocorrncia frequente de condies crnicas que acarretam diminuio das capacidades fsicas nesse perodo da vida , uma possvel razo para a prevalncia de dependncia encontrada entre os apo sentados e pensionistas deste estudo .
pesquisa realizada em cuiab com idosos tambm verificou que o maior grau de dependncia estava associado aos idosos sem atividade laboral .
algumas doenas associam - se a piores condies funcionais , dentre elas as cardiovasculares , cerebrovasculares e demncia . anlise de 329 idosos de minas gerais evidenciou associao de doenas como diabetes mellitus , acidente vascular enceflico e doenas carda cas , com a dependncia para as abvd e aivd .
essas condies de sade resultam em maior nmero de visitas mdicas e tempo de internao hospitalar e , aps a alta hos pitalar , o paciente pode apresentar declnio de sua capacidade funcional no decorrer do tempo .
dados do servio de emergncia de um hospital australiano , em que foi avaliada a dependncia de pacientes aps 1 e 3 meses da alta do servio de emergncia , mostraram que entre a alta hospitalar e no intervalo de 1 ms , 26,4% apresentaram reduo em todos os escores das aivd e , at o terceiro ms , esse percentual elevou - se para 36,7% .
a associao da escala de lawton e brody com a de katz mostrou correlao significativa ( p<0,0001 ) para todos os domnios da escala de lawton e brody , ou seja , quanto maior a dependncia nos domnios desta escala , maior foi a dependncia , segundo a escala de katz . os domnios que apresentaram maior percentual de dependncia nas aivd foram o manuseio da medicao ( 92,3% ) e uso do meio de transportes ( 90,3% ) ; eles tambm tiveram associao com a elevada dependncia para as abvd .
resultado divergente foi observado em outro estudo , no qual as atividades de arrumao foram as mais comprometidas .
comumente , o declnio da capacidade funcional do idoso tem incio nas aivd , possivelmente por estarem relacionadas a atividades que exigem do indivduo melhores condies fsicas e cognitivas .
a limitao do presente estudo esteve no fato de ele ter sido realizado em um nico hospital universitrio , que prestava assistncia a pacientes do sistema pblico , podendo no representar outras realidades . a dependncia no considerada um estado permanente , mas um processo dinmico , cuja evoluo pode ser modificada , prevenida ou reduzida .
para que esse processo acontea , so necessrios profissionais qualificados e comprometidos com a assistncia ao idoso , e que estes reconheam potenciais fatores que favoream os comprometimentos funcionais , para que sejam estabelecidas medidas preventivas e de interveno precoce para melhoria da autonomia e independncia com vistas a favorecer a qualidade de vida .
importante ressaltar o papel do cuidador nos casos de dependncia , pois estes devem ser orientados e estimulados pelos profissionais de sade .
os idosos internados no servio de emergncia apresentavam faixa etria mais elevada , em sua maioria eram homens , aposentados , com baixa escolaridade e baixa renda .
a aplicao das escalas de avaliao da capacidade funcional evidenciou que a maioria dos idosos era independente para as atividades bsicas de vida diria e parcialmente dependente para as atividades instrumentais de vida diria .
os idosos mais velhos , do sexo feminino , solteiros e vivos , e com doenas cerebrovasculares e demncia relacionaram - se a maior dependncia funcional .
houve associao significativa entre a escala de lawton e brody e a de katz , ou seja , quanto maior a dependncia dos idosos considerando os domnios da escala de lawton e brody , maior foi a sua dependncia pela escala de katz .
os domnios com maior percentual de dependncia nas atividades instrumentais de vida diria foram o manuseio da medicao ( 92,3% )
e uso do meio de transportes , e tambm tiveram associao com a elevada dependncia para as atividades bsicas de vida diria .
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### Summary:
: abstractobjective : to assess the functional capacity of elderly patients in the emergency department as to basic and instrumental activities of daily living.methods:a cross - sectional study of 200 elderly patients admitted to the emergency department of a teaching hospital in so paulo ( sp ) , brazil .
the functional capacity of the elderly was assessed by the katz index and lawton & brody scale .
statistical analyses were performed using analysis of variance , bonferroni correction , 2 test , or the likelihood ratio test.results:most seniors were independent ( 65% ) , and the degree of dependence was related to age , female gender , being single and widowed , and presence of cerebrovascular disease and dementia . the more dependent elderly for instrumental activities of daily living had increased dependence for basic activities.conclusion:we emphasize the importance of assessing the functional capacity of the elderly in the emergency department as it provides data for the nursing care in order to minimize or to avoid their functional impairment .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: during the last 2 centuries , cholera has spread from the indian subcontinent to cause seven global pandemics , during which this rapidly dehydrating diarrheal disease has killed millions in asia , africa , europe , and the americas .
how has cholera toxin - producing vibrio cholerae serogroup o1 , the cause of the sixth and ongoing seventh cholera pandemics , spread from continent to continent ?
remarkably , john snow , who founded modern epidemiology with his groundbreaking analyses of the spread of cholera in london in the late 1840s and 1850s ( 3 decades before koch s discovery of v. cholerae in 1883 ) , provided the answer .
he noticed that the first case of cholera in 1848 in london , which had been free of the disease for several years , occurred in a seaman from hamburg , a city that had recently experienced a large cholera outbreak . to snow ,
the conclusion was clear : the causative agent of cholera was transported from germany to england by the infected seaman ( 1 ) .
his hypothesis that contamination of the local environment by this sick seaman caused the outbreak provided a controversial but ultimately compelling alternative to the miasma theory of cholera transmission , the predominant model at the time , which linked disease to the noxious air of unsanitary spaces . in subsequent years
, the sixth and ongoing seventh cholera pandemics have wreaked havoc in the americas , but there is no reported history of cholera in haiti until 2010 ( 2 ) . however , an earthquake in january 2010 severely damaged the already marginal haitian public sanitation system , creating ideal conditions for the spread of the disease following its introduction .
the extent of the outbreak has been devastating . since the first cholera cases were recognized in october 2010 , nearly 8,200 cholera deaths and more than 668,000 cholera cases ( almost 7% of the population )
have been reported by the haitian ministry of public health ( http://www.mspp.gouv.ht/site/index.php ) . despite compelling epidemiological and genomic evidence linking united nations security forces from nepal to the introduction of cholera to haiti ( 35 ) ,
questions have been raised about the role of autochthonous v. cholerae strains in triggering the haitian cholera outbreak and serving as a source of horizontally transmitted genetic material that was incorporated into the initial outbreak strain ( 6 , 7 ) . given questions about accountability for the outbreak and the possible associated legal ramifications ( see http://www.law.yale.edu/news/17237.htm ) , new insights into this controversy will be welcomed by scientists and lay persons alike . in a recent mbio paper , katz et al . used whole - genome - based analyses to investigate the nature and pace of genomic changes in a series of v. cholerae o1 isolates from the ongoing haitian epidemic ( 8) . as the authors noted ,
an unprecedented natural experiment for characterizing in detail the intrinsic tempo and mode of genome evolution in this deadly pathogen .
their findings reinforce the evidence that the haitian outbreak began after the introduction of a v. cholerae o1 strain from nepal , argue convincingly against the idea that indigenous v. cholerae contributed to the genome of the outbreak strain , provide insights into the evolution of this ancient pathogen , and demonstrate the enormous power and utility that whole - genome - based investigations can bring to epidemiology and forensics .
the authors sequenced 23 v. cholerae o1 genomes drawn from over 20 months , 13 locations dispersed across haiti , and multiple pulsed - field gel electrophoresis ( pfge ) patterns .
comparisons of these genomes with 108 v. cholerae genomes from other global sources , including contemporaneous isolates from thailand , bangladesh , nepal , cameroon , india , pakistan , and benin , demonstrated not only that the haitian isolates were nearly identical to isolates from nepal but also that the nepal - haiti isolates were clearly distinct from isolates circulating elsewhere in the world .
notably , reconstruction of the phylogeny of the haitian isolates with a bayesian coalescent model was consistent with a single introduction of v. cholerae to haiti sometime between 23 july and 17 october 2010 , dates remarkably in keeping with epidemiological findings of the beginnings of the cholera outbreak in haiti ( 4 ) .
although the authors did not extend their model to include the three closely related isolates from nepal , the very few single - nucleotide polymorphisms ( snps ) separating the haiti and nepal isolates ( as shown in fig .
1 [ and fig . s4 in the supplemental material ] of reference 8) suggest that the two sets of isolates diverged very shortly before the estimated date of introduction into haiti , a narrow window of time that further fastens the link of transmission of cholera from nepal to haiti .
the snp - based phylogenetic reconstruction offers a framework for understanding v. cholerae evolution over this short time span .
this reconstruction is built on snps determined by mapping reads to a reference genome and therefore is based on regions of the genome that reflect shared descent . to characterize larger - scale genome variation ,
these analyses revealed several independent deletions and inversions within sxt , a mobile genetic element that contains most of the genes that confer antibiotic resistance on v. cholerae ( 9 ) .
the observations of deletions and inversions may also explain the variations among the pfge patterns of these strains , as well as phenotypic variations in antibiotic susceptibility .
the notable absence of insertions from the sequenced genomes firmly establishes that horizontal gene transfer from indigenous v. cholerae did not introduce novel genetic elements into the genome of the outbreak strain , contrary to a recent hypothesis ( 6 ) .
furthermore , the authors found that outbreak isolates were virtually untransformable , perhaps explaining the absence of dna from environmental organisms .
the work by katz and coauthors adds to a growing body of work that explores the power and utility of pathogen population genomics in elucidating the origins and dynamics of outbreaks ( 10 ) .
a key issue facing investigators who use this approach to study outbreaks is determining the ideal sampling strategy that can provide statistically robust answers while also being cost - effective .
while the continuing decline in sequencing costs is making monetary considerations less important , the collection of clinical microbiological isolates and their storage and processing for sequencing remain nonstandard and still require considerable financial support .
what prior knowledge is needed to devise rational , evidence - based sampling strategies that provide sufficient power to test hypotheses about the origins of an outbreak ?
answers may be outbreak or pathogen specific and may require integration of transmission modeling , considering , for example , the impact of the mode of transmission on the ideal sampling method .
one important aid to devising sampling strategies may come from published estimates of molecular clock rates ( see reference 11 for an estimate for v. cholerae ) .
we anticipate that these rates may establish a starting point for making inferences about the history of a pathogen population from its diversity
. it will be important to test the assumption that the molecular clock for a given species remains relatively stable across niches and lineages .
additionally , public databases with pathogen genome sequences and associated metadata ( epidemiological and demographic information associated with the sequences ) broaden the range of questions and provide a historical set of samples with which to compare data or integrate them into an analysis , as done by katz and colleagues .
quality metrics are needed so that results can be compared and data readily imported from one study into another .
refer to high - quality snps , presumably to distinguish them from those derived from less stringent snp - calling thresholds and to emphasize the low likelihood of false - positive snps .
ideally , study - specific methods of snp calling and quality assessment should be replaced with rigorous methods yielding reproducible results that account for varying sequencing and analytic platforms and study quality ( 12 ) .
the ongoing revolution in dna sequencing technology is ushering in a new era of whole - genome - based molecular epidemiology .
coupled with the adoption of standards that permit rigorous cross - study analyses and the development and implementation of sophisticated statistical methods , these new technologies will transform our ability to understand microbial evolution and epidemics and ultimately to create improved public health interventions . for cholera in particular ,
we can take advantage of the power of these new methods to address a fundamental question : are humans always involved in the spread of this ancient disease over great distances ( such as between continents ) ?
if so , such a conclusion has profound implications for our ability to eliminate this ancient scourge from our planet with appropriate interventions .
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### Summary:
: abstractthe devastating haitian cholera outbreak that began in october 2010 is the first known cholera epidemic in this island nation .
epidemiological and genomic data have provided strong evidence that united nations security forces from nepal introduced toxigenic vibrio cholerae o1 , the cause of epidemic cholera , to haiti shortly before the outbreak arose . however , some have contended that indigenous v. cholerae contributed to the outbreak . in a recent paper ( mbio
4:e00398 - 13 , 2013 ) , l. s. katz et al . explored the nature and rate of changes in this ancient pathogen s genome during an outbreak , based on whole - genome sequencing of 23 haitian v. cholerae clinical isolates obtained over a 20-month period .
notably , they detected point mutations , deletions , and inversions but found no insertion of horizontally transmitted dna , arguing strongly against the idea that autochthonous v. cholerae donated dna to the outbreak strain
. furthermore , they found that haitian epidemic v. cholerae isolates were virtually untransformable .
comparative genomic analyses revealed that the haitian isolates were nearly identical to isolates from nepal and that the nepalese - haitian isolates were distinguishable from isolates circulating elsewhere in the world .
reconstruction of the phylogeny of the haitian isolates was consistent with a single introduction of v. cholerae to haiti sometime between late july and late october 2010 , dates remarkably concordant with epidemiological observations . in aggregate , this paper provides additional compelling evidence that the v. cholerae strain responsible for the haitian cholera epidemic came from nepal and illustrates the power of whole - genome - based analyses for epidemiology , pathogen evolution , and forensics .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: we retrospectively evaluated the pretreatment radiological presentation and the clinicoradiological outcome at the completion of 1 year chemotherapy in osteoarticular tuberculosis of hip in children to prognosticate correlation between them .
we retrospectively analyzed the clinical and plain radiographic findings in 27 patients with an age of 12 years or younger in whom hip tuberculosis was diagnosed and treated between 2006 and 2010 .
the pre and post treatment plain radiographs were evaluated according to shanmugasundaram radiological classification and our observations regarding unclassified cases which were not fit in this classification were suggested .
the functional outcome at the completion of chemotherapy was assessed using modified moon 's criteria .
the average age was 7.37 years ( range , 2 - 12 years ) . in the pretreatment radiographs , 9 hips were normal , 6 traveling , 4 dislocating , 1 protrusio acetabuli , 3 atrophic and 4 unclassified types ( 3 triradiate ; 1 pseudarthrosis coxae ) .
posttreatment , the types changed to 9 normal , 3 perthes , 1 protrusio acetabuli , 1 atrophic , 4 mortar pestle and 9 unclassified types ( 3 triradiate , 3 pseudarthrosis coxae and 3 ankylosed ) .
the prognosis was best with initial triradiate and normal types and worst with posttreatment atrophic and ankylosed types .
the shanmugasundaram radiological types accurately predict prognosis only in normal types and triradiate pattern .
before the advent of modern antitubercular drugs , the treatment of tuberculosis hip was expectant .
arthrodesis was considered the ultimate aim for tubercular arthritis of hip as it was believed that mobility will reactivate the tubercular bacteria.1234 plaster spica were used for 2 - 8 years before fusion was attempted in children leading to many complications.4 gradually , with availability of antitubercular chemotherapy , concept of regaining or restoring mobility in the diseased hip came into vogue .
the management of tuberculosis hip in children aims at identifying the disease in predestruction stage , instituting multidrug antitubercular chemotherapy combined with necessary surgical interventions and restoring hip function to normal / near normal as possible.5 although chemotherapy is highly effective , the presentation is frequently delayed and results compromised .
it is believed that the most important variable predicting outcome is the radiological stage of the disease at presentation.56 however , later observers have described better results despite morphological changes in hip.7 our aim in this retrospective series was to study pretreatment radiographic type and correlate it with the clinicoradiological outcome achieved at the completion of chemotherapy to find possible correlation between them .
we retrospectively analyzed the clinical and plain radiographs of 27 patients with an age of 12 years or younger in whom hip tuberculosis was diagnosed and treated at our center between 2006 and 2010 .
no attempt was made to elicit the range of movements at initial presentation due to associated pain and spasm .
the histopathological criteria for diagnosis were the presence of chronic granulomatous inflammation with caseation and/or presence of epitheloid cells and lymphocyte configuration of tubercle .
the clinical criteria were pain , limping , deformity and fullness around the hip joint , restriction of movements , presence of abscess with or without discharging sinus , limb shortenings .
plain radiological findings were osteopenia , diminution in joint space , erosions of articular margins , lytic lesions , pathological fractures , subluxations or dislocations .
a combination of the above clinicoradiological findings in the presence of supportive laboratory investigations was used to make a diagnosis of tuberculosis .
we classified the pretreatment and posttreatment radiological presentation according to shanmugasundaram radiological classification [ table 1 and figure 1].68 there were some hip involvements which can not be classified based on these conventional types .
three different patterns were observed in the unclassified type - triradiate , pseudarthrosis coxae and ankylosed type .
the pseudarthrosis coxae pattern is probably a result of primary femoral epiphyseal focus resulting in complete loss of femoral head and sometimes the femoral neck .
it is distinct from the dislocating type as it lacks a femoral head . the third pattern , ankylosed hip is old or healing disease with ankylosis . modified shanmugasundaram radiological types for pediatric hip tuberculosis a line diagram of hip joint showing original 7 radiological types of shanmugasundaram and unclassified type 8 following diagnosis ,
the children were treated with initial 4 weeks rest ( hip spica for children < 5 years and traction for children > 5 years ) followed by early ambulation as pain subsided and patients were able to tolerate weight bearing .
multidrug antitubercular chemotherapy was given for 1 year91011 ( isoniazid , rifampicin , ethambutol and pyrazinamide for 2 months and thereafter isoniazid , rifampicin for 10 months ) .
there was no resistance of the organism to anti tubercular treatment during the period under observation .
the patient profile , pretreatment shanmugasundaram radiographic type and posttreatment clinoradiological outcome is given in table 3 . in the pretreatment radiographs ,
9 hips were normal , 6 traveling , 4 dislocating , 1 protrusio acetabuli , 3 atrophic and 4 unclassified type ( 3 triradiate and 1 pseudarthrosis coxae ) .
posttreatment , the types changed to 9 normal , 3 perthes , 1 protrusio acetabuli , 1 atrophic , 4 mortar pestle , 9 unclassified types ( 3 triradiate , 3 pseudarthrosis coxae and 3 ankylosed ) [ figures 25 ] .
there were 37% excellent , 18.5% good , 26% fair and 18.5% poor results as per the moon 's criteria .
the prognosis was best with initial triradiate pattern ( 3 excellent/3 hips ; 100% ) and normal ( 7 excellent to good/9 hips ; 78% ) types [ table 3 and figure 3 ] . for clinical outcome , excellent to good outcome was seen with posttreatment 8 out of 9 normal , 1 out of 3 perthes , 2 out of 4 mortar pestle and 4 unclassified types ( 3 triradiate and 1 pseudarthrosis coxae pattern ) .
thus , except for triradiate pattern and most normal types , for other shanmugasundaram radiological types , there were different clinical outcomes especially in smaller children [ figures 2 , 4 and 5 ] .
patient profile ( n=27 ) an 11 year old girl child ( case 7 ) ( a ) x - ray left hip joint anteroposterior view showing pretreatment atrophic type head .
( b and c ) x - ray left hip joint anteroposterior view showing changes during treatment , course protrusio acetabuli and perthoid type changes respectively ( d ) x - ray left hip joint anteroposterior view showing post treatment pseudarthrosis coxae pattern ( e and f ) clinical photographs showing range of motion ( post treatment ) an 8 years old boy ( case 8) ( a and b ) x - ray of right hip joint anteroposterior and frog leg lateral views showing triradiate pattern with pathological fracture in pubic rami ( c and d ) x - ray anteroposterior and frog leg lateral views showing posttreatment radiological pattern remained the same with sclerosis in the lesion and healing of pathological fracture ( e and f ) clinical photographs of same patient showing excellent results x - ray right hip joint anteroposterior view of a 11-year - old girl child showing ( a ) pretreatment normal type radiographs .
there was fixed flexion deformity of 20 in the hip with no other movements possible .
the outcome was classified as poor x - ray right hip joint anteroposterior view in a 11-year - old male child showing ( a ) pretreatment normal type .
skeletal tuberculosis in the pediatric age group is uncommon with a reported incidence of 5 - 6% of pediatric extra pulmonary cases.10 hip tuberculosis constitutes nearly 20% of all cases of skeletal tuberculosis.11 the exact proportion of tubercular hip affection in the pediatric age group is not known but the disease is rare .
there is a paucity of literature regarding osteoarticular tuberculosis of hip in children with only few dedicated series available in recent indexed english literature and probably none from the indian subcontinent.67 thus , the clinicoradiological course in osteoarticular tuberculosis of hip following modern anti tubercular chemotherapy is scantly studied.67 our aim in this retrospective series was to study pretreatment radiographic type and correlate it with the clinicoradiological outcome achieved at the completion of chemotherapy to find possible prognosticating correlation between them . the initial radiological presentation of tubercular hip in children has been mainly described according to distribution of the primary site of infection ( acetabular roof , femoral neck , epiphysis , trochanteric apophysis , synovium , undetermined)512 or shanmugasundaram 7 types ( normal , travelling acetabulum , dislocating , perthes , protrusio - acetabuli , atrophic , mortar and pestle).689 mortar and pestle and atrophic types originally described for adults by shanmugasundaram were also reported in the pediatric series by campbell and hoffman.6 however , there are some hip involvements which can not be classified based on these conventional types .
we added an additional radiological type to the shanmugasundaram radiological classification - unclassified based on different primary site of infection and extent of involvement found in our series .
the ankylosed presentation following treatment have been referred in other series also.468 all radiological types were observed in our pediatric series either during the initial presentation or during the course of treatment .
another finding was initial clinical presentation with advanced radiological destruction ( except normal and triradiate ) in our population ( 12/27 ; 44% ) .
the new radiological types described in the present series could possibly indicate the treatment and prognosis . in triradiate pattern , the lesion being extra articular ,
prolonged hip immobilization is not required and the patient could be mobilized quickly and permitted early weight bearing as local symptoms subside .
. the hip might be unstable and limb shortened and treatment may be needed accordingly .
treatment would mainly aim at deformity correction at the hip , if the condition has become painless .
we believe that the radiological classification of tuberculosis hip proposed by shanmugasundaram8 is a description of various stages of disease rather than distinct radiological types i.e. one encounters the different radiological types in the same patient during the course of the disease . the changing
the radiological morphology of tubercular hip is thus a cross sectional observation of the disease process which is influenced by multiple factors - initial focus ( synovial or bony ) , localization of bony focus , severity of the disease process , age of the child , immunity status , duration from disease onset , treatment taken / intervention done , radiological view and exposure part , etc .
the severity increases in travelling acetabulum , dislocating , perthes , protrusio - acetabuli , atrophic , mortar and pestle types , pseudarthrosis coxae and ankylosed patterns . the primary site of infection will determine whether the lesion will advance as travelling acetabulum ( initial focus : acetabular roof ) , dislocating ( exudative response / chronic synovial hypertrophy / capsular incompetence / advanced destruction hip capsule ) , protrusio - acetabuli ( initial focus : advanced triradiate / acetabular floor ) , atrophic ( initial focus : ?
synovium ) ; mortar and pestle ( initial focus : femoral head and acetabulum ) ; pseudarthrosis coxae ( initial focus : femoral epiphysis ) ; ankylosed ( healing / old ) . in advanced cases with extensive joint destruction ,
distinction between these radiological types becomes difficult and it is impossible to determine whether initial lesion was synovial or osseous in nature or from where did it originate . in post anti tubercular chemotherapy era ( 1950 ) ,
campbell and hoffman described the outcome in pediatric hip tuberculosis in two series.6 in the first series ( n = 28 ) with shorter immobilization period and short course chemotherapy , the outcome has been described as excellent in 43% of hips , good in 28.5% , fair in 3.5% and poor in 25% respectively . in the other series ( n = 46 ) with longer immobilization and chemotherapy , the outcome has been excellent in 41% of hips , good in 19.5% , fair in 6.5% and poor in 33% respectively .
traveling , mortar pestle and atrophic types had poorer results . in another pediatric series of 43 children by moon et al .
, results were described as excellent to good in 73% , fair in 18% and poor in 9% respectively.7 poor results were obtained with protrusio acetabuli and mortar pestle types in this series .
our series had 37% excellent , 18.5% good , 26% fair and 18.5% poor results .
campbell and hoffman demonstrated that shanmugasundaram radiological appearance of the hip at presentation accurately predicts the final outcome.6 however , later series by moon et al . , have shown that disease healing and residual pain did not correlate with the radiological stage.7 in their series , 22 patients had morphological changes on plain radiographs with no clinical abnormalities at the time of followup .
the present series also had similar conclusions namely the clinical outcome correlates poorly with radiological morphology . except for triradiate pattern and normal types , other shanmugasundaram radiological types ( pre or posttreatment )
triradiate pattern is a focal lesion in a relatively nonweight bearing area of the acetabulum and normal type is an early disease and therefore better prognosis appears logical .
our study thus exposes the knowledge gap and need for a better classification and prognosticating factors in tuberculosis of the hip
. the limitations of study are its retrospective nature , short followup , different radiological types at presentation , different management in age groups and surgical interventions in selected patients .
there are chances that the radiological features could have been affected by other factors ( e.g. premorbid condition , multifocal involvement , clinical management , etc . ) . however , tuberculosis of the hip region in children is a rare disease and conclusions have to be drawn on a small sample size .
long term followup is highly desirable in view of weight bearing characteristics , growing epiphysis in children , high remodeling potential of hip and to detect late recurrences , if any .
unfortunately , these children often fail to followup soon after anti tubercular treatment is over .
the radiological type although may remain same posttreatment , but there may be differences in bony density and texture .
better delineation may be obtained by sophisticated imaging methods such as magnetic resonance imaging ( mri ) and computed tomography scan and these should be done where necessary .
the shanmugasundaram radiological types accurately predict prognosis only in normal types and triradiate pattern .
hence the shanmasundaram 's radiological classification ( 1983 ) can not be relied upon to prognosticate pediatric patients except in few select types .
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### Summary:
: background : we retrospectively evaluated the pretreatment radiological presentation and the clinicoradiological outcome at the completion of 1 year chemotherapy in osteoarticular tuberculosis of hip in children to prognosticate correlation between them.materials and methods : we retrospectively analyzed the clinical and plain radiographic findings in 27 patients with an age of 12 years or younger in whom hip tuberculosis was diagnosed and treated between 2006 and 2010 .
the diagnosis was based on histopathology in 14 and clinicoradiological basis in 13 patients .
the pre and post treatment plain radiographs were evaluated according to shanmugasundaram radiological classification and our observations regarding unclassified cases which were not fit in this classification were suggested .
the functional outcome at the completion of chemotherapy was assessed using modified moon 's criteria.results:the male female ratio was 11:16 .
the left hip was involved more frequently than the right ( 17:10 ) .
the average age was 7.37 years ( range , 2 - 12 years ) . in the pretreatment radiographs , 9 hips were normal , 6 traveling , 4 dislocating , 1 protrusio acetabuli , 3 atrophic and 4 unclassified types ( 3 triradiate ; 1 pseudarthrosis coxae ) .
there were no perthes and mortar pestle at the initial presentation .
posttreatment , the types changed to 9 normal , 3 perthes , 1 protrusio acetabuli , 1 atrophic , 4 mortar pestle and 9 unclassified types ( 3 triradiate , 3 pseudarthrosis coxae and 3 ankylosed ) .
there were 37% excellent , 18.5% good , 26% fair and 18.5% poor results .
the prognosis was best with initial triradiate and normal types and worst with posttreatment atrophic and ankylosed
types.conclusions:the shanmugasundaram radiological types accurately predict prognosis only in normal types and triradiate pattern .
the functional outcome is independent of radiological morphology of the hip in smaller children .
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:
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### Summary:
: the mechanism of the trichomonicidal activity of metronidazole and other 5-nitroimidazoles appears to depend on the ferredoxin - mediated reduction of their nitro group , with generation of a reactive metabolite or metabolites which interact with dna leading to a subsequent inhibition of nucleic acid and protein synthesis .
redox cycling of these compounds under aerobic conditions appears to be a detoxification reaction by inhibiting net reduction of the drugs , thereby inhibiting their uptake . on the other hand , redox cycling of nitrofurans or other compounds with more positive reduction potential results in formation of high steady - state concentrations of oxygen - derived metabolites that might be of toxicological significance .
it seems likely that reduced metabolites of nitroimidazoles ( perhaps through covalent binding to tissue macromolecules and/or thiols depletion ) are also involved in the nitroimidazoles ' toxic effects to animal tissues and in their mutagenic and carcinogenic action.imagesfigure 1 .
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: diabetes mellitus ( dm ) is the leading cause of the end - stage renal disease ( esrd ) in many countries of the world . in bosnia and herzegovina , 17.3% of dialysis patients
have primarily diabetes mellitus , while in korea as many as 44.9% dialysis patients developed esrd as a consequence of diabetes nephropathy . although the survival rate in dm patients with esrd partially improved , it is still significantly lower than that in general population .
the results of necosad study showed that survival in diabetic patients with esrd was worse compared to nondiabetic patients and that diabetes mellitus has a very strong impact on survival even if it is not the primary cause of esrd .
risk factors for cardiovascular death in these patients include those that affect the general population as well as those related to end - stage renal disease and those that are specific to peritoneal dialysis .
the development of over hydration after loss of residual renal function ( rrf ) is probably the most important cardiovascular risk factor specific to peritoneal dialysis .
the high glucose load associated with peritoneal dialysis may lead to insulin resistance and to the development of an atherogenic lipid profile .
the presence of glucose degradation products in conventional dialysis solutions , which leads to the local formation of advanced glycation end products , is also specific to peritoneal dialysis .
although nonatherosclerotic cardiovascular diseases , like volume overload and left ventricular hypertrophy , can mostly contribute to the high prevalence of mortality in peritoneal dialysis ( pd ) patients , the recent studies suggest that pd patients are especially susceptible to the accelerated atherosclerotic process [ 5 , 6 ] .
peritoneal dialysis is increased with higher frequency of several traditional ( arterial hypertension , diabetes mellitus , and hyperlipidemia ) and uremia - related risk factors ( anemia , hypoalbuminemia , hyperhomocysteinemia , oxidative stress , microinflammation , and secondary hyperparathyroidism ) , which can affect the creation of vascular changes .
important predictors of discovery of the development of accelerated atherosclerosis in pd patients are considered to be morphologic changes on common carotid arteries ( cca ) in the form of the intima - media thickness ( imt ) and hemodynamic changes expressed through parameters
peak systolic velocity ( psv ) , end - diastolic velocity ( edv ) , and cca diameter to the aim of the assessment of the stage of stenosis on cca [ 7 , 8 ] . in this study
, we explored the impact of pd on atherosclerotic process in patients with and without dm , monitored through morphologic and hemodynamic parameters on cca in esrd patients during the period of one year after the start of pd treatment .
also , the aim of the study is to establish factors that predict changes on carotid arteries as a surrogate atherosclerosis in patients with dm on pd .
this prospective longitudinal study includes 50 esrd patients ( diabetic type 2 and nondiabetic ) who were treated with continuous ambulatory pd ( capd ) at the clinic for nephrology of the clinical center of sarajevo university and who were observed for a year after the commencement of dialysis treatment .
all examined patients underwent 4 to 5 dialysis changes with 2 liters of dialysis solution .
the patients with the verified diagnosis of carotid artery stenosis , heart valve diseases , and cerebral vascular diseases , as well as with signs of peritonitis during the study period , were excluded from the study . in all patients ' antihypertensive therapy , as well as therapy ( e.g. , nitrites , sildenafil , captopril , nsaid 's , nitroprusside , etc . ) that can influence the values of monitored laboratory parameters were excluded 24 hours before taking blood samples for determination of concentration of endothelin-1 ( et-1 ) and nitric oxide ( no ) .
the patients were free from taking diuretic therapy prior to diuresis level measurement and sampling .
the baseline of laboratory findings with determination of et-1 and no in serum complemented with ultrasonography of carotid arteries at the very beginning of dialysis treatment and after one year .
the study was conducted with the approval of the local ethics committee and with the respect for the rules of ethical principles in medical research .
the baseline of laboratory findings was done by standard laboratory procedures at the institute for clinical chemistry and biochemistry , clinical center of sarajevo university .
the measurement of serum concentration of et-1 was done by the elisa method ( enzyme immunoassay for the quantitative determination of human endothelin ( 1 - 21 ) in serum , kit biomedica medizinprodukte gmbh & co kg , wien ) . for determination of concentration of no in the serum ,
r&d system total nitric oxide kit was utilized , while the concentration of no was expressed in mol / l .
blood samples for both methods were analyzed at the institute for biochemistry of the clinical hospital sestre milosrdnice in zagreb , croatia .
intima - media thickness of common carotid artery ( imt cca ) and the presence of atherosclerotic plaque were measured by means of highly - resolute transducer sond of 7.5 mhz frequency in b mode ( wall - track system : w - t , maastricht , the netherlands ) from the angiologist who was not familiar with the clinical status of the study patients .
the cca , carotid bulbus , and the first 2 cm of the internal and external carotid artery were scanned , bilaterally .
the carotid plaques were defined and counted as silent grey echo 's ( soft plaques ) or bright white echo 's ( calcified plaques ) that protrude into the lumen of the artery .
the measurements of imt were done at the distance of 20 mm from bifurcation into the plaque - free area on cca .
three measurements were done on the left and right cca , while the mean values of these measurements were utilized in the analysis .
plaque score in the carotid artery was calculated by summing the three measurements imt values , bilaterally .
adequacy of dialysis ( kt / vurea ) was calculated from weekly total removed urea mass by daily volume of dialysate and urine ( kt ) and divided with urea distribution volume ( v ) .
residual renal function was estimated as the mean of renal creatinine clearance ( ml / min ) .
a simplified peritoneal equilibration test was performed using 4.25% glucose - based solution to obtain the dialysate to plasma creatinine concentration ratio at 4 hours of dwell ( d / p cr ) .
patients were categorized as high , high - average , and low - average transporters according to criteria of chung and colleagues .
all data were expressed as the mean sd or as median and interquartile range .
significant change in the variables from baseline to 12 months after treatment was tested by paired t - test for the variables that followed normal distribution or by the wilcoxon signed - rank test for the variables that had skewed distribution .
a multiple regression analysis was applied to examine the relationship between ultrasound parameters of cca and a set of clinical and laboratory parameters .
the significant independent variables were ordered according to their standardized effect , defined as regression coefficient / standard error of the regression ( ) .
all statistical calculations were performed with the spss 16 software ( version 16.0 , spss inc . , chicago , il , usa ) .
mean blood pressure and serum lipids values significantly decreased after 12 months on pd treatment both in patients with dm type 2 and in group of patients without dm .
after the 12-month pd treatment , patients with dm type 2 had significantly higher blood pressure and serum lipids level compared to group of patients without dm . although median serum crp levels significantly decreased after pd treatments in both groups of patients , patients with dm type 2 had significantly increased median serum crp concentration compared to patients without dm 12 months after pd treatment ( table 1 ) . in group of patients with dm type 2 significant reduction in mean p , caxp , pth , and fibrinogen levels were observed 12 months after pd compared to the values before the treatment .
mean serum albumin was significantly lower , and product caxp , pth , and fibrinogen levels were significantly increased in patients with dm type 2 compared to the group of patients without dm 12 months after pd treatment ( table 1 ) . in group of patients with dm type 2 significant reduction in mean diuresis level , serum creatinine levels
mean diuresis values were significantly lower , while mean creatinine and rrf levels were significantly increased in patients with dm type 2 compared to the group of patients without dm 12 months after pd treatment .
in the group of patients with dm type 2 , a significant higher number of patients with kt / vurea < 2.0 were observed before the treatment compared to 12 months after . also 44% of patients with dm type 2 at the beginning of the pd treatment had low - average transport characteristics , while 12 months after pd treatment start significantly fewer patients were with high transport characteristics of peritoneum ( 24% ) ( table 2 ) .
mean imt , plaque score , psv , edv , and cca diameter significantly decreased 12 months on pd treatment in group of patients without and in group of patients with dm type 2 .
however , after 12 months on pd , mean imt , plaque score , psv , edv , and cca diameter values were still significantly higher in patients with dm type 2 compared to patients without dm ( table 3 ) .
median et-1 concentration in patients with dm type 2 was significantly increased compared to median et-1 concentration in patients without dm type 2 ( 7.6 ( 5.513.4 ) versus 3.6 ( 2.66.8 ) pg / ml ; p < 0.001 ) before pd as well as 12 months on peritoneal dialysis ( 5.9 ( 4.17.8 ) versus 3.3 ( 2.36.0 ) pg / ml ; p < 0.001 ) .
significant reduction in median serum et-1 concentration was observed in the group of patients with dm and without dm type 2 after 12 months of renal replacement treatment ( figure 1 ) .
median no concentration in patients with dm type 2 was significantly decreased compared to median no concentration in patients without dm type 2 ( 25.0 ( 12.844.3 ) versus 49.6 ( 32.863.5 ) pg / ml ; p < 0.001 ) before pd as well as 12 months on peritoneal dialysis ( 34.3 ( 26.749.6 ) versus 56.5 ( 44.989.5 ) pg / ml ; p < 0.001 ) . significant increase in median serum no concentration was observed in the group of patients with dm type 2 and without dm ( figure 2 ) . in multivariate linear regression analysis
independent predictors of imt and psv were only serum no level , while independent predictors of plaque score were product caxp and ca levels .
independent predictors of cca diameter were serum no , rrf , caxp , and serum ca levels .
independent negative predictor of edv was no and serum et-1 levels were positive predictor of edv ( table 4 ) .
in previous researches it was established that vascular alterations on carotid arteries can be an early sign of atherosclerosis and a predictor of generalized vascular changes in pd patients . in this study
we confirmed that esrd patients at the very start of pd treatment had signs of advanced atherosclerosis , which suggests that the uremia itself is an independent risk factor for functional atherosclerotic damage .
also , in diabetic patients on pd , compared to patients without dm on pd , imt of cca had significantly higher values . despite these differences , other markers of atherosclerotic changes , primarily endothelial dysfunction , were of similar values and of significantly higher values in diabetic patients .
blood vessel endothelium modulates vascular structure and tonus affecting the production of nitric oxide , which is considered to have a protective role in the creation of vascular atherosclerotic damage .
endothelial dysfunction is a very important process which participates in the creation of the process of atherosclerosis and arteriosclerosis and is under the direct influence of traditional and nontraditional risk factors .
to date numerous studies showed that the function of endothelium is weakened in esrd patients and it is a predictor of cardiovascular mortality in these patients , but also in general population .
hyperglycemia , insulin resistance , oxidative stress , and lipid metabolism disorder are involved in the development of endothelial dysfunction in patients with dm type 2 .
recurrent hyperglycemia , with accumulation of advanced glycation end - products ( ages ) , leads to chronic endothelial dysfunction , which is especially expressed in pd patients . in patients on peritoneal dialysis atherosclerotic disease
is associated with the presence of calcification in the wall of blood vessels and it is a response to hemodynamic humoral abnormalities in chronic uremia .
the mutual mixture of traditional and nontraditional risk factors is one of the reasons for accelerated atherosclerosis in patients on pd .
these changes lead to the increased stiffness and the loss of elasticity of big arteries , as well as aorta and cca . in our study
the verified increased et-1 values in serum of uremic patients before the start of dialysis treatment may be a consequence of the reduced elimination of et-1 from circulation due to esrd and the damage of vascular endothelial cells .
the concentration of serum endothelin-1 was significantly higher in pd patients with dm type 2 , compared to nondiabetic patients , which can indicate more expressive damage of endothelium in this group of patients .
it was established that hyperproduction of et-1 , accompanied by increased concentration of circulating et-1 in dialysis patients , may lead to the development of endothelial dysfunction , with a high risk of cardiovascular mortality and morbidity in this population of patients .
the increased mean value of imt and the plaque score on cca in our patients , with hemodynamic changes on the flow of blood on cca at the very start of peritoneal dialysis , speaks about the significant presence of morphologic and functional macrovascular changes in these patients .
the mentioned results agree with the previous reports by other authors and thereby support the presumption about the accelerated atherogenesis even in pd patients and suggest a positive effect of peritoneal dialysis on the process of vascular remodeling . using multivariate analysis we found a statistically significant influence of caxp product and the serum calcium on plaque score cca .
hypercalcaemia and the increased product of caxp in pd patients are linked to the development of cca calcification , especially in diabetic patients , independent of parathormone values .
this study did not show the dependence of changes on carotid arteries from transport characteristics of peritoneum , which is in accordance with the research of rodrigues and associates , who ascertained that the increased mortality of pd patients does not depend on peritoneal permeability but is probably the result of associated comorbidity , basic atherosclerosis , volume overload , chronic inflammation , and humoral abnormalities in uremia .
the same author concluded that peritoneal transport characteristics are primarily dependent on the vasoactive intermediate compounds concentration , produced by mesothelium .
the decrease in rrf is closely related to the volume overload , anemia , inflammation , malnutrition , and eventually increased morbidity .
the reduction of creatinine clearance is very much associated with endothelial dysfunction and arterial rigidity in patients with chronic kidney disease , which indicates that the function of kidneys plays an important role in the protection of blood vessels . in our results
, we concluded that rrf appeared as an independent predictor of cca diameter but not other morphological and functional parameters of cca in diabetic patients .
esrd patients on pd have significant morphologic and hemodynamic changes on cca before the start of dialysis treatment .
patients with dm type 2 have significantly higher values of imt cca in relation to nondiabetic patients on pd .
the results of this study suggest the association of no concentration in serum with significant morphological and functional changes on cca , which are considered surrogate - generalized atherosclerosis in dm type 2 patients but also in non - dm pd patients , which in turn gives this biomarker the importance of a predictor of the development of accelerated atherosclerosis in this patients .
the treatment with peritoneal dialysis , with the regulation of these vasoactive molecules and other vascular risk factors , importantly impedes vascular remodeling , especially in dm type 2 patients .
intensive monitoring of hemodynamic and nonhemodynamic vascular risk factors and vascular parameters in pd patients is necessary for the purpose of prevention and even regression of undesired changes on vascular system .
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### Summary:
: diabetes mellitus ( dm ) is the leading cause of the end - stage renal disease ( esrd ) .
vascular diseases are the most common cause of morbidity and mortality in the chronic kidney disease .
the aim of this study was to analyze the impact of peritoneal dialysis ( pd ) treatment on morphologic and hemodynamic vascular parameters of carotid arteries in diabetic type 2 and nondiabetic patients with esrd during the period of one year after the start of pd treatment using ultrasonography of carotid arteries and their relation on uremia and pd inherent factors .
mean intima - media thickness , plaque score , peak systolic velocity , end - diastolic velocity , and carotid diameter significantly decreased 12 months after pd treatment start in both groups . significant reduction in median serum endothelin-1 concentration after 12 months on pd treatment was observed in the group of patients with dm ( 7.65.9 pg / ml ) and also in group of patients without dm ( 3.63.3 pg / ml ) . also median nitric oxide concentration significantly increased after 12 months on pd compared to baseline levels both in patients with dm ( 25.034.3 mol / l ) as was observed in patients without dm ( 49.656.5
mol / l ) . pd treatment , with the regulation of these vasoactive molecules and other vascular risk factors , significantly contributes to vascular remodeling , especially in dm patients .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: hemophagocytic lymphohistiocytosis ( hlh ) is a rare syndrome characterized by reactive , systemic proliferation of benign histiocytes throughout the reticuloendothelial system.1 hlh results from impaired functions of natural killer ( nk ) and cytotoxic t cells , whereas activities of lymphocytes and histiocytes are augmented , leading to phagocytosis of hematopoietic cells.1 hlh comprises two different conditions that may be difficult to distinguish from one another .
the primary autosomal recessive form , familial hemophagocytic lymphohistiocytosis , is a fatal disease with its onset during infancy or early childhood and has a median survival of less than 2 months if untreated.2 secondary hlh may develop as a result of strong immunological activation of the immune system , which may be caused by a severe infection . among the infections ,
viral pathogens reported to be associated with hlh include epstein - barr virus , cytomegalovirus , parvovirus , herpes simplex virus , varicella - zoster virus , measles virus , human herpes virus-8 , and human immunodeficiency virus , alone or in combination.1 hlh may also coincide with various bacterial infections , parasite infections , and fungal infections.1 it is important to realize that early therapeutic interventions are required when strong clinical suspicion of infection - associated hlh is present to prevent irreversible end organ damage .
our report describes an unusual case of hlh associated with plasmodium vivax infection , which was treated successfully with antimalarial agents .
a 64-year - old woman living in gimpo , gyeonggi province , visited the emergency room of seoul st .
she complained of chills followed by fever up to 40 for several hours occurring every two days and diffuse abdominal pain for 7 days .
her vital signs were as follows : blood pressure 130/70 mmhg , heart rate 96/min , temperature 38.2 , and respiratory rate 24/min .
she appeared acutely ill and hepatosplenomegaly was noted , but there were no palpable lymph nodes .
her leukocyte count was 2,380/mm ( 4,000 - 10,000/mm ) , her absolute neutrophil count was 830/mm , her hemoglobin was 11.7 g / dl ( 13.0 - 18.0 g / dl ) , her platelet count was 36,000/mm ( 150,000 - 450,000/mm ) , and her reticulocyte count was 0.52% ( 0.2 - 2% ) .
u / l ) , alanine aminotransferase of 30 u / l ( 9 - 45
u / l ) , total bilirubin of 3.97 mg / dl ( 0.47 - 1.58 mg / dl ) , blood urea nitrogen of 15.3 mg / dl ( 7.0 - 20.0 mg / dl ) , creatinine of 0.94 mg / dl ( 0.6 - 1.2 mg / dl ) , lactate dehydrogenase of 1,451 u / l ( 250 - 450 u / l ) , triglyceride of 210 mg / dl ( 40 - 200 mg / dl ) , and ferritin of 923 g / l ( 20 - 300
the fibrinogen assay showed > 500 mg / dl ( 160 - 350 mg / dl ) . cultures of blood and urine were done twice at 1-hour intervals , and all of the results were negative .
antibodies against viral pathogens including epstein - barr virus ( ebv ) , cytomegalovirus ( cmv ) , and herpes simplex virus ( hsv ) were not detected in the serum .
specifically , hsv igm , hsv igg , cmv igm , ebv early antigen igg , and ebv viral capsid antigen ( vca ) igm were negative , but cmv igg , ebv vca igg , and ebv nuclear antigen igg were positive .
also , serologic tests for hepatitis a , b , and c viruses and human immunodeficiency virus were negative .
additional serologic tests for leptospira , orientia tsutsugamushi , haantan virus , and connective tissue diseases were also negative , but trophozoites and gametocytes of p. vivax were observed in a peripheral blood smear ( fig .
bone marrow aspirate revealed rare intracellular parasites with hypocellular bone marrow , but proliferation of histiocytes with prominent hemophagocytosis was noted ( fig .
diagnosis of p. vivax malaria - associated hlh was made , and hydroxychloroquine ( 25 mg / kg ) was administered for 3 days , followed by primaquine ( 15 mg per day ) for 14 days .
the patient recovered completely with the antimalarial medication , and all the abnormal laboratory findings and follow - up peripheral blood smear and bone marrow aspirate were normalized on the 12th day of hospitalization without additional implementation of immunosuppressive agents .
the histiocyte society hlh study group revised the diagnostic guidelines of hlh in 2004.3 according to them , the diagnosis of hlh is established either by a molecular diagnosis consistent with hlh ( primary hlh ) or by having five out of eight of the following : 1 ) fever ; 2 ) splenomegaly ; 3 ) cytopenia affecting more than two cell lineages ; 4 ) hypertriglyceridemia and/or hypofibrinogenemia ; 5 ) hemophagocytosis in the bone marrow , spleen , or lymph nodes without evidence of malignancy ; 6 ) low or absent natural killer cell cytotoxicity ; 7 ) hyperferritinemia ; and 8) elevated soluble cd25.3 in our report , the patient presented with fever , hepatosplenomegaly , cytopenia of more than 2 cell lineages , hyperferritinemia , and hemophagocytosis in the bone marrow aspirates , meeting the diagnostic criteria for hlh ( table 1 ) .
secondary hlh may occur most commonly in the setting of malignancy , autoimmune disease , drug hypersensitivity reaction , or infection.1 infection - associated hlh has been reported in a great variety of viral , bacterial , fungal , and , rarely , parasitic infections.1 p. vivax , a causative agent of relapsing tertian human malaria , is the second most important human malaria and affects several hundred million people annually . it has the widest geographic distribution throughout the world , and is usually found in central and south america , india , and southeast asia.4 presently , p. vivax is the only endemic malarial species in korea . a search of the english and korean language literature revealed seven other cases of p. vivax - associated hlh.4 - 8
of these cases , patients ' data were available for four cases , including our case ( table 2).4 - 6 in all four cases , including our case , treatment of p. vivax malaria was sufficient for the patients to recover , and no immunosuppressive agents were applied in any of these cases.4 - 6 the possible immunological mechanism of hlh may be excessive production of th1 cytokines , such as interferon - gamma , tumor necrosis factor - alpha , interleukin-1 , or interleukin-6 , from activated mononuclear cells.9 patients with epstein - barr virus - associated hlh , which can be fatal due to hemorrhage , infection , or multi - organ failure , may be required to be treated with a combination of immunosuppressive agents.10 otherwise , patients with infection - associated hlh with other pathogens can usually recover with supportive care and treatment targeted to the underlying infection.10 unless associated with underlying immunodeficiency , the outcome for hlh caused by parasitic infections , including p. vivax infection , is generally good when antimalarial drugs are properly applied , as occurred in our patient.4 - 6 when a patient with bicytopenia or pancytopenia presents with fever or documented infection , the possibility of infection - associated hlh should be raised . in particular , systemic parasitic infections , such as malaria , should be included in the differential diagnosis of pancytopenia and infection - associated hlh .
laboratory tests to confirm the etiologic pathogen should be guided by epidemiological data and the patient 's medical history .
in korea , malaria from p. vivax infection has reemerged recently and shows a high transmission rate .
when p. vivax - associated hlh is confirmed , administration of antimalarial drugs can result in the resolution of clinical symptoms and cytopenias without end organ damage .
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### Summary:
: hemophagocytic lymphohistiocytosis ( hlh ) is an unusual syndrome characterized by fever , hepatosplenomegaly , cytopenias , hypertriglyceridemia , hypofibrinogenemia , and pathologic findings of hemophagocytosis in the bone marrow and other tissues .
hlh may be familial or associated with different types of infections , autoimmune disorders , or malignancies .
infection - associated hlh has been reported in various viral , bacterial , fungal , and parasitic infections , and case reports of parasitic infections implicated in hlh include rare cases from plasmodium vivax infection , which occasionally affects both military personnel and civilians in korea .
we describe an unusual case of hlh resulting from plasmodium vivax infection and review the literature .
this case suggests that clinical suspicion of hlh is important when p. vivax infection is accompanied by cytopenias .
administration of antimalarial drugs may prevent irreversible end organ damage resulting from p. vivax - associated hlh .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: a 74-year - old man presented with sudden dizziness and falling to the right side .
he had been hypertensive for 30 years and had a 30-pack - year smoking history .
his blood pressure was 130/80 mmhg and his heart rate was 78 beats / minute .
the patient was drowsy ; however , he was able to cooperate during the neurological examination .
he showed complete ptosis of the left eye and mild lid retraction of the right eye ( fig .
manual opening of the left eye did not result in resolution of right lid retraction , which suggested true rather than compensatory retraction to overcome left - eye ptosis .
the left pupil was dilated to 5 mm without reflexes . in the left eye ,
however , the elevation ( < 25% of the normal range ) and depression ( < 50% of the normal range ) of the right eye were both limited .
the function of the left trochlear nerve was determined to be normal from intorsion of the left eye on attempted downward gaze .
diffusion mri revealed an acute infarction in the left medial midbrain that extended to the left medial thalamus ( fig .
mr angiography revealed mild stenoses in both the left proximal posterior cerebral and right distal vertebral arteries .
the patient was presumed to have suffered from an " artery - to - artery embolism " that originated in the right distal vertebral artery and was subsequently treated with anticoagulation drugs .
however , ophthalmoplegia and truncal contrapulsion remained unchanged at 1 month after the initial presentation .
our patient presented with characteristic ocular motor findings that could have been due to the lesion involving both the pretectum and upper midbrain.4 among the symptoms of our patient , ophthalmoplegia in the left eye may have been due to the lesion that involved either the oculomotor fascicle or nucleus in the midbrain .
however , involvement of the oculomotor nucleus may be excluded in view of the presence of unilateral ptosis .
accordingly , vertical ophthalmoplegia and lid retraction in the right eye required the additional involvement of supranuclear structures involved in vertical gaze and eyelid function in the mesodiencephalic junction .
the mesodiencephalic junction contains the rostral interstitial nucleus of the medial longitudinal fasciculus ( rimlf ) , the interstitial nucleus of cajal ( inc ) , the rostral portion of the mesencephalic reticular formation ( mrf ) , and the posterior commissure ( pc ) , all of which are involved in the premotor control of vertical eye movements .
the rimlf lies in the prerubral area near the midline and contains medium - lead burst neurons that generate vertical saccades.5 inactivation of the rimlf in monkeys has been shown to reduce the velocity or completely abolish conjugate vertical saccades.6 the inc , together with vestibular nuclei , is an element of the neural integrator for vertical eye motion , which transforms vertical eye velocity signals to position signals.7 the rostral portion of the mrf , adjacent to the inc and rimlf , contains neurons that have low -frequency , long - lead burst activity prior to vertical saccades.8 unilateral inactivation of the rostral mrf produces slowed and hypometric upward and downward saccades without postsaccadic drift.9 the pc contains several groups of decussating axons from the adjacent nucleus of the pc ( npc ) and axons from both the rimlf and inc that project to corresponding structures in the contralateral midbrain tegmentum.10 the npc also contains neurons that discharge shortly before upward saccades.11 the pc is critical for upward saccades.12 our patient also showed mild lid retraction od ( right eye ) and complete ptosis os ( left eye ) that resembled the " plus - minus syndrome " that was reported previously in a thalamus - midbrain infarction . in patients with unilateral ptosis , the contralateral eyelid may appear retracted since excessive innervation ( to overcome the ptosis ) to the levator palpebra of the ptotic eye is delivered to the normal levator palpebra in the contralateral eye ( i.e. , hering 's law ) . in this case
, manual elevation of the ptotic eyelid would result in resolution of lid retraction in the contralateral eye . in our patient , however , the persistence of lid retraction in the right eye even during manual opening of the left eye suggested true - lid retraction .
the cortex , extrapyramidal motor systems , and rostral brainstem structures are known to contribute to the control of the levator palpebra muscle in various eyelid functions.13 pc and rimlf signals may be involved in lid - eye coordination by providing inhibitory modulation of levator palpebra motor activity .
lesions of the medial or principal portion of the pc nuclear complex appear to be essential for the production of lid retraction.13 truncal lateropulsion is a well - known sign of wallenberg syndrome and has rarely been described in either anterolateral thalamic or cingulated gyrus lesions.14,15
so - called thalamic astasia is believed to interrupt the projections that run from the ventrolateral nucleus of the thalamus to the medial portion of the precentral gyrus where the trunk and leg are represented .
the involvement of the fastigial projections through which the thalamus receives information from the vestibulocerebellum is the presumed mechanism of thalamic astasia , even though the exact mechanism remains to be elucidated.3 disruption of the connection between the cingulate motor area and the vestibulocerebellar system via the thalamic nuclei was assumed to underlie the truncal contrapulsion observed in a patient with posterior cingulate infarction.14 however , there have been no previous reports of truncal contrapulsion with medial thalamic lesions . in view of two cases of rubral lateropulsion that were not accompanied by cerebellar ataxia , we also postulate that the lateropulsion observed in our patient with a mesodiencephalic lesion was due to the disruption of the ascending fibers in the crossed cerebellothalamic tract.15 this explanation is also supported by previous reports that the vestibulothalamic , dentatorubrothalamic , and fastigiothalamic fibers join the thalamic fascicle adjacent to the red nucleus and that interruption of any of these fibers can cause lateropulsion.15 frequent occurrences of axial lateropulsion ( i.e. , ipsipulsion ) in patients with infarctions in the region of the medial superior cerebellar artery , which presumably damages the cerebellothalamic tract prior to decussation , also supports our hypothesis.16
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### Summary:
: truncal contrapulsion in association with pretectal syndrome has not been described previously .
we report a patient with vertical - gaze palsy and severe truncal contrapulsion due to an infarction in the mesodiencephalic junction .
truncal contrapulsion in this patient may have resulted from the disruption of the ascending fibers in the crossed cerebellothalamic tract .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: autism and related autism spectrum disorders ( asds ) are heterogeneous neurodevelopmental disorders behaviorally defined by significant deficits in social interaction and communication and by the presence of restricted interests and repetitive behaviors .
autism disorder ( ad ) comorbidy with seizures and mental retardation occurs in up to 30% and in 80% of autistic patients , respectively .
genetically , the picture is complicated by significant interindividual heterogeneity , numerous contributing loci , and multiple genes and gene - environment interactions .
several lines of evidences strongly support a prenatal onset for developmental abnormalities later leading to autism .
autism in its very broad spectrum of severity is known to have many different etiologies . in the last few years ,
significant progresses have been made in comprehending the causes of autism , and their multiple impacts on the developing brain .
the primary goals of treatment are optimizing the quality of life and minimizing the impairment due to the core symptoms of autism . in this article
we discuss current understanding of the pathogenesis of syndromic autism and the multiple pathways responsible for the asd phenotype .
several inborn errors of metabolism , including phenylketonuria , biotinidase deficiency , disorders of cerebrospinal fluid ( csf ) neurotransmitters such as deficiencies of folic acid , smith - lemli - opitz syndrome ( slos ) , creatine deficiency syndromes , metabolic purine disorders , have an autistic phenotype . a better understanding of some of them has implications both for discovery of the pathophysiologic underpinnings of the disorder and for the development of effective interventions . in untreated children affected by phenylketonuria , the high levels of phenylalanine may have toxic effects on the brain cells , causing reduction of myelin , neuronal loss , and decreased levels of interneuronal connections .
hyperphenylalaninemia also competes with the absorbition of other amino acids and consequently lower tyrosine and tryptophan concentrations can result in a low production of dopamine and serotonin in the prefrontal cortex . in some of the most severe metabolic diseases , like adenylosuccinase deficiency or creatine deficiency syndromes , neurological and behavioral symptoms are probably not caused by deficiency of metabolites , but are more likely due to the toxic effects of the accumulating substances on the brain . a direct role in modulation of dopaminergic and serotoninergic neurotransmission systems and axonal
guidance has been hypothesized for the adenosine deaminase deficiency as pathologic mechanisms for the development of altered pathways involved in autistic symptoms .
the role of mitochondrial disorders has been revitalized by the association between autism and variants of the slc25a12 gene , which encodes the predominant isoform of the mitochondrial aspartate ( asp)/glutamate ( glu ) carrier ( agc ) in brain . altered ca2 + homeostasis is responsible for boosting agc activity , mitochondrial metabolism , and , to a more variable degree , oxidative stress in autistic brains .
based on our clinical experience , routine metabolic screening studies should be used on a case by - case basis , in the presence of the autistic regression , or suggestive clinical findings , such as lethargy , cyclic vomiting , early onset seizures , dysmorphic features , mental retardation with neurologic deficits , unexplained immune deficiency or unexplained hemolytic anemia , hyper- or hypotonia , self - mutilation , and muscle weakness .
table 1 summarizes the main clinical features , diagnostic test and therapeutic options of the metabolic diseases most frequently associated with asd .
the relationship among epilepsy , autism , and regression is a poorly understood and controversial subject .
there are several epilepsy syndromes in which regression of language , cognition , and behavior may lead to clinical manifestations that overlap with the behavioral syndrome of autism , such as infantile spasms , slow spike - wave discharges during sleep , and focal centrotemporal spikes .
an epileptic disorder must be considered in all children with a low functioning asd , especially when a history of regression and electroencephalogram ( eeg ) epileptic abnormalities is present .
severe epileptiform abnormalities may permanently alter the critical synaptogenesis by strengthening synaptic contacts that should have been naturally pruned .
cognitive functions decline in those patients who have early - onset eeg abnormalities and a prolonged active phase of continuous spike - and - wave discharges during sleep . in children with autistic regression
, there is no evidence that treatment of the seizures or of the interictal epileptiform activity makes a difference in regard to the outcome of the language and social deficits .
because the relationship between autism , epilepsy , and regression is complex , the clinician 's index of suspicion for epilepsy should be high , and treatment of the epilepsy should be pursued when necessary .
although the pathogenetic link between autism and epilepsy is poorly understood , the existence of altered ca2 + signaling in asd and the bioelectrical instability resulting from mutations of the l - type voltage - gated ca2 + channels associated to autism may account for the high prevalence of seizures and/or eeg abnormalities present among autistic individuals .
single gene defects and chromosomal abnormalities may account for approximately up to 10% of individuals with autism , and the fraction is likely to be higher when microarray comparative genome hybridization is used .
abnormalities in long - term synaptic plasticity of excitatory synapses and in baseline synaptic connectivity may be the underlying neurological substrate of autism associated with fxs [ 20 , 21 ] .
alterations in the neocortical excitatory / inhibitory balance as well as abnormal neural synchronization have been also reported in mouse model of fxs , resulting in hyperexcitability of neocortical circuits .
an immature dendritic morphology may also increase susceptibility to epilepsy and anxiety in fxs patients .
tuberous sclerosis complex ( tsc ) is an inherited disorder resulting from mutations in one of two genes , tsc1 ( hamartin ) and tsc2 ( tuberin ) , characterized by benign hamartomatous tumors that involve multiple organ systems .
it is commonly associated with neuropsychiatric complications like epilepsy , mental retardation , autism , and other behavioral problems .
seizures can be present in the first year of life and up to one third of children develop infantile spasms .
neurobehavioral phenotypes in tsc may arise from perturbations of interneurons development , which can selectively impact frontal and parietal areas .
tsc2 gene localized on 16p13.3 locus encodes for tuberin , a protein highly expressed in frontal regions .
furthermore , several studies have described the tsc 1 locus 9q34 as an important region of vulnerability for the developmental of autism .
a loss of a single tsc1 gene copy in mice is sufficient to perturb cytoskeletal dynamics and dendritic spine structure , highlighting generalized neurotrophic roles for these genes , in addition to cell growth regulation .
a wide number of cytogenetic abnormalities have been described , particularly in the low functioning autistic population with dysmorphic features .
chromosomal rearrangements in 15q11 - 15q13 region might be the most frequent cytogenetic abnormality in asd , accounting for 12% of patients . a chromosome
15 phenotype ii , characterized by ataxia , language delay , epilepsy , mental retardation , repetitive movement disorders , and facial dysmorphic features , has been described in individuals with chromosome 15 duplications . within the 15q1115q13 locus , gamma - aminobutyric acid a receptor beta 3 ( gabrb3 ) , an inhibitory neurotransmitter receptor ,
are currently thought to be central likely to play a significant role in the development of asd , due to its role in the neuronal inhibition and its expression in early development .
this finding is particularly interesting in light of the high incidence of seizures and eeg abnormalities in autistic patients .
two of the loci most commonly associated with asd by genetic linkage studies [ 37 , 38 ] ( 7q22 and 7q31 regions ) contain several genes implicated in the pathogenesis of autism .
the reln gene , found within the 7q22 region , has a pivotal role in neuronal migration and prenatal development of neural connections , [ 39 , 40 ] and is potently inhibited by toxic substances , such as organophosphates .
increased risk for autism can be also linked to a functional polymorphism in the met gene , found within the 7q31 locus , which plays a role into development of the cerebral cortex and cerebellum .
the williams - beuren syndrome ( wbs ) region ( 7q11.23 ) also contains several genes associated with impairment in language and social interaction [ 4345 ] , suggesting the existence of a specific subgroup of autistic patients , characterized by dysmorphic features , mental retardation , language delay , congenital heart disease , and hypersensitivity to sound .
an association between a larger microdeletion on 16p11.2 and a syndrome that included developmental delay and distinct facial appearance ( hypertelorism , a broad nasal bridge and a broad nasal tip with a prominent columella , a short philtrum , long ears , a large mouth ) has been described [ 4648 ] .
the chromosomal region 16p11.2 also encompasses the prkcb1 locus , an interesting gene previously found associated with autism , and expressed in the cns , the immune system , the digestive tract , and the kidney .
a recent study has described an association between prkcb1 and an enhanced urinary peptide excretion rate .
deletions involving 2q37 have been observed in more than 70 individuals with autism , mental retardation , and dysmorphic features ( prominent forehead , depressed nasal bridge , dysmorphic ears and nose , short stature , and short hands and feet ) [ 51 , 52 ] .
three different breakpoints of 2q37 ( 2q37.1 , 2q37.2 , 2q37.3 ) have been analyzed to clarify the genotype - phenotype relationships associated with different terminal deletions , and several candidate genes for autism have been identified in 2q37.3 band .
furthermore , a correlation between autism and a de novo cryptic deletion of chromosome 2p25.2 has been described .
the interaction between potential candidate genes that are expressed on these loci may explain the phenotypical heterogeneity and the spectrum of neuropsychological deficits associated with 2q37 and 2p25.2 deletion syndromes .
other regions implicated in the asds with possible candidate genes are summarizes in table 3 .
several molecular pathways potentially involved in the disruption of neurodevelopmental trajectories during intrauterine or postnatal brain development may be associated with abnormal developmental processes , from neuronal migration and cortical organization to synaptic and dendritic conformation .
furthermore , environmental factors , including maternal / intrauterine infections , exposure to toxins , and ossidative stress , may modify the underlying genetic substrate and leading to abnormalities in neuronal organization and cortical network development .
figure 1 summarizes both genetic background and epigenetic factors involved in the pathogenesis of asd , and explains how their multifactorial influence may be necessary for full expression of the autistic phenotype .
defined medical syndromes , chromosomal abnormalities and de novo copy number variations ( cnvs ) may account for 10% of asd cases .
figure 2 illustrates many different types of potential pathogenetic mechanisms responsible for the asd phenotype in the most common medical conditions associated with autism .
widespread genetic testing would be expensive , time - consuming , and generally inappropriate due to the etiological complexity , while the appropriate use of genetic testing in subgroups of autistic patients showing particular clinical features is relevant to good clinical practice and may allow the identifications of new susceptibility variants .
the advent of fluorescent in situ hybridization ( fish ) techniques has expanded the list of chromosomal hot spots in autism .
individual fish studies may be indicated in the confirmation of a clinically suspected condition , and in the evaluation of low functioning patients with an iq < 50 .
when dysmorphic features are present , it is reasonable to suspect chromosomal rearrangements even if the karyotype appears normal , and oligo - array - based cgh analysis is highly advisable in these cases .
whole genome - scanning by array - based technology has detected copy - number variations ( cnvs ) , which are copy - number changes involving a dna fragment , and represent submicroscopic deletions or duplications that are undetectable at the routine cytogenetic analysis [ 7578 ] . in conclusion , as etiologies of asd are progressively discovered , the number of individuals with idiopathic autism will progressively shrink .
the role of the neuropediatrician will be to understand the neurological basis of autism , and to identify more homogenous subgroups with specific biologic markers .
because autism represents an extremely heterogeneous group of disorders , a better understanding of underlying biological processes will lead to more targeted intervention approaches that can be designed for specific subtypes of autism .
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### Summary:
: background .
current advances in genetic technology continue to expand the list of medical conditions associated with autism .
clinicians have to identify specific autistic - related syndromes , and to provide tailored counseling .
the aim of this study is to elucidate recent advances in autism research that offer important clues into pathogenetic mechanisms of syndromic autism and relevant implications for clinical practice .
data sources .
the pubmed database was searched with the keywords autism and chromosomal abnormalities , metabolic diseases , susceptibility loci .
results .
defined mutations , genetic syndromes , and metabolic diseases account for up to 20% of autistic patients .
metabolic and mitochondrial defects may have toxic effects on the brain cells , causing neuronal loss and altered modulation of neurotransmission systems .
alterations of the neocortical excitatory / inhibitory balance and perturbations of interneurons ' development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in fragile x - syndrome and tuberous sclerosis complex .
chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections , brain growth , and synaptic / dendritic morphology .
conclusion .
metabolic testing may be appropriate if specific symptoms are present .
high - resolution chromosome analysis may be recommended if a specific diagnosis is suspected because of obvious dysmorphisms . identifying cryptic chromosomal abnormalities by whole genome microarray analysis can increase the understanding of the neurobiological pathways to autism .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: when they occur , the ovaries are most often affected , and the uterus , especially the uterine cervix , is rarely involved by metastatic tumors . in cases of metastatic involvement of the cervix , most present with abnormal vaginal bleeding or abnormal cervical cytology in the follow - up of known primary cancers . here
we report a case of metastasis of breast cancer to the cervix appearing as a large cervical leiomyoma which was diagnosed before the discovery of the primary tumor .
a 52-year - old woman , gravida 1 , para 1 , without significant past medical or family history , presented with a 2-week history of lower abdominal discomfort and pollakisuria .
vaginal inspection revealed a fibroid - like lesion protruding into the vaginal cavity without abnormal bleeding .
an ultrasound scan showed a solid large mass in the cervix measuring over 10 cm in diameter appearing as a leiomyoma .
magnetic resonance imaging revealed several tumors in the uterine corpus and cervix , suggestive of multiple leiomyomas ( fig .
serum levels of ca125 , ca19 - 9 , ldh and estradiol were 30.1 u / ml , 5.5 u / ml , 182 iu / l , and 131 pg / ml , respectively .
( a ) t2-weighted mri shows a large mass with heterogeneous signal intensity in the cervix ( arrows ) .
( b ) gross appearance of the resected uterus . a total abdominal hysterectomy with bilateral salpingo - oophorectomy was performed .
a bulging 11-cm mass in the cervix had a whitish appearance on cut section and seemed to be a leiomyoma which was not unusual grossly ( fig .
unexpectedly , however , microscopic examination of the cervical tumor showed carcinoma cells displaying the linear , indian - file arrangement characteristic of invasive lobular carcinoma ( ilc ) of the breast ( fig .
immunohistochemical staining of the tumor was positive for estrogen receptor and cytokeratin 903 ( 34 e12 ) , also suggestive of breast origin .
several microscopic foci of carcinoma cells were also observed in the stroma of the endometrium .
after the diagnosis of cervical metastasis of probable breast origin , mammography and ultrasound detected a 5-cm lesion in the left breast .
a left modified radical mastectomy with axillary lymph node dissection was performed ( the histologic appearance of the tumor is shown in fig .
estrogen and progesterone receptors were positive while epidermal growth factor receptor 2 ( her2/neu ) was negative .
postoperative adjuvant therapy was anastrozole for 3.5 years , which was changed to s-1 ( an oral fluoropyrimidine derivative composed of tegafur , 5-chloro-2,4-dihydroxypyridine and oteracil potassium ) due to the rise in serum ca15 - 3 levels .
seven years after laparotomy , the patient remains alive and well with elevated ca15 - 3 levels .
( a ) histologic aspect of the cervical tumor showing indian - file pattern of tumor cell infiltration ( he 400 ) .
( b ) histology of the primary breast tumor with pleomorphic variant pattern of invasive lobular carcinoma ( he x400 ) .
although adenocarcinoma of the cervix as direct spread of an adenocarcinoma of the endometrium is not unusual , metastasis to the cervix from extragenital sites is a rare occurrence .
mazur et al . reported that , among 149 metastatic tumors to the female genital tract from extragenital primaries , the ovary and vagina were the most frequent locations of metastases ( 75.8% and 13.4% , respectively ) , and only 8.1% were to the uterus ( 4.7% to the endometrium , 3.4% to the cervix ) .
breast was the second most common primary site next to gastrointestinal tumors ; of 52 breast cancer cases metastatic to the gynecologic organs , ovaries were affected in 88.5% cases , vagina in 5.8% , endometrium in 3.8% , vulva in 1.9% and no case to the cervix .
limoine and hall found 33 cases of distant metastasis to the cervix , four of which ( 12.1% ) were from a breast primary .
breast cancer includes a number of histological subtypes of which the two most common are invasive ductal carcinoma ( idc ) and ilc .
more than seventy percent of all breast cancers are idcs while ilc represents 515% . with respect to metastasis , ilc spreads more frequently to gynecologic organs than idc .
ilc is often a poorly circumscribed tumor , which can be difficult to detect by palpation or by mammography .
this feature may lead to a delay in diagnosis , as is the case in the present patient .
in fact , she had taken a mammography showing no abnormality three years previously , and she was unaware of any breast masses at the time of presentation . to date , approximately 35 cases of breast cancer metastases to the cervix have been reported and , in the majority of the cases , the primary tumor was diagnosed before the discovery of the metastasis . a review of the english literature disclosed only seven cases in which the presenting symptoms due to metastatic cervical tumor precede diagnosis of the primary tumor in the breast ( summarized in table 1 ) . at presentation
, the previously reported cases seemed to be advanced primary cervical cancer , which contrasts with the present case in that the initial diagnosis was a cervical leiomyoma .
presence of multiple fibroids in the corpus , serum ca125 and ldh levels within normal limits , and serum estradiol level in premenopausal state favored that diagnosis rather than a malignant tumor .
this case highlights the difficulty and the importance to consider a metastatic tumor in the differential diagnosis of a cervical mass without abnormal vaginal bleeding or abnormal cervical cytology in women of perimenopausal ages .
reported cases of breast cancer with synchronous metastasis to the uterine cervix avb : abnormal vaginal bleeding ; pap : pap smear ; np : not performed ; nm : not mentioned ; aar : alive at time of report
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### Summary:
: abstractmetastasis to the uterine cervix is a complication of breast cancer that is not commonly known .
detection of cervical metastasis before the diagnosis of the primary tumor is even rarer .
the present report describes a case of a 52-year - old woman who had a large cervical tumor appearing as a leiomyoma .
she underwent a total abdominal hysterectomy with bilateral salpingo - oophorectomy .
histopathological examination of the cervical tumor showed patterns characteristic of invasive lobular carcinoma of the breast , leading to the discovery of the primary in the left breast .
she subsequently underwent mastectomy , hormone therapy and chemotherapy , and is alive at 7-year follow - up .
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: each year more than 500,000 bone graft procedures are performed in the united states , and more than 2.2 million are performed annually worldwide .
although an autograft is considered as the gold standard , the use of an autograft is limited due to its associated donor site morbidity and the restricted availability for large bone defect repair . compared with autografts ,
however , due to the absence of osteogenic cells , bone allografts are inferior in new bone induction and revascularization . a 10-year failure rate of cortical allograft transplantations is reported at 60% due to nonunions , infection , and propagation of microdamages in devitalized bone . a novel approach to revitalize structural bone allografts has been proposed .
the approach centers on engraftment of bone - forming cells around bone allografts , mimicking periosteal response in autograft repair .
the key to the success of this approach is to create a tissue - engineered periosteum replacement carrying osteogenic and angiogenic signals capable of recapitulating the effective repair elicited by periosteum . to the end of identifying critical osteogenic and angiogenic signals
underlying periosteum - initiated repair and reconstruction , we recently isolated a population of mesenchymal progenitor cells from the healing autograft periosteum ( pdmpcs ) .
these cells express typical mpc markers such as sca-1 , ssea4 , cd105 , and cd140b .
they can further give rise to multiple cell types , such as osteoblasts , chondrocytes , and adipocytes in vitro .
examination of the osteogenic differentiation of these cells shows that activation of hh pathway leads to marked induction of osteoblasts in vitro and copious bone formation in vivo . using a loss - of - function approach to delete the receptor of all hh ligands , smoothened-1
, we further show that hh activation is required for effective periosteum - dependent bone graft repair and reconstruction . as a family of key morphogens in embryonic development , hedgehogs , such as indian hedgehog ( ihh ) and sonic hedgehog ( shh ) ,
both ihh and shh have been shown to induce osteogenic differentiation of mpc lines through induction of runx2 , an essential transcriptional factor for osteoblast differentiation and bone formation .
in addition to bone formation , the hedgehog pathway has also been intimately linked to vascular formation and angiogenesis .
ihh is implicated in blood island formation and early yolk sac angiogenesis , whereas shh is critical for the assembly of angioblasts ( endothelial precursors ) into blood vessel network , a process known as vasculogenesis during embryonic development .
hedgehog signaling is active in adult coronary vasculature , and disruption of hh signaling led to loss of coronary blood vessels and subsequent cardiomyocyte cell death in mice .
delivery of shh improves the repair of ischemic myocardium by promoting angiogenesis and microvascular remodeling .
the combined effects of hedgehog on osteogenesis and angiogenesis warrant further investigation for the use of hh agonists in bone defect repair and reconstruction . to this end
, we used an ex vivo hedgehog gene therapy approach and implanted pdmpcs that overexpressed an n - terminal peptide of human sonic hedgehog ( shhn ) around a devitalized bone allograft via a collagen scaffold .
the treated allograft was used to repair a 4-mm segmental defect created in the immunodeficient mouse femurs .
our results demonstrated that overexpression of shhn in periosteal cells markedly enhanced donor cell survival and revascularization of the scaffold at the site of repair , leading to a complete restoration of periosteal bone formation around bone allografts .
adenovirus - mediated gene transduction led to ~45,000-fold induction of human shhn gene expression in pdmpcs ( figure 1a ) .
overexpression of shhn markedly enhanced osteogenic differentiation of pdmpcs as evidenced by enhanced alkaline phosphatase staining ( figure 1b ) and increased expression of osteogenic genes such as runx2 and osteocalcin ( figure 1c , d ) .
overexpression of shhn further enhanced the level of runx2 protein in the western blot analyses ( supplementary figure s1 ) .
in addition to the enhanced expression of osteogenic genes , a strong induction of angiogenic genes such as ang1 , ang2 , ang4 , and vegf was also observed in cells transduced with ad - shhn ( figure 1e h ) . to enable tracking of the donor cells
adenoviral transduced pdmpcs were loaded onto collagen scaffolds and wrapped around devitalized bone allografts in immunodeficient mice .
healing of the allografts treated with ad - shhn - pdmpcs or ad - gfp - pdmpcs was examined .
x - ray analyses showed limited bone callus formation at the host side of cortical bone junction in allografts treated with ad - gfp - pdmpcs 6 weeks following implantation .
by contrast , in allografts treated with ad - shhn - pdmpcs , a complete bridging callus was observed around the bone allograft ( figure 2a ) .
microct 3d reconstruction of the allograft at 6 weeks showed that the allograft engrafted with shh - overexpressing pdmpcs formed a contiguous periosteal collar bone callus around allograft ( figure 2b , top panel ) .
quantitative volumetric analyses showed a 4.6- , 2.5 , and 3.5-fold increase of new bone formation at the donor site , the host site , and the total callus , respectively , in ad - shhn - pdmpc treated allografts as compared with the control ad - gfp - pdmpc treated allografts ( figure 2c ; p < 0.05 ; n = 6 ) .
histologic analyses showed that ad - gfp - pdmpc treated allograft had minimal periosteal bone formation at the donor site , with persistent collagen scaffold around allograft ( figure 2d , * indicates scaffold ) .
by contrast , ad - shhn - pdmpc treated allograft formed a contiguous bone callus across the entire length of the donor bone ( figure 2e , indicated by arrows ) .
histomorphometric analyses at 6 weeks showed a 4.6-fold increase in bone formation and a 3.5-fold decrease in fibrotic tissue at the donor site ( figure 2f ; p < 0.05 ; n = 6 ) . in the host side callus ,
bone formation was increased by 35% and fibrotic issue was reduced by 63% in ad - shhn - pdmpc treated allografts ( figure 2 g ; p < 0.05 ; n = 6 ) .
persistent cartilage observed at the cortical bone junction in the control allografts was completely eliminated in ad - shhn - pdmpc treated allografts ( figure 2f , g ; p < 0.05 ; n = 6 ) .
gfp donor cells were tracked at the repair sites for a period of 6 weeks using immunohistochemistry . in ad - gfp - pdmpc treated allografts , only a small number of donor progenitor cells were detected in collagen scaffold at 2 weeks ( figure 3a , e , i , m ) .
most of the cells were found at the cortical bone junction or close to the surface of the scaffold ( figure 3a , i ) .
a few of the donor cells were incorporated into bone and cartilage tissues at the cortical bone junction ( figure 3e , i , arrow in i ) .
sparsely distributed cells were found in the scaffold further away from the junction ( figure 3 m ) .
by contrast , in ad - shhn - pdmpc treated allografts , abundant gfp cells were found throughout the collagen scaffold at 2 weeks after surgery ( figure 3b , f , j , n ) . at a higher magnification , dense gfp cellular layers were observed in the scaffold ( figure 3j ) . by 6 weeks
, abundant gfp cells were found to be incorporated into the new bone matrix at the donor site ( figure 3h , l ) . at a higher magnification , gfp osteocytes and osteoblasts were readily identified along new bone surface and within bone matrix in the periosteal callus ( figure 3p , arrows ) . by contrast , in ad - gfp - pdmpc treated allografts ( figure 3c , g , k , o ) , gfp cells were found scattered within the scaffold at the donor site ( figure 3k ) .
a few of them were found embedded within poorly differentiated cartilage tissue ( figure 3k , arrow ) . at a higher magnification ,
the majority of gfp cells in the collagen scaffold were seen as undifferentiated elongated fibroblastic cells ( figure 3o ) .
immunohistochemical staining of cd31 demonstrated a marked increase in cd31 microvessel formation in ad - shhn - pdmpc seeded scaffold as compared with the control ad - gfp - pdmpc seeded scaffold at 2 weeks after implantation ( figure 4a , c vs. 4b , d ) .
many of the vessels found in ad - shhn - pdmpc scaffold had larger , more mature lumens containing red blood cells ( figure 4d , arrows ) .
quantification of the numbers of microvessels within the scaffold showed a threefold increase in ad - shhn - pdmpc scaffold as compared with the control ( figure 4 g ; p < 0.05 ; n = 4 ) . with enhanced vascularity
, trap cells were also found to be increased within collagen scaffold ( figure 4e , f ) .
quantification analyses showed a 10-fold increase in the number of trap cells in ad - shhn - pdmpc scaffold as compared with the control ( figure 4h ; p < 0.05 ; n = 4 ) .
the rapid induction of microvessel formation in ad - shhn - pdmpc scaffold prompted us to investigate the potential effects of shhn on recruitment and morphogenesis of endothelial progenitors from the surrounding tissues of periosteum , such as skeletal muscles or subcutaneous fat .
it has been shown that both tissues contained abundant endothelial progenitors . to determine whether shhn could recruit more endothelial progenitors into the scaffold and further enhanced the assembly of microvessels , we first characterized different fractions of mononuclear cells isolated from muscle and fat using fluorescence - activated cell sorting ( facs ) .
culturing of different fractions of the mononuclear cells from muscle and fat in matrigel showed that cd45sca-1cd34 and cd45sca-1cd34vegfr2 cells were capable of forming abundant and robust cd31 microvessels in vitro ( supplementary figure s3 and figure 5a2,b2 ) .
facs analyses showed that muscle and fat contained an average of 7.7 and 5.8% cd45sca-1cd34vegfr2 endothelial progenitors , respectively , in the mononuclear cell preps ( figure 5a1,b1 , arrows ) . in comparison ,
fewer cd45sca-1cd34vegfr2 cells were identified in bone marrow ( supplementary figure s2 ) . next we examined the frequency of cd45sca-1cd34vegfr2 endothelial progenitor cells in ad - lacz - pdmpc or ad - shhn - pdmpc seeded collagen scaffold at day 7 following surgical implantation .
facs analyses show that ad - shhn - pdmpc scaffold contained a 2.4- , 1.8- , and 2.1-fold more cd45cd34vegfr2 , cd45sca-1vegfr2 , or cd45sca-1cd34vegfr2 endothelial progenitors than ad - lacz - pdmpc scaffold ( figure 6a , b ; p < 0.05 ; n = 3 ) . to determine whether shhn overexpression could affect the differentiation and morphogenesis of the endothelial progenitors from the peripheral tissues , we cocultured cd45sca-1cd34 endothelial progenitor cells with ad - shhn - pdmpcs .
our data showed that ad - shhn transduced pdmpcs significantly increased cd31 microvessel formation by 1.8-fold as compared with the control ad - lacz - pmdpcs ( figure 6e ; n = 4 ; p < 0.05 ) .
compared with the controls , ad - shhn transduced cells visibly induced the formation of more microvessel branches with more complex morphology and network in vitro ( figure 6c , d ) .
adenovirus - mediated gene transduction led to ~45,000-fold induction of human shhn gene expression in pdmpcs ( figure 1a ) .
overexpression of shhn markedly enhanced osteogenic differentiation of pdmpcs as evidenced by enhanced alkaline phosphatase staining ( figure 1b ) and increased expression of osteogenic genes such as runx2 and osteocalcin ( figure 1c , d ) .
overexpression of shhn further enhanced the level of runx2 protein in the western blot analyses ( supplementary figure s1 ) .
in addition to the enhanced expression of osteogenic genes , a strong induction of angiogenic genes such as ang1 , ang2 , ang4 , and vegf was also observed in cells transduced with ad - shhn ( figure 1e h ) . to enable tracking of the donor cells
adenoviral transduced pdmpcs were loaded onto collagen scaffolds and wrapped around devitalized bone allografts in immunodeficient mice .
healing of the allografts treated with ad - shhn - pdmpcs or ad - gfp - pdmpcs was examined .
x - ray analyses showed limited bone callus formation at the host side of cortical bone junction in allografts treated with ad - gfp - pdmpcs 6 weeks following implantation .
by contrast , in allografts treated with ad - shhn - pdmpcs , a complete bridging callus was observed around the bone allograft ( figure 2a ) .
microct 3d reconstruction of the allograft at 6 weeks showed that the allograft engrafted with shh - overexpressing pdmpcs formed a contiguous periosteal collar bone callus around allograft ( figure 2b , top panel ) .
quantitative volumetric analyses showed a 4.6- , 2.5 , and 3.5-fold increase of new bone formation at the donor site , the host site , and the total callus , respectively , in ad - shhn - pdmpc treated allografts as compared with the control ad - gfp - pdmpc treated allografts ( figure 2c ; p < 0.05 ; n = 6 ) .
histologic analyses showed that ad - gfp - pdmpc treated allograft had minimal periosteal bone formation at the donor site , with persistent collagen scaffold around allograft ( figure 2d , * indicates scaffold ) .
by contrast , ad - shhn - pdmpc treated allograft formed a contiguous bone callus across the entire length of the donor bone ( figure 2e , indicated by arrows ) .
histomorphometric analyses at 6 weeks showed a 4.6-fold increase in bone formation and a 3.5-fold decrease in fibrotic tissue at the donor site ( figure 2f ; p < 0.05 ; n = 6 ) . in the host side callus ,
bone formation was increased by 35% and fibrotic issue was reduced by 63% in ad - shhn - pdmpc treated allografts ( figure 2 g ; p < 0.05 ; n = 6 ) .
persistent cartilage observed at the cortical bone junction in the control allografts was completely eliminated in ad - shhn - pdmpc treated allografts ( figure 2f , g ; p < 0.05 ; n = 6 ) .
gfp donor cells were tracked at the repair sites for a period of 6 weeks using immunohistochemistry . in ad - gfp - pdmpc treated allografts , only a small number of donor progenitor cells were detected in collagen scaffold at 2 weeks ( figure 3a , e , i , m ) .
most of the cells were found at the cortical bone junction or close to the surface of the scaffold ( figure 3a , i ) .
a few of the donor cells were incorporated into bone and cartilage tissues at the cortical bone junction ( figure 3e , i , arrow in i ) .
sparsely distributed cells were found in the scaffold further away from the junction ( figure 3 m ) .
by contrast , in ad - shhn - pdmpc treated allografts , abundant gfp cells were found throughout the collagen scaffold at 2 weeks after surgery ( figure 3b , f , j , n ) . at a higher magnification , dense gfp cellular layers were observed in the scaffold ( figure 3j ) . by 6 weeks
, abundant gfp cells were found to be incorporated into the new bone matrix at the donor site ( figure 3h , l ) . at a higher magnification
, gfp osteocytes and osteoblasts were readily identified along new bone surface and within bone matrix in the periosteal callus ( figure 3p , arrows ) . by contrast , in ad - gfp - pdmpc treated allografts ( figure 3c , g , k , o ) , gfp cells were found scattered within the scaffold at the donor site ( figure 3k ) .
a few of them were found embedded within poorly differentiated cartilage tissue ( figure 3k , arrow ) . at a higher magnification ,
the majority of gfp cells in the collagen scaffold were seen as undifferentiated elongated fibroblastic cells ( figure 3o ) .
immunohistochemical staining of cd31 demonstrated a marked increase in cd31 microvessel formation in ad - shhn - pdmpc seeded scaffold as compared with the control ad - gfp - pdmpc seeded scaffold at 2 weeks after implantation ( figure 4a , c vs. 4b , d ) .
many of the vessels found in ad - shhn - pdmpc scaffold had larger , more mature lumens containing red blood cells ( figure 4d , arrows ) .
quantification of the numbers of microvessels within the scaffold showed a threefold increase in ad - shhn - pdmpc scaffold as compared with the control ( figure 4 g ; p < 0.05 ; n = 4 ) . with enhanced vascularity
, trap cells were also found to be increased within collagen scaffold ( figure 4e , f ) .
quantification analyses showed a 10-fold increase in the number of trap cells in ad - shhn - pdmpc scaffold as compared with the control ( figure 4h ; p < 0.05 ; n = 4 ) .
the rapid induction of microvessel formation in ad - shhn - pdmpc scaffold prompted us to investigate the potential effects of shhn on recruitment and morphogenesis of endothelial progenitors from the surrounding tissues of periosteum , such as skeletal muscles or subcutaneous fat .
it has been shown that both tissues contained abundant endothelial progenitors . to determine whether shhn could recruit more endothelial progenitors into the scaffold and further enhanced the assembly of microvessels , we first characterized different fractions of mononuclear cells isolated from muscle and fat using fluorescence - activated cell sorting ( facs ) .
culturing of different fractions of the mononuclear cells from muscle and fat in matrigel showed that cd45sca-1cd34 and cd45sca-1cd34vegfr2 cells were capable of forming abundant and robust cd31 microvessels in vitro ( supplementary figure s3 and figure 5a2,b2 ) .
facs analyses showed that muscle and fat contained an average of 7.7 and 5.8% cd45sca-1cd34vegfr2 endothelial progenitors , respectively , in the mononuclear cell preps ( figure 5a1,b1 , arrows ) . in comparison ,
fewer cd45sca-1cd34vegfr2 cells were identified in bone marrow ( supplementary figure s2 ) . next we examined the frequency of cd45sca-1cd34vegfr2 endothelial progenitor cells in ad - lacz - pdmpc or ad - shhn - pdmpc seeded collagen scaffold at day 7 following surgical implantation .
facs analyses show that ad - shhn - pdmpc scaffold contained a 2.4- , 1.8- , and 2.1-fold more cd45cd34vegfr2 , cd45sca-1vegfr2 , or cd45sca-1cd34vegfr2 endothelial progenitors than ad - lacz - pdmpc scaffold ( figure 6a , b ; p < 0.05 ; n = 3 ) . to determine whether shhn overexpression could affect the differentiation and morphogenesis of the endothelial progenitors from the peripheral tissues , we cocultured cd45sca-1cd34 endothelial progenitor cells with ad - shhn - pdmpcs .
our data showed that ad - shhn transduced pdmpcs significantly increased cd31 microvessel formation by 1.8-fold as compared with the control ad - lacz - pmdpcs ( figure 6e ; n = 4 ; p < 0.05 ) .
compared with the controls , ad - shhn transduced cells visibly induced the formation of more microvessel branches with more complex morphology and network in vitro ( figure 6c , d ) .
to exploit the use of hedgehog agonist as an osteogenic and angiogenic agent for bone defect repair and reconstruction , in this study , we used an ex vivo gene therapy approach overexpressing an n - terminal peptide of human shh in pdmpcs . to determine the efficacy of progenitor cell - based gene therapy ,
an immune - deficient mouse model was used to test the effects of shhn on donor and host cells .
ad - gfp - pdmpc treated devitalized allografts showed absence of periosteal bone formation and poor osseointegration at the cortical bone junctions , similar to allograft transplantation in immunocompetent mice .
by contrast , ad - shhn - pdmpc treated allografts completely restored periosteal collar bone formation and markedly improved osseointegration of the allografted bone .
shhn additionally promoted the recruitment and morphogenesis of peripheral endothelial progenitors , leading to rapid revascularization of the cellular scaffold .
our previous study further shows that hedgehog pathway is required for postnatal long bone defect healing that implicates periosteum . by implantation of pdmpcs
overexpressing shhn in a bone allograft model , here we provide further evidence to show that activation of hh pathway in mpcs effectively enhances long bone defect repair and reconstruction . by tracking the donor cell fate for a period of 6 weeks
, we demonstrated that shhn markedly enhanced donor cell survival , repopulation , and differentiation in the scaffold . without shhn stimulation , only a few pdmpcs survived in the scaffold , with a small proportion of the cells incorporated into cartilage or bone at the cortical bone junction .
the majority of the donor pdmpcs remained as undifferentiated fibroblastic cells in the scaffold at 6 weeks after implantation .
by contrast , shhn - transduced pdmpcs exhibited better survival capability and quickly repopulated the scaffold , with a large number of cells differentiating into osteoblasts and participating in collar bone formation at the donor site ( figure 3 ) .
in addition to the direct effects on donor cells , our data also showed that ad - shhn - pdmpc treatment enhanced host bone callus formation , suggesting a paracrine effect of shhn on host progenitor cells . in the allografts treated with control pdmpc ,
persistent cartilaginous tissue was observed at the cortical bone junction 6 weeks after surgery ( figure 3 g ) . by contrast , the persistent cartilaginous tissue was eliminated from the host and donor callus in ad - shhn - pdmpc treated allografts , indicating an improved endochondral bone formation at the cortical bone junction . as a result of the elimination of the residue cartilage , ad - shhn - pdmpc treated allografts demonstrated better osseointegration at the cortical bone junction .
indeed , due to the lack of a cholesterol - binding site , shhn peptide is shown to be able to diffuse to a greater distance than the native protein .
this unique property of shhn favors postnatal repair , which is less dependent on a morphogen gradient .
similar to shhn , a number of therapeutic genes , such as bmps and vegf , have been previously demonstrated to elicit both paracrine and autocrine effects on repair of large bone defect .
besides enhancing cellular survival and differentiation , our data further showed that hh overexpression induced rapid revascularization of the scaffold at the site of repair .
the enhanced neovascularization is associated with the induction of several key angiogenic gene expression , such as vegf , ang1 , ang2 , and ang4 in pdmpcs ( figure 1 ) .
in addition to vegf , hh signaling is also known to regulate both ang1 and ang2 .
ang1 promotes angiogenesis and arteriogenesis , whereas both ang2 and ang4 are classified as antagonists of ang1-tie2 signaling during development .
however , despite an antagonizing role of ang2 during development , recent data have shown that ang2 is required for postnatal remodeling of the vessels .
ang2 can further exert proangiogenic functions and enhance vessel sprouting in a tie2-independent manner via activation of integrins / focal adhesion kinase signaling in endothelial tip cells .
nevertheless , it is shown that ang4 can induce angiogenesis in vivo in the mouse corneal micropocket assays .
future experiments are needed to establish the role of angiopoietin genes in hh - induced neovascularization .
in addition to the induction of angiogenic factors by shhn , our current data further suggest a novel mechanism that involves the recruitment of endothelial progenitors from the peripheral tissues such as fat and muscles .
it has been shown that exogenous administration of shh accelerates the repair of ischemic myocardium by enhancing the recruitment of bone marrow derived endothelial progenitor cells to the injury site .
a similar mechanism is further noted in diabetic skin wound closure treated with shh protein . by comparing the frequency of endothelial progenitors from bone marrow , muscle , and fat
, we found that bone marrow contained fewer endothelial progenitors than muscles and subcutaneous fat ( supplementary figure s2 ) .
by contrast , cd45cd34sca-1vegfr2 cells constituted 510% of the isolated mononuclear cell populations in muscle and fat .
the presence of abundant endothelial progenitors in surrounding soft tissues suggests the potential involvement of these cells in rapid vascularization of the scaffold . in support of this notion
, we provided evidence to show that ad - shhn - pdmpc scaffold contained more cd45cd34sca-1vegfr2 endothelial progenitor cells than ad - lacz - pdmpc scaffold at day 7 after transplantation ( figure 6 ) . furthermore , shhn overexpression significantly enhanced the formation and morphogenesis of cd31 microvessels in coculture of cd45cd34sca-1 endothelial progenitors with pdmpcs , demonstrating the advantage of using shhn - transduced mesenchymal progenitors in revascularization of the scaffold .
the data from this study are consistent with those from several recent reports that show a synergistic effect of shh in vitro on osteogenesis and angiogenesis .
a marked increase of trap osteoclasts in ad - shhn - pdmpc seeded collagen scaffold at 2 weeks postimplantation was also noticed ( figure 4 ) .
shhn overexpression has been shown to increase the opg / rankl ratio in bone marrow stromal cells . in this study
, we found that ad - shhn increased opg / rankl ratio by fivefold ( data not shown ) , consistent with the probone formation effects of shhn on pdmpcs .
it has been shown that osteoclasts can be recruited to the scaffold in vivo and participate in the resorption of scaffold .
hence , the increased number of trap osteoclasts in collagen scaffold is likely due to the increased neovascularization and enhanced calcification of ad - shhn - pdmpc seeded scaffolds .
periosteum has been shown to exhibit strong regenerative capacity in vitro and in vivo .
ex vivo culture - expanded pdmpcs from human and animals have also been shown to enhance bone formation and bone defect repair .
however , culture - expanded mesenchymal progenitors often requires seeding on calcium containing scaffold , which could enhance osteogenic differentiation of the seeded cells . without calcium ,
one recent report shows that ex vivo expanded mesenchymal progenitors , regardless of their sources , have limited advantage in repair of critical bone defect .
it is worth noting that a noncalcium - containing collagen sponge was used as scaffold in this study . in these types of nonosteoinductive scaffold
, we found only a modest contribution of pdmpcs to cartilage / bone formation at the cortical bone junction in the absence of shhn , indicating that transplantation of culture - expanded periosteal mpcs alone is not sufficient to induce effective periosteal bone formation .
taken together , our data demonstrate that enhancing the survival and osteogenic differentiation of the donor mpcs and using an adequate osteoinductive scaffold are prerequisites for inducing sufficient bone formation for repair and reconstruction of large bone defects . in summary , we demonstrate that overexpression of hedgehog agonist shhn in pdmpcs restores periosteal bone formation in bone allograft transplantation model .
shhn further improves host bone formation and host - dependent vascular microenvironment by enhancing endothelial progenitor cell infiltration and rapid revascularization of the scaffold .
this study therefore provides strong rationale for the use of hh agonists in tissue - engineering applications to engender a periosteum replacement for enhanced bone defect repair and reconstruction .
further investigation using immunocompetent mice and large animal models will help in determining the translatability of this study to human .
c57bl/6 , gfp transgenic mice were purchased from the jackson laboratory ( bar harbor , maine ) .
immunocompromised mice ( bg - nu / nu - xid ) were purchased from harlan sprague dawley ( frederick , md ) .
all surgical interventions were approved by the institutional animal care and use committee at the university of rochester .
adenoviruses encoding green fluorescence protein or n - terminal peptide of human shh ( ad - shhn ) were purified as previously described .
ad - lacz was purchased from vector development lab at baylor college of medicine ( houston , tx ) .
a segmental femoral bone allograft transplantation model , described previously , was used to determine the effects of shhn on bone repair and reconstruction .
briefly , a 10-week - old mouse was anesthetized via intraperitoneal injection of ketamine and xylazine .
a 4-mm mid - diaphyseal segment was removed from the femur of the donor mice using a sharp diamond - cutting wheel attached to a cordless dremel .
a 4-mm devitalized bone allograft was inserted to repair a same sized segmental defect created in mid - diaphyseal region of the mouse femur .
the transplanted allograft was stabilized by a 22 g stainless pin placed through the intramedullary marrow cavity .
all allografts were harvested from 129s1 mice , cleaned , and processed in 75% ethanol to remove cellular debris as previously described .
after digestion with collagenase d ( roche applied science , indianapolis , in ) at a concentration of 1 mg / ml for 1 hour , cells released from periosteal tissues were pooled and cultured in -mem medium containing 1% penicillin and streptomycin , 1% glutamine , and 20% fetal bovine serum ( fbs ) .
once confluent , cells were trypsinized and further expanded in -mem medium containing 10% fbs .
pdmpcs were infected with ad - gfp or ad - shhn at a multiplicity of infection of 100 .
a total of 1 10 cells were seeded onto a collagen scaffold ( cat no .
354613 , bd biosciences , san jose , ca ) and wrapped around a bone allograft .
the treated bone allograft was used to repair a 4-mm segmental bone defect created in the immunodeficient mice .
a total of 20 immunodeficient mice were split into two experimental groups : allografts treated with ad - gfp - pdmpcs or allografts treated with ad - shhn - pdmpcs .
four animals from each group were harvested at 2-week postsurgery for cell tracking and vascular analyses .
the remaining six mice per group were harvested at 6 weeks for histologic and microct analyses .
paraffin - embedded tissue sections were prepared by h&e / alcian blue staining as previously described .
histomorphometric analyses were performed using at least three nonconsecutive sections of each sample , 50 m apart in the center region of the callus .
the percentages of bone , cartilage , and fibrotic tissue formation at the side of donor and host were determined using osteometrics , which allows interactive tracing of the area of new bone , cartilage , and fibrotic tissue ( total callus subtracted from bone and cartilage tissue ) .
briefly , a line was drawn in the middle of the distal or proximal junctions between graft and host bone to separate new bone formation on the surface of the graft and the host bone .
areas of bone , cartilage , and fibrotic tissue on the side of the host or graft were measured separately at both ends to evaluate host and graft bone formation .
femurs were harvested at 6 weeks and scanned by a viva microct system ( scanco medical , fabrikweg , switzerland ) at a voxel size of 10.5 m . from the two - dimensional slice images
generated , an appropriate threshold was chosen for the bone voxels by visually matching thresholded areas to gray - scale images .
each sample was contoured around the external callus and along the edge of the cortical bone , excluding the marrow cavity .
new bone volume was measured on the surface of the host and donor bone , as well as in the total callus in grafted samples as previously described .
immunohistochemical staining to examine donor cell fate and microvessel formation at the site of repair .
immunohistochemical staining for gfp or cd31 was performed separately on paraffin - embedded tissue sections using a maxpoly - two polymer hrp mouse detection kit ( maxvision biosciences , seattle , wa ) .
primary antibodies for gfp ( ab6673 ) and mouse cd31 ( ab28364 ) were purchased from abcam ( cambridge , uk ) and used in the staining . to determine the number of microvessels in the scaffold region , cd31 vessels consisting of at least three cells with a lumen structure were counted .
the mean of the three nonconsecutive sections from each allograft sample , harvested at 2 weeks after implantation , was used to determine revascularization of the scaffold .
at least four allograft samples in each group were used to quantify the number of microvessels per mm area of the scaffold .
exactly 0.5 g of mrna from four different samples was pooled and reverse transcribed to make single - strand cdna , using a commercial first strand cdna synthesis kit ( invitrogen ) . quantitative reverse transcriptase
polymerase chain reaction reaction was performed using sybergreen ( abgene , rochester , ny ) in a rotorgene real time polymerase chain reaction machine ( corbett research , carlsbad , ca ) .
all gene expressions were normalized to -actin and presented as relative to that observed in cells transduced with ad - gfp or ad - shhn .
isolation and facs sorting of endothelial progenitors from skeletal muscle , subcutaneous fat , and bone marrow .
endothelial precursors were isolated from the hind limb skeletal muscle of c57bl6 mice as previously described .
briefly , muscle was minced into small pieces , digested with a final concentration of 2 mg / ml collagenase type iv ( worthington ) supplemented with 2 mm cacl2 in phosphate buffered saline ( pbs ) for 45 minutes at 37 c . to eliminate connective tissue and fibers
, samples were passed through 70 and 40 m nylon cell strainers ( bd falcon , franklin lakes , nj ) .
mononuclear cells from muscle , fat , and bone marrow were washed , centrifuged , and resuspended in pbs containing 4% fbs for antibody staining .
the following antibodies were used for facs analyses and cell sorting : percp conjugated antimouse cd45 ( bd pharmingen , san jose , ca , cat no .
557235 ) , phycoerythrin - conjugated antimouse sca-1 ( ebioscience , cat no . 12 - 5981 - 81 ) , allophycocyanin - conjugated antimouse vegfr2 ( ebioscience , cat no . 12 - 5921 - 80 ) , and antimouse cd34 conjugated with brilliant violet 421(bd pharmingen , cat no . 562608 ) .
cell sorting was conducted using a 13-color aria cell sorter statler ( biorad , hercules , ca ) . in vitro microvessel formation assay .
isolated cells were seeded in matrigel ( r&d ) at a density of 5 10 in ebm2 media ( lonza , basel , switzerland ) in 8-well chamber slides ( corning , corning , ny ) . the complete ebm2 media supplemented with lonza growth factor kit including ga100 , rhfgf - b , rhegf , vegf , igf1 , ascorbic acid , heparin , and fbs were used for microvessel formation assay in matrigel .
after 37 days of culture , tube formation was inspected under an inverted light microscope .
isolated cells were also seeded on pdmpc monolayer culture in an 8-well chamber slide ( corning ) . in the coculture experiments ,
after 37 days of coculture , capillary - like structure could be observed following cd31 immunofluorescent staining .
cells in the chamber slides were fixed with cold 4% paraformaldehyde for 1 hour at 4 c , followed by washing with pbstx ( 0.3% triton x-100 in pbs ) at room temperature , and blocking with pbsmt ( 3% bsa in 0.3% pbstx ) for 1 hour at room temperature .
the number of cd31-positive vessels was counted under a fluorescent microscope ( zeiss axio imager , oberkochen , germany ) .
the average number of vessel fragments per mm culture area from four samples of each group was calculated and used for statistical analyses .
cells were infected with control adenovirus ad - lacz or ad - shhn at a multiplicity of infection of 100 .
a total of 1 10 cells were seeded onto a collagen scaffold and implanted into immunodeficient mice as previously described .
three implants from control and shhn - treated group were harvested 7 days after surgery .
tissues were minced into small pieces followed by digestion with 2 mg / ml collagenase type iv ( worthington , lakewood , nj ) .
collected cells were passed through cell restrainers and immediately stained with indicated antibodies for facs analyses .
frequencies of various populations of cells were analyzed and presented as means of three implants in each treatment group .
all data are expressed as a mean value plus or minus the sem . the statistical significance illustrated in figures 1 and 6 between control adenovirus - transduced and ad - shhn
the statistical significance illustrated in figures 2 and 4 between ad - gfp - pdmpc and ad - shhn - pdmpc treated allografts was determined using one - way analysis of variance and a tukey 's post hoc test .
data analysis was performed using graphpad prism version 5.0 ( graphpad software , san diego , ca ) .
western blot analyses show that pdmpcs transduced with shhn have higher level of runx2 protein .
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### Summary:
: although activation of hedgehog ( hh ) signaling has been shown to induce osteogenic differentiation in vitro and bone formation in vivo , the underlying mechanisms and the potential use of hh - activated mesenchymal progenitors in bone defect repair remain elusive . in this study
, we demonstrated that implantation of periosteal - derived mesenchymal progenitor cells ( pdmpcs ) that overexpressed an n - terminal sonic hedgehog peptide ( shhn ) via an adenoviral vector ( ad - shhn ) restored periosteal bone collar formation in a 4-mm segmental bone allograft model in immunodeficient mice .
ad - shhn enhanced donor cell survival and microvessel formation in collagen scaffold at 2 weeks after surgery and induced donor cell
dependent bone formation at 6 weeks after surgery .
fluorescence - activated cell sorting analysis further showed that ad - shhn - pdmpc seeded scaffold contained a twofold more cd45sca-1+cd34+vegfr2 + endothelial progenitors than ad - lacz - pdmpc seeded scaffold at day 7 after surgery .
ad - shhn transduced pdmpcs induced a 1.8-fold more cd31 + microvessel formation than ad - lacz transduced pdmpcs in a coculture of endothelial progenitors and pdmpcs . taken together ,
our data show that overexpression of shhn in mesenchymal progenitors improves bone defect reconstruction by enhancing donor progenitor cell survival , differentiation , and scaffold revascularization at the site of compromised periosteum .
hh agonist based therapy , therefore , merits further investigation in tissue engineering based applications aimed at enhancing bone defect repair and reconstruction .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: due to protracted clinical course of prostate cancer ( pca ) , clinical guidelines recommend treatment in men with life expectancy of more than 10 years .
appropriate treatment of pca is largely dependent on the preoperative risk of disease progression among patients .
based on patient 's risk stratification , patients may be offered with different treatment modalities .
all of these factors should be considered in offering any intervention among patients with localized disease . nowadays , due to the upstream availability of minimally invasive options low risk pca
are likewise being offered with minimally invasive approach with the aid of robotic system . in counseling , physicians rely mostly on biopsy gleason score ( gs ) of their patients .
. showed that men 55 to 74 years old with biopsy gs 6 have 18% to 30% risk of dying from pca in the next 15 years of their lives .
it is estimated in previous literatures that 50% of needle biopsy score will be upgraded on final pathology specimen . in our previous study , our results showed that patients treated with radical prostatectomy for clinically low risk disease has 12.9% to 36.4% chance of upgrading .
this inaccuracy has serious impact on pretreatment decision - making , predominantly in patients who choose active surveillance or nonsurgical options .
increase in biopsy gs in men with pathological gs 8 to 10 put them on higher risk of death from pca .
likewise , upgrade in gs put them in increased chances of biochemical recurrence ( bcr ) .
several articles involving patients treated with open radical prostatectomy have discussed the predictors of gs upgrading .
nevertheless , no one among them reported the predictor of the degree of upgrading into higher pathologic gs ( 8 ) .
to the best of our knowledge this is the first study to report on the predictors of upgrading and the degree of upgrade exclusively on gs 6 patients treated with rarp . in this study , we report predictors of gs upgrading and degree of upgrading among patients who have an initial gs 6 biopsy treated with rarp .
we retrospectively reviewed records from our prospectively maintained institutional review board - database ( approval number : 2014 - 009 - 001 ) of patients who underwent rarp for pca between july 2005 to june 2010 .
patients with clinically localized pca based on magnetic resonance imaging , digital rectal examination , are included in the study .
twelve - core transrectal ultrasound guided needle biopsy was done on all patients . after excluding patients with nonorgan confined pca , prostate - specific antigen ( psa)>20 ng / ml and patients with missing information needed to classify disease risk ,
rarp was performed via a transperitoneal approach as described in our previous study , using the davinci surgical system ( intuitive surgical , sunnyvale , ca , usa ) with the pelvic lymph node dissection being performed when predicted probability of lymph node metastasis based on clinical information is more than 3% .
patients ' clinical and pathological variables : age , body mass index ( bmi ) , prostate volume , psa , number of core involvement , biopsy and prostatectomy gs were obtained .
a dedicated pathologist evaluated the prostatectomy specimens with particular attention to pathologic stage , gs , surgical margins , perineural invasion and angiolymphatic invasion .
gs upgrading is considered if initial biopsy gs6 increased on prostatectomy specimen to gs 7 .
patients were grouped into group 1 ( nonupgrade gs ) and group 2 ( upgraded gs ) and comparative analysis was performed . the primary aim was to evaluate the predictors of gs upgrading and its degree , meanwhile the secondary outcome was to evaluate the oncological outcomes of upgraded gs degrees 7 ( 3 + 4 , 4 + 3 ) , and 8 .
follow - up with physical examination and psa quarterly for the first year , semiannually for the second year , and annually thereafter was done .
bcr was defined as postoperative psa0.2 ng / ml taken twice at least 6 weeks apart .
counts of frequencies were expressed as percentages , and continuous data were presented as meanstandard deviation ( sd ) or median and interquartile range ( skewed data ) .
student t - test was used for continuous variables while chi - square test was used for categorical variables .
the probability of bcr , cancer specific survival ( css ) and overall survival ( os ) among upgraded patients were calculated by the kaplan - meier analysis .
the univariable and multivariable logistic regression models were used to estimate the impact of clinical features on upgrading and degree of upgrading .
22.0 ( ibm co. , armonk , ny , usa ) was used for all statistical analyses . a p - value of < 0.05 was considered significant , and all p - values were 2-sided .
the mean age of the patient was 63 years old ( sd , 7.5 ) . mean bmi , prostate volume , and psa were 24.22.6 kg / m ( interquartile range [ iqr ] , 15.930.8 kg / m ) , 39.220.9 ( ml ) ( iqr , 10.5164 ml ) , and 6.8 ng / ml ( iqr , 510 ng / ml ) , respectively .
patients in the upgraded group were older ( p=0.007 ) and had higher psa and smaller prostate in volume ; 7.7 ng / ml ( iqr , 5.212.4 ng / ml ) and 36.416.4 ml , respectively .
the mean age of patients in the group 2 was 62.27.6 years while it was 64.37.3 years for group 1 ( p=0.007 ) . likewise , psa density is higher in group 2 compared to group 1 with 0.300.28 and 0.210.14 , respectively . among group 2
patients , 35.9% ( 52 of 145 ) had a psa of 1020 compared to group 1 with 17.3% .
moreover , 77.2% ( 112 of 145 ) of group 2 patients had 2 core involvements .
more than 25% positive core involvement was seen in 43.4% of patients who upgraded compared to 26.2% who did not upgrade ( p=0.001 ) .
group 2 patients had higher pathologic t stage with 44.1% having > t3 ( p0.001 ) .
positive surgical margin ( psm ) was higher in upgraded group with compared to nonupgraded patients ( p0.009 ) .
significantly , perineural invasion was higher in upgraded group 51.7% versus 19.2% among the nonupgraded group ( p0.001 ) .
ten percent of group 2 patients showed angiolymphatic invasion compared to 2.3% of group 1 ( p=0.002 ) .
age , psa , psa density , clinical t stage , percentage of cores and number of positive had significant result hence further analyzed on regression analysis . moreover , on multivariable analysis age , psa , psa density and > 2 cores positive were predictors of upgrading with ( odds ratio [ or ] , 1.03 ; 95% confidence interval [ ci ] , 1.011.06 ; p=0.003 ; or , 1.006 ; 95% ci , 1.011.11 ; p=0.018 ; or , 0.65 ; 95% ci , 0.430.98 , p=0.04 ) , respectively were strongest predictors of gs upgrade among clinicopathological variables .
on subanalysis of the predictors of degree of upgrading on table 4 , we found out that only psa level of 1020 is significantly associated with the degree of upgrading to gs8 ( p=0.000 ) .
patients with upgraded gs 8 or more had lower rates of 5 years of bcr - free survival , css , and os ( p0.001 , p=0.003 , and p=0.01 , respectively ) ( figs . 1 , 2 , 3 ) .
in this study , we have shown that patients preoperative psa level of 1020 ng / ml have increased likelihood of upgrading from gs 6 into pathologic gs8 .
likewise , we report the predictors of upgrading like age , psa , psa density , and number of cores among patients who have solely gs 6 on needle biopsy .
knowledge on the impact of gs upgrading is of great importance especially at the point of shared decision - making between the physician and the patient prior to any planned intervention . in a study done by carlsson et al . , they concluded that having surgery as primary treatment for low risk pca might result in favorable oncologic outcome but may also jeopardize men 's potency and continent rate postoperatively .
this scenario may have an impact on patients ' overall quality of life and great importance is often placed during counseling . at this point , preoperative predictors of upgrading may help urologist in proper counseling of their patients .
previous reports have discussed that psa level is a significant predictor of upgrading . at some point the level of psa to which upgrading is most likely to occur have been discussed by colleselli et al . .
they reported that patients with psa range of 2.03.9 and 4.010.0 ng / ml had a 32.6% and 44% risk of upgrading , respectively . among the previously mentioned studies ,
no one has investigated on the predictor of the degree of upgrading among their cohorts . to our knowledge
, our study is the first to discuss the predictor of the degree of upgrading on exclusively gs 6 patients on needle biopsy .
hwang et al . , reported that not only psa but percent positive biopsy core were predictors of upgrading .
similarly , colleselli et al . found out that tumors are likely to get upgraded when the number of biopsy cores was high even if their psa is low .
greater than one core positive for cancer on needle biopsy is associated with increased chances of upgrading . in the current study
, we found out that patients with more than or equal to 2 cores involved had higher chances of upgrading .
this might be explained by the fact that presence of multiple cores increases the likelihood of lymph node invasion and less organ - confined disease ( pt3 ) .
thus , even on patients with gs 6 on biopsy risk of upgrading is increased whenever multiple cores are present . in a cohort of 2,771 men ,
the group of serkin et al . reported that patients with higher psa density were likely to upgrade . and
in support to their findings , psa density was also a significant predictor of overall upgrading among our patients .
however , when psa density was entered on the model for predicting degree of upgrading it has lost its significance . this might be due to the small number of patients who upgraded to 8 .
meanwhile , prostate volume has long been a point of debate ; several reports have stated that prostate volume is a significant predictor of upgrading among patients who underwent radical prostatectomy .
there seems to be an inverse relationship between prostate size and chances of upgrading which was also evident in our current study . on the other hand
this may be explained by the fact that as man ages psa level tends to increase stepwise .
this was also evident in the cohort of 25,858 patients reported by caster et al . , that older age was associated with gs upgrading and pathologically advanced disease .
corcoran et al . reported that change in gs on prostatectomy was a predictor of bcr .
moreover , boorjian et al . also found out that upgrading in gs was associated with bcr and progression to systemic disease , though their study included all gs .
likewise , our findings suggest that bcr was notably higher among patients who upgraded into higher gs in support of the aforementioned studies .
reported in their series of 2,766 patients a bcr of 7.3% however its median follow - up was only 22 months . on the other hand ,
menon et al . , did a study with a median follow - up of 60.2 months however , their study included all gs .
in our current study , we reported the oncologic outcome of our cohort at a median follow - up of 59 months for specifically gs 6 patients alone after rarp .
this reflects a more realistic oncologic behaviour of patients who were initially gs 6 on biopsy but subsequently changed on pathologic specimen .
upgraded group of patients have had significant differences in psm , extraprostatic extension , seminal vesicle invasion , and lymphovascular invasion .
accordingly , the rate of extraprostatic extension , and psm were noted to be higher among patients who have gs upgrading during radical prostatectomy . in concordance
, our results also showed that upgraded group had higher psm , perineural invasion and angiolymphatic invasion compared to nonupgrade group depicting probably a more aggressive disease .
small number of patients which represents a higher degree of upgrading from gs 6 is one of its main limitation .
comparative analysis of patients with originally gs 8 from biopsy and those who upgraded from gs 6 to 8 is likewise recommended .
a longer follow - up maybe needed to portray satisfactory oncologic impact of upgrading to clinical course and disease progression of patients with initially gs 6 treated with radical prostatectomy . despite these limitations , our study showed that patients with higher preoperative psa level has increased risk of upgrading to higher degree of gs which should be discussed thoroughly before offering any treatment options to patients .
patients with gs 6 on biopsy with psa level of 1020 ng / ml carries an increased risk of upgrading into higher pathologic gs ( 8 ) with poorer oncologic outcome .
we recommend strict counseling especially in choosing treatment options between surgical and nonsurgical for patients with gs 6 on biopsy whenever these parameters are present .
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### Summary:
: purposethis study aimed to identify the predictors of upgrading and degree of upgrading among patients who have initial gleason score ( gs ) 6 treated with robot - assisted radical prostatectomy ( rarp).materials and methodsa retrospective review of the data of 359 men with an initial biopsy gs 6 , localized prostate cancer who underwent rarp between july 2005 to june 2010 was performed .
they were grouped into group 1 ( nonupgrade ) and group 2 ( upgraded ) based on their prostatectomy specimen gs .
logistic regression analysis of studied cases identified significant predictors of upgrading and the degree of upgrading after rarp.resultsthe mean age and prostate - specific antigen ( psa ) was 637.5 years , 8.98.77 ng / ml , respectively .
median follow - up was 59 months ( interquartile range , 4770 months ) . on multivariable analysis , age , psa , psa density and 2 cores positive were predictors of upgrading with ( odds ratio [ or ] , 1.03 ; 95% confidence interval [ ci ] , 1.011.06 ; p=0.003 ; or , 1.006 ; 95% ci , 1.011.11 ; p=0.018 ; or , 0.65 ; 95% ci , 0.430.98 , p=0.04 ) , respectively .
on subanalysis , only psa level of 1020 ng / ml is associated with upgrading into gs 8 .
they also had lower biochemical recurrence free survival , cancer specific survival , and overall survival ( p0.001 , p=0.003 , and p=0.01 , respectively).conclusionsgleason score 6 patients with psa ( 1020 ng / ml ) have an increased risk of upgrading to pathologic gs ( 8 ) , subsequently poorer oncological outcome thus require a stricter follow - up .
these patients should be carefully counseled in making an optimal treatment decision .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: given iran transition from a traditional society to a society of industry and modernism , family issues and communication problems are the most important problems of the families in the realm of mental health ( 1 ) .
plenty of reference to family therapy centers and crisis intervention and increasing special help - seeking behavior show the existence of a serious problem in families mental health ( 2 ) .
divorce is the result of the most acute and serious communication problems of the family .
unfortunately , in terms of divorce and marriage ratio , iran is among the first seven countries in the world ( 3 ) .
sexual pleasure makes couples ignore many of daily life problems and marital disputes and increases emotional dependency between them ( 5 ) .
people who have a high level of satisfaction with their sex partner report a considerably better quality of life compared to those who are not satisfied ( 6 ) . ignoring the problem without solving it ,
some of the destructive effects of marital conflicts can be named as physical consequences and increased risk of different types of mental disorders such as depression , drug addiction , sexual dysfunction and behavioral problems ( 7 ) .
numerous studies show that the most common cause of marital conflict is the result of inappropriate sexual relationship ; if for any reasons , there is no healthy sexual relationship between couple , one of the partners will be unhappy , disappointed and bored and it will cause conflicts and communication problems between them ( 8) . hulbert and farley stated that dissatisfaction of sexual performance is closely related to divorce and social problems such as crimes , sexual assaults and mental illnesses . in this
regard , bentovim , in a quotation from johnson and masters , believed that the cause of 50% of marriage failures is sexual dissatisfaction ( 7 ) .
one of the cognitive models recently raised to explain family problems , which has gained a lot of attention due to its theoretical basis and strong experimental background , is cognitive model ( 9 ) . according to this model ,
irrational beliefs and cognitive distortions are the important factors in creation and continuation of pathological behaviors ( 10 ) .
recently , the research literature in this area is more specific and is focused on inefficient beliefs in relationships .
an example for that are thoughts and beliefs about interpersonal relationships with spouse , relationships between parents and children s relationships ( 11 ) .
firish , in a research program to explain a structural model of cognitive factors , sexual satisfaction and quality of life , showed that both for males and females , cognitive factors and attitudes , a causal relationship and subsequently sexual satisfaction , marital relationship quality and stability of marriage are involved ( 3 ) .
people s reaction to situations is influenced by their cognitive assessment and interpretation of situations ; this is derived from a theory that gained attention in the last two decades and is based on individuals explanation style for stress - inducing events that can have an important role in mental health and can be named as attribution theory ( 9 ) .
the purpose of attribution theory is to examine how people give causal explanations , how people respond to questions that begin with why , explaining the processes of events and emotional and behavioral consequences arising from these explanations ( 9 ) .
individuals continuously choose specific causes for good and bad events that are sometimes incompatible attributions .
in other words , attributing negative events to internal causes , and attributing general , stable and positive events to external causes without stability and specificity ; these are called incompatible attribution styles and theses incompatible ; in other words , pessimistic attributions are associated with psychological and physical problems ( 9 ) .
the current study aimed to determine the the relationship between cognitive distortions and attribution styles among divorce applicant couples and its impact on sexual satisfaction .
statistical population of the study was divorce applicant couples ( 281 people referred to courts in the first four months of 2014 ) referred to family courts or divorce reduction centers ( green opportunities ) of urmia welfare organization , urmia , iran .
accordingly , 55 couples were selected by convenience sampling method . the total sample involved 110 people , 55 females and 55 males .
it should be mentioned that others who referred to divorce reduction centers individually ( husband or wife ) were excluded from the study and the statistical sample involved 55 couples referred to the same center .
the questionnaires were filled by the couples who applied for divorce and then , they were collected by one of the authors in the court .
anonymous questionnaire was prepared to ensure that the results obtained by the participants in the study would not hurt anyone .
measuring instruments were as follows : 1 ) interpersonal cognitive distortions scale : the scale is designed by hommamci ( 2004 ) to assess cognitive distortions in interpersonal relationships based on aaron t. beck s cognitive theory .
its reliability was checked through internal consistency by cronbach s alpha and test - retest after two weeks .
the results showed that the obtained cronbach s alpha coefficient for the whole scale was 0.67 , in test - retest 0.74 and for its subscales 0.72 , 0.76 and 0.74 , respectively ( 3 ) .
the correlation of its scores with the scales of irrational beliefs , spontaneous thoughts and conflicts in interpersonal relationships were 0.45 , 0.53 and 0.53 , respectively with a significance of 0.99 .
- questions of rejection in interpersonal relationships subscale : 1 - 3 - 10 - 12 - 13 - 14 - 15 - 19 - questions of unrealistic expectations in relationships subscale : 5 - 7 - 8 - 9 - 11 - 16 - 17 - 18 - questions of interpersonal relationships misperception subscale : 2 - 4 - 6 according to this scale , respondents are placed in four groups based on the use of their cognitive distortions : no use , little use , relative use and full use . according to the selected choice , a score between one and five
is given to each question and at the end , given the total obtained score ( the sum of all scores ) they are classified into four groups ; therefore scores below 19 indicate no cognitive distortions use ; from 19 to 38 low cognitive distortions use ; from 38 to 57 relative cognitive distortions use and above 76 full cognitive distortions use ( 3 ) .
2 ) larson sexual satisfaction scale : larson sexual satisfaction scale questionnaire has 25 questions with these choices : never , rarely , sometimes and always ( 7 ) . according to this scale , respondents are divided into four groups of full satisfaction , relative satisfaction , low satisfaction and dissatisfaction . given the selected choice in each question ,
each question is given a score from one to five , and at the end , based on their total score ( the sum of all score ) they are placed in four groups .
scores below 25 indicate no satisfaction ; from 25 to 50 low satisfaction ; from 50 to 100 relative satisfaction and above 100 full satisfaction . in iran
used this questionnaire in their studies in 2010 and 2011 and to determine the reliability of the instruments test - retest method was used and the obtained results in 2010 and 2011 were 0.86 and 0.86 , respectively ( 7 ) .
3 ) attribution style questionnaire : this questionnaire is a self - report instrument and was first used to measure individuals attributions for uncontrollable events .
attribution style questionnaire includes twelve hypothetical situations ( six good events and six bad events ) . for each event ,
the first question is about the most significant reason for the event , and although it is not used in scoring , the subject is required to respond to its following three questions .
these questions include internal or external , stable or unstable and general or specific events .
scores can be given to each of the three mentioned aspects ; for example , the internal - external aspect is obtained from the total score of the first question . if someone is in the position of total success and in the first question he checks items 6 , 4 , 2 , 3 , 5 , 4 , this person s internal - external score will be the sum of these numbers divided by six .
for attribution style questionnaire s reliability , cronbach s alpha coefficient was 0.8 ( 12 ) .
cronbach s alpha coefficients were 0.75 , 0.43 , 0.73 , 0.74 , 0.56 and 0.76 for internal failure , stable failure , total failure , internal success , stable success and total success , respectively .
the range of 36 questions is from 36 to 144 . if the subjects total score is below 144 , they are introvert and as their scores get closer to 36 , they are more introverted . if the score is above 144 , the subject is extrovert and if it is closer to 252 , he is more extroverted .
the questionnaire of attribution style consists of twelve hypothetical situations with six good events and six bad events .
the first question is about the most important cause of the event , although it is not used in scoring , it is necessary for subjects to respond to the following three questions based on these aspects : internal or external , stable ( steady ) or unstable and general or specific events .
scores can be considered for each of these three dimensions , for example , internal - external dimension is obtained from total score of the first question .
if a person marks items 4 - 5 - 3 - 2 - 4 - 6 for success situation and the first question , the score of this person for the internal - external dimension is the sum of the numbers divided by six 24.6 = 4 ; therefore , the score is calculated in the same way for other dimensions such as failure situation ( 13 ) .
pearson correlation coefficient and t - independent groups were provided , and spss version 20 ( spss inc . , chicago , il , usa ) was used to analyze the data .
the investigated samples of the study are presented separately in table 1 based on gender and educational level .
the educational degree of 62.7% of the subjects ( 43 cases ) , males and females who were divorce applicants was below high school diploma and that of 47.3% ( 36 cases ) had high school diploma .
the investigated sample based on age at the time of divorce . in the study 42.6% of divorce applicant couples ( 47 people ) , were in the age range of 26 - 35 ( table 2 ) .
( % ) . to determine the relationship between cognitive distortions and attribution style of the divorce applicant couples , pearson correlation coefficient was used . according to table 3 ,
the correlation coefficients between the internal - external pleasant variables with interpersonal rejection was -0.25 , and it was -0.19 between external - internal pleasant and interpersonal cognitive distortions ( total ) , which was significant ( p < 0.05 ) ; it means that , with 95% confidence interval , there was a negative significant relationship between these variables .
the results of table 3 showed that , the correlation coefficients of all other variables were not significant , which means that there was no significant relationship between these variables ( p > 0.05 ) . to determine the relationship between cognitive distortions and sexual satisfaction in divorce applicant couples , pearson correlation was used .
the results of table 4 shows that the correlation coefficient between the variables of interpersonal relationships rejection was 0.004 , for unrealistic expectations was 0.07 , for interpersonal misperception was 0.005 and for interpersonal cognitive distortions ( total ) was 0.04 ; for sexual satisfaction it was insignificant ( p > 0.05 ) .
pearson correlation coefficient was used to determine the relationship between attribution styles and sexual satisfaction among divorce applicant couples .
the results of table 5 showed that the correlation coefficients between pleasant unstable - stable variables ( 0.22 ) , pleasant events ( 0.19 ) and attribution style ( total ) ( 0.19 ) , and sexual satisfaction variable were significant , which means with 95% confidence interval , there was a significant relationship between these variables and sexual satisfaction ( p < 0.05 ) .
the results in table 5 also showed that , the correlation coefficient between pleasant internal - external variables ( 0.16 ) , pleasant specific - general ( 0.13 ) , unpleasant internal - external ( 0.13 ) , unpleasant unstable - stable ( 0.14 ) , unpleasant specific - general ( 0.12 ) , unpleasant events ( 0.14 ) and sexual satisfaction variable were not significant , which means that there is no significant relationship between these variables and sexual satisfaction(p > 0.05 ) .
the investigated samples of the study are presented separately in table 1 based on gender and educational level .
the educational degree of 62.7% of the subjects ( 43 cases ) , males and females who were divorce applicants was below high school diploma and that of 47.3% ( 36 cases ) had high school diploma .
the investigated sample based on age at the time of divorce . in the study 42.6% of divorce applicant couples ( 47 people ) , were in the age range of 26 - 35 ( table 2 ) .
to determine the relationship between cognitive distortions and attribution style of the divorce applicant couples , pearson correlation coefficient was used . according to table 3 ,
the correlation coefficients between the internal - external pleasant variables with interpersonal rejection was -0.25 , and it was -0.19 between external - internal pleasant and interpersonal cognitive distortions ( total ) , which was significant ( p < 0.05 ) ; it means that , with 95% confidence interval , there was a negative significant relationship between these variables .
the results of table 3 showed that , the correlation coefficients of all other variables were not significant , which means that there was no significant relationship between these variables ( p > 0.05 ) . to determine the relationship between cognitive distortions and sexual satisfaction in divorce applicant couples , pearson correlation was used .
the results of table 4 shows that the correlation coefficient between the variables of interpersonal relationships rejection was 0.004 , for unrealistic expectations was 0.07 , for interpersonal misperception was 0.005 and for interpersonal cognitive distortions ( total ) was 0.04 ; for sexual satisfaction it was insignificant ( p > 0.05 ) .
pearson correlation coefficient was used to determine the relationship between attribution styles and sexual satisfaction among divorce applicant couples .
the results of table 5 showed that the correlation coefficients between pleasant unstable - stable variables ( 0.22 ) , pleasant events ( 0.19 ) and attribution style ( total ) ( 0.19 ) , and sexual satisfaction variable were significant , which means with 95% confidence interval , there was a significant relationship between these variables and sexual satisfaction ( p < 0.05 ) .
the results in table 5 also showed that , the correlation coefficient between pleasant internal - external variables ( 0.16 ) , pleasant specific - general ( 0.13 ) , unpleasant internal - external ( 0.13 ) , unpleasant unstable - stable ( 0.14 ) , unpleasant specific - general ( 0.12 ) , unpleasant events ( 0.14 ) and sexual satisfaction variable were not significant , which means that there is no significant relationship between these variables and sexual satisfaction(p > 0.05 ) .
the current study aimed to investigate the pathology of interpersonal conflicts among divorce applicant couples and its impact on sexual satisfaction .
the results confirmed the presence of some pathological factors such as unpleasant attribution style and cognitive distortions among couples .
the results of investigating the relationship between cognitive distortions and attribution style showed a negative significant relationship between pleasant internal - external variables and rejection in interpersonal relationships , and pleasant internal - external interpersonal relationships and interpersonal cognitive distortions .
it means that as pleasant internal - external variables increased , the extent of rejection in interpersonal relationships and interpersonal cognitive distortions ( general ) decreased and vice - versa .
the findings of the study were compatible with those of the study on the relationship between mental pathology of family relationships and cognitive vulnerability ( inefficient attitudes and interpersonal cognitive distortions ) ( 14 ) .
this study concluded that there was a significant relationship between interpersonal cognitive distortions , irrational beliefs in marital relationship and inefficient attitudes and marital conflicts .
marital conflicts were predictable based on the scores of cognitive distortions , irrational beliefs and inefficient attitudes in marital relationships .
showed that three positive characteristics ( hope , self - perception and suitable attribution styles ) can result in predicting emotional adaptation and better learning for a learner ( 15 ) , which were compatible with the results of the current study ; for example , if the applied attribution style among couples is pleasant internal - external , the extent of rejection in interpersonal relationships and interpersonal cognitive distortions ( total ) is reduced and vice - versa . the other finding of the current research revealed no significant relationship between interpersonal cognitive distortions and sexual satisfaction .
the results of the study were not compatible with those of abrahim , zeinedini and maracy ( 14 ) . in a research conducted on 60 people , referred to family therapy centers in isfahan , iran , to find the relationship between mental pathology of family relationships and cognitive vulnerability ( inefficient attitudes and interpersonal cognitive distortions )
, the conclusion was reached that there was a significant relationship between interpersonal cognitive distortions , irrational beliefs in marital relationships and inefficient attitudes and marital conflicts .
marital conflicts were predictable based on the scores of cognitive distortions , irrational beliefs in marital relationships and inefficient attitudes .
no research on the relationship between cognitive distortions and its relationship with sexual satisfaction was found to be compared with the result of the hypothesis .
the other finding of the current research indicated a significant relationship between some attribution styles and sexual satisfaction .
the results showed a significant relationship between pleasant unstable - stable variables , pleasant events and attribution styles ( general ) and sexual satisfaction .
as the pleasant stable - unstable variables increased , pleasant events , attribution styles , and sexual satisfaction increased and vice versa .
but there was no significant relationship between attribution style variables and those of sexual satisfaction .
the results of a study on 20 iranian couples , who referred to counseling centers in isfahan , iran , to find out the relationship between retraining attribution style and marital satisfaction showed that retraining attribution styles significantly increased sexual satisfaction ( 5 ) .
another study showed a bilateral interaction between using attribution styles , a habitual approach in evaluation and processing of life events as well as explanatory flexibility to find the cause of the events ( 16 ) . a study on attributions , cognitions and coping styles indicated that internal attributions were more associated with problematic coping styles ; negative attributions ( pessimistic ) were associated with emotion - centered coping styles and negative psychological results , which were compatible with the results of the current research ; in other words , if couples had optimistic explanatory style , their sexual satisfaction increased ( 16 ) .
as a conclusion , it is advised to follow the same procedure on people in different cities , age groups , educational backgrounds and different cultures
. limitations of this research can be regarded as the use of self - reporting questionnaires that make it almost impossible to overgeneralize the results to other communities .
it is advised that further studies investigate the relationship between interpersonal cognitive distortions , attribution styles and tendency to the divorce among couples .
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### Summary:
: backgroundthe current study aimed to investigate the relationship between cognitive distortions and attribution styles among divorce applicant couples and its impact on sexual satisfaction.materials and methodsit was a cross - sectional study and its statistical samples were 55 divorce applicant couples ( 110 individuals ) referred to urmia courts , urmia , iran , from 2012 to 2013 .
the required data were gathered by interpersonal cognitive distortions , larson sexual satisfaction and attribution style questionnaire.resultsthe findings of the research indicated the existence of a significant relationship between attribution styles for pleasant events and cognitive distortions .
the results showed that an increasing amount of pleasant events reduces cognitive distortions among the divorce applicant couples ( p < 0.05 , r = 0.19 ) . attribution style has a significant relationship with sexual satisfaction among the divorced couples .
as stable - unstable variables increase ( p < 0.05 , r = 0.22 ) , pleasant events , ( p < 0.05 , r = 0.19 ) , attribution styles ( total ) ( p < 0.05 , r = 0.19 ) and sexual satisfaction increases and vice versa . also , there was no significant relationship between sexual satisfaction and cognitive distortions ( p < 0.05 , r = 0.04).conclusionsnormal and abnormal cognitive components are among the main factors affecting satisfaction or dissatisfaction in couples who are living together ( sexual satisfaction is one of its main elements ) .
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: increasingly , magnetic resonance imaging ( mri ) of the lung is being advanced from a technological niche to the doorsteps of clinical routine imaging . the key technique for mri of lung morphology
is based on the resonant high - frequency signal of protons in tissues and liquids , so - called proton - mri or h - mri .
the recent technical advances have helped mri to challenge its well - known limitations as they are defined by the low proton density in the lung and the fast signal decay due to susceptibility artefacts at air - tissue interfaces . besides chest radiography , the most commonly employed first - line test for chest disorders , and computed tomography ( ct ) , so far the most comprehensive and detailed modality for cross - sectional and three - dimensional ( 3d ) imaging of the lung
, mri is becoming an alternative , third method for the assessment of pulmonary diseases .
once broadly available and sufficiently robust , it will likely become a modality of choice for cases in which exposure to ionising radiation should be strictly avoided .
this would comprise children , pregnant women and disorders requiring repeated examinations over prolonged periods , such as in patients with neutropenia , in which mri could contribute significantly to lowering the cumulative radiation dose .
however , mri offers additional advantages beyond the scope of x - ray - based techniques due to its functional imaging capacities .
more than any other modality , mri combines excellent soft tissue contrast and functional information .
it allows for multiple and repeated measurements and can be used to assess motion and perfusion of the thoracic organs .
these advantages are already well appreciated in mri of the heart , which combines morphological information ( wall thickness , edema , scarring of the myocardium ) with functional assessment ( wall motion , contractility , ejection fraction ) and viability / perfusion ( e.g. at rest and during stress ) .
advances in mri technology and a broad consensus on the basic imaging protocols have helped to establish a complex technology such as cardiac mri within a relatively short period of time . since imaging technology has brought similar advances to mri of the lung
, it is basically the lack of comprehensive and standardised imaging protocols that delay its introduction for broader clinical use .
every single sequence covers different aspects of lung pathology , e.g. liquid content of infiltrates or sharp delineation of solid nodules , etc .
sequence packages and customised protocols to combine strengths and diagnostic yields of the available sequences have been suggested ( for an example of detailed vendor - specific recommendations see : biederer j , hintze c , fabel m , jakob pm , horger w , graessner j , bolster bd , heller m ( 2011 ) mri of the lung ready
however , based on the platforms offered by different vendors , the protocols tend to be difficult to compare and make clinical introduction unnecessarily complicated . on the occasion of the first european school of radiology courses on lung mri and dedicated sessions at the european congress of radiology ( ecr ) 2010 and the european society of thoracic imaging ( esti ) meeting 2010 as well as the meeting of the chest imaging workshop ( ag thorax ) at the german roentgen society ( drg ) ,
it was suggested that a group of experts in the field should generate a consensus statement on the current state of the art , indications and applications and future developments of lung mri . after introducing the principles of the available technology in the first of this set of three articles [ mri of the lung ( 1/3 ) ] , it is the aim of the following lines to summarise the currently available protocols , comment on their clinical value based on the discussions within a panel of experts who are already practising lung mri and to make updated uniform protocol suggestions for general use at state - of the - art mri scanners .
a third manuscript will subsequently describe the current applications and future directions of lung mri [ mri of the lung ( 3/3 ) ] .
the prerequisites for the introduction of a new technique into the clinical setting are practicality of the application as well as robustness and reproducibility of image quality and diagnostic accuracy .
the practicality of an mri technique is further enhanced by a set of readily prepared protocols customised for specific clinical questions and available for standard scanners [ 1.5 tesla ( t ) ] .
preferably , additional features complicating the procedure such as the need for ecg - triggering or contrast material administration would be avoided .
furthermore , solutions for typical problems such as patients not being able to hold their breath or young children should be offered . in practice
, it has been useful to design a common basic protocol trunk to cover the majority of expected clinical problems .
this basic protocol will be extended for specific questions such as the staging of malignancy , evaluation of pulmonary vessels and perfusion , etc .
furthermore , if the use of mri is intended for emergency conditions , such as acute pulmonary embolism , fast and efficient procedures are required with in - room times that make it possible to squeeze the exam into a full mr schedule during the day .
given the high investment into state - of - the - art mri equipment and the running costs for maintenance and personnel , the key parameter for cost - effectiveness of the method is in - room time .
based on the currently available standards , in - room times of 15 min for the basic protocol or an emergency examination were considered desirable .
additional protocol extensions , e.g. contrast - enhanced series , to detect tumour necrosis and pleural reaction / carcinosis or dynamic contrast - enhanced mri and visualisation of respiratory motion contribute functional information should not exceed further 5 - 15 min in addition to the time needed for the basic protocol . to match this frame of expectancies as far as possible was the aim of the presented consensus on lung mri protocol suggestions .
tables 1 , 2 , 3 , 4 provide a systematic overview over indications for lung mri and imaging protocol set - ups as well as a list of abbreviations / glossary of terms in order to facilitate comparisons and cross - vendor correlation throughout the manuscript.table 1indications for lung mri ( in compliant patients)role of mrisituation / pathological conditioni.v .
contrastsituations that warrant the use of mrichildrenoptionalpregnant womenoptionalyoung patients with need for repeated imaging of the lungsoptionalto replace ct if contrast media are contra - indicatedoptionalscientific studiesoptionalpharmaceutical trialsoptionalin discussion : lung cancer screeningoptionalindications covered by mricomplicated thoracic mass ( mediastinum and chest wall invasion)optionalwith advantages over ctdifferentiation of atelectasis and pulmonary massoptionaldifferentiation of mediastinal massesoptionalevaluation of respiratory mechanicsnodiagnosis of pulmonary perfusion deficits ( embolism , hypoxic vasoconstriction)yescystic fibrosis ( with perfusion study)yesindications covered by mripneumonianoas effectively as with ctatelectasisno(if situation warrants use of mri)cystic fibrosis ( without perfusion study)notuberculosisnopulmonary nodules ( > 3 mm)nosarcoidosisoptionalacute and chronic pulmonary embolismyesabnormalities of pulmonary venous drainageyespulmonary arterial aneurysmyeslung sequestrationyesav malformation ( m. osler)yesstaging of lung canceryesvasculitis ( e.g. wegeners)yespleural effusion of unclear originyesmesotheliomayesindications covered less effectivelypulmonary miconodules ( < 3 mm)optionalthan with ctinterstitial lung diseaseoptionalemphysema / copd*optionalspecific topics covered with more detail in the third article of this seriestable 2sequences used for lung mrisequence typefeatures or variationsvendor specific acronymsrespiration manoeuvrespatial resolutiontemporalresolutionparticular use for lung mri ( pathology)protocol suggestionsiemensphilipsgehitachitoshiba(typical acquisition time)(typical pixel size)(s per slice or volume)3d gradient echo t1-weightedvolume interpolation ( ce with fat saturation)vibethrivelavatigrequick3dbreath hold ( 21 s)high ( 1.5 1.5 mm)lowpulmonary nodules , masses , airwaysg , t , vmax . spatial resolution for angiographyflash 3dffespgrrf spoiled sargefe , ffebreath - hold ( 21 s)high ( 1.2 1 mm)lowhigh resolution angiogram ( embolism avm)vecho sharingtwisttraktrickstraqdrksbreath - hold or shallow breathinglow ( 3.5 2 mm)high ( < 1.5 s / vol)first pass lung perfusion ( embolism , hypoxic vasoconstriction)v , ( t)fast spin echo t2-weightedhalf fourier acquisitionhastehalfscan fse nex fsehalf scan single shot fseafi romultiple breath - hold ( 2 20 s)low ( 1.8 1.8 mm)highinfiltratesg , trotating phase encodingblademultivanepropellerradarjetmultiple breath hold ( 4 - 5 20 s)moderate ( 1.8 1.5 mm)moderatenodules and massesg , trespir . triggered , high res.tse-rttsefsefsefserespiration triggered ( 5 - 10 min)moderate - high ( 1.3 1 mm)lowmasses(g ) , ( t)fat saturatedtse fs blade fstse fs or multivanefse fs or propellerfse fs or radarfse fs or jet fsmultiple breath - hold(4 - 5 20 s ) or respiration triggered ( 4 - 8 min)moderate ( 1.8 1.5 mm)moderatelymph nodes bone metastasesg , tshort tau inversion recoveryfast spin echostirstirstirstirstirdiffusion weighted imaging ( dwi)echo planar imaging or other fast techniquereveal ( dwi)dwibs ( dwi)whole body diffusion ( dwi)dwibody vision ( dwi)multiple breath - hold ( 3 - 4 20 s ) or respiration triggered ( 4 - 5 min)low ( 3 2 mm)lownodules and masseststeady state gret1/t2 contrasttruefispbffefiestabasgtruessfpfree breathing ( 60 s ) or instructed br .
manoeuvresmoderate ( 2.4 1.6 mm)high ( < 0.5 s / sl.)pulmonary embolismg , t , vrespiration mechanicstg general , t tumour , v vesseltable 3protocol selection for lung mrisequence combination dedicated to clinical problemspatients compliant , able to hold breath for 20 si.v .
contrastalternative approach in patients unable to hold breath for 20s , e.g. childrengeneral question ( 15 min)thoracic mass ( 20 min)pulmonary embolism , avm ( 15 min)mass w/ vessel invasion ( 25 min)sequence selectionslice orientationslice thicknessrespiration manoeuvrexxx3d gradient echo t1-w.transverse4 mm ( interpolated)breath - holdnonot available / to be developedxxxfast spin echo t2-w . , half fouriercoronal6 - 8 mmbreath - holdnotriggered or non triggered acquisition in free breathing ( 0 - 5 min increase in acquisition time)xxxxsteady state grecoronal4 - 6 mmfree breathingnono change neededxxxfast spin echo t2-w .
, rotating phase encodingcoronal ( non - fat sat.)4 - 6 mmbreath - holdnotriggered acquisition in free breathing ( 5 min increase in acquisition time)x(x)(x)fast spin echo t2-w .
rotating phase encodingtransverse ( fat sat . or ir)4 - 6 mmbreath - holdnotriggered acquisition in free breathing ( 5 min increase in acquisition time)x(x)diffusion weighted imagingmulti breath - holdnotriggered acquisition in free breathing ( 5 min .
dynamic angiocoronal5 mmbreath - holdyesacquisition in shallow free breathing possible ( no increase in acquisition time)xx3d gradient echo t1-w .
angiocoronal1.5 - 3 mmbreath - holdyesnot available / to be developedxxx3d gradient echo t1-w .
fat saturatedtransverse4 mm ( interpolated)breath - holdyesnot available / to be developedx3d gradient echo t1-w .
fat saturatedcoronal4 mm ( interpolated)breath - holdyesnot available / to be developedtable 4list of abbreviations /
acronyms as used in the text and in tables 2 and 3 nexhalf fourier acquisition ( ge)2dtwo - dimensional ( single image in one plane)2d + ttemporally resolved ( dynamic ) imaging in a single plane ( used to differentiate from 3d for spatially resolved acqisitions)3dthree - dimensional ( spatial resolution)3d + ttemporally resolved ( dynamic ) imaging in multiple volumes4dfour - dimensional ( with spatial and temporal resolution , a term often used as synonym to 3d
+ t)afi roadvanced fourier imaging in read out ( partial / half fourier acquisition sequence ; toshiba)aslarterial spin labelingbasgbalanced spoiled steady state acquisition rewinded gradient ( gradient echo sequence with steady state acquisition ; hitachi)bffebalanced fast field echo ( gradient echo sequence with steady state acquisition ; philips)bladebrand name / not an acronym ( rotating phase encoding sequence ; siemens)body visionbrand name / not an acronym ( diffusion weighted imaging sequence ; toshiba)cecontrast enhancedctcomputed tomographydce mridynamic contrast enhanced mri ( can be 2d + t or 3d + t)drksdifferent rate k - space sampling ( temporally resolved 3d gradient echo sequence with temporal resolution ( 3d + t ) achieved by echo sharing ; toshiba)dwidiffusion - weighted imagingdwibsdiffusion - weighted whole body imaging with body bbackground signal suppression ( diffusion - weighted imaging sequence ; philips)fefield echo ( gradient echo sequence syn . to flash ; toshiba , philips)ffefast field echo ( gradient echo sequence syn . to flash ; toshiba , philips)fiestafast imaging employing steady state acquisition ( gradient echo sequence with steady state acquisition ; ge)flashfast low angle shot ( the basic technique for ge sequences ; siemens)fsefast spin echo ( sequence ; ge , hitachi , toshiba)gegradient echo ( gradient echo sequence)gregradient recalled echo ( gradient echo sequence)half scanhalf fourier acquisition technique ( philips , hitachi)hastehalf fourier short turbo spin echo ( sequence ; siemens)jetbrand name / not an acronym ( rotating phase encoding sequence ; toshiba)lavaliver acquisition with volume acceleration ( a 3d gradient echo sequence with volume interpolation and rf fat saturation ; ge)mramagnetic resonance angiographymrimagnetic resonance imaging ( mr imaging)multivanebrand name / not an acronym ( rotating phase encoding sequence ; philips)propellerperiodically rotated overlapping parallel lines with enhanced reconstruction ( rotating phase encoding sequence ; ge)quick3d3d gradient echo with volume interpolation ( sequence ; toshiba)radarradial acquisition regime ( rotating phase encoding sequence ; hitachi)revealbrand name / not an acronym ( diffusion weighted imaging sequence ; siemens)rfradio frequencysargespoiled steady state acquisition rewinded gradient echo ( sequence syn . to flash ; hitachi)sf6sulphur hexafluoridespgrspoiled gradient echo recalled ( sequence syn . to flash ; ge)ssfpsteady state free precession ( gradient echo sequence with steady state acquisition)stirshort tau inversion recovery ( sequence)ttesla ( unit for field strength)t1 , t2time constants for signal decay in mrit1-w./t2-w.sequences producing images with t1- or t2-weighted contrastthrivet1 high resolution isotropic volume excitation ( a 3d gradient echo sequence with volume interpolation and rf fat saturation ; philips)tigrebrand name / not an acronym ( a 3d gradient echo sequence with volume interpolation and rf fat saturation ; hitachi)traktime - resolved angiography using keyhole ( a temporally resolved 3d gradient echo sequence with temporal resolution ( 3d + t ) achieved by echo sharing ; philips)trickstime - resolved imaging of contrast kinetics ( a temporally resolved 3d gradient echo sequence with temporal resolution ( 3d + t ) achieved by echo sharing ; ge)truefisptrue fast imaging with steady state precession ( gradient echo sequence with steady state acquisition ; siemens)truessfptrue steady state free precession ( gradient echo sequence with steady state acquisition ; toshiba)tseturbo spin echo ( fast spin echo sequence ; siemens , philips)twisttime - resolved angiography with stochastic trajectories ( temporally resolved 3d gradient echo sequence with temporal resolution ( 3d + t ) achieved by echo sharing ; siemens)vibevolumetric interpolated breath hold examination ( a 3d gradient echo sequence with volume interpolation and rf fat saturation ; siemens ) indications for lung mri ( in compliant patients ) specific topics covered with more detail in the third article of this series sequences used for lung mri g general , t tumour , v vessel protocol selection for lung mri list of abbreviations / acronyms as used in the text and in tables 2 and 3
pathological conditions in the lung related to changes of lung structure result either in an increase of lung density ( collapse of lung with atelectasis , fluid accumulation inside the alveolar space and/or the lung interstitium , fluid and cell accumulation in infiltrates or growth of soft tissue resulting in nodules and masses ) or decrease of lung density ( over - inflation due to air - trapping , enlargement of air spaces in emphysema ) [ 610 ] . given the well - known limitations of mri in visualising low - proton - density structures with high susceptibility artefacts at tissue - air interfaces , any pathology resulting in an increase of lung density ( and consequently proton density )
should be easy to detect , while a decrease of lung density will remain more challenging to visualise with mri . however , most conditions resulting in destruction and over - inflation of lung parenchyma , such as in emphysema , are associated with characteristic changes in the remaining lung parenchyma ( fibrosis , septae , parenchymal distortion , bronchial wall thickening , etc . ) .
hence morphological mri can still provide a correct diagnosis based on widened spaces of missing signal due to over - inflation and associated findings with increased signal intensity .
a direct visualisation of the airspace remains the domain of sophisticated imaging technology in specialised centres ( see airways and lung ventilation disorders ) .
furthermore , changes in lung perfusion ( hypoxic vasoconstriction , pulmonary embolism , congestion due to heart failure ) result in changes of lung signal on mri .
non - enhanced mri can directly visualise the vessel tree to detect macro - vascular pathology . quite a lot of experience exists for detection of pathological conditions that result in an increase of lung proton density .
experimental work has shown the high sensitivity of mri with t2-weighted and proton - density weighted sequences for fluid accumulation inside the lung [ 1214 ] .
one can conclude that the sensitivity of mri for pulmonary infiltrates is at least as good as with chest radiography and ct [ 2 , 12 , 1517 ] .
the majority of the applied protocols are based on t2-weighted or proton - density - weighted fast spin echo sequences , either with respiration gating or triggering or in breath - hold acquisition modes ( fig .
the plain chest x - ray ( a ) demonstrates a dense infiltrate in the left lower lung lobe which is confirmed on non - contrast - enhanced low dose ct ( b ; arrows ) . the patient volunteered to undergo mri on the same day .
multi - breath - hold coronal t2-weighted fast spin echo ( c ) and single breath - hold t1-weighted 3d gre imaging ( d ) as well as free breathing coronal steady state ssfp ( e ) and multi - breath - hold fat - saturated t2-weighted fast spin echo series ( f ) clearly demonstrate the infiltrates with particularly high signal on t2-weighted images a 66-year - old male patient with fever and coughing , clinically suspected pneumonia .
the plain chest x - ray ( a ) demonstrates a dense infiltrate in the left lower lung lobe which is confirmed on non - contrast - enhanced low dose ct ( b ; arrows ) .
multi - breath - hold coronal t2-weighted fast spin echo ( c ) and single breath - hold t1-weighted 3d gre imaging ( d ) as well as free breathing coronal steady state ssfp ( e ) and multi - breath - hold fat - saturated t2-weighted fast spin echo series ( f ) clearly demonstrate the infiltrates with particularly high signal on t2-weighted images another key clinical demand is the detection of small solid or soft tissue lesions ( nodules ) .
the sensitivity of mri for lung nodules larger than 4 mm ranges between 80 and 90% and reaches 100% for lesions larger than 8 mm .
depending on the sequence technique and the signal intensity of the lesions and given that conditions are optimal ( i.e. patient can keep a breath - hold for 20 s or perfect gating / triggering ) , a threshold size of 3 - 4 mm can be assumed for lung nodule detection with mri [ 19 , 20 ] . in comparison with ct , it might be even faster and more efficient to read lung mri for pulmonary nodules , since they appear with bright signal against the dark background of the healthy lung tissue ( fig . 2 ) .
calcified nodules tend to disappear in the background , as they have no inherent signal , whereas contrast - filled vascular lesions will be highly visible on t1-weighted images .
so far , a variety of sequence types has been evaluated for lung nodule detection with mri .
the spectrum comprises t2-weighted fast spin echo imaging with and without fat saturation [ 2326 ] , inversion recovery techniques , t1-spin echo [ 26 , 28 ] and gradient echo sequences [ 29 , 30].fig .
2a 64-year - old woman with the incidental finding of an unspecific , 4-mm nodule in the right middle lobe .
the nodule ( open arrow ) is clearly depicted on the coronal multi - breath - hold t2-weighted ( a ) and transverse contrast - enhanced , fat - saturated 3d gre images ( b ) a 64-year - old woman with the incidental finding of an unspecific , 4-mm nodule in the right middle lobe .
the nodule ( open arrow ) is clearly depicted on the coronal multi - breath - hold t2-weighted ( a ) and transverse contrast - enhanced , fat - saturated 3d gre images ( b ) the implications for protocol design are to include at least one t2-weighted or proton - density - weighted or short tau inversion recovery ( stir ) sequence to cover infiltrates and nodular lesions with high fluid content .
this should be combined with a second sequence to cover nodules with high signal on t1-weighted images as well .
in particular , for the detection of malignant lesions with hyperperfusion and intense enhancement , the i.v .
not yet clarified is the role of diffusion - weighted imaging ( dwi ) of lung lesions .
dwi is recommended for the whole - body staging of lung cancer , including mediastinal metastases [ 31 , 32 ] ; however , in the chest a clear advantage of dwi over other mri protocols has not been confirmed so far [ 33 , 34 ] .
stir sequences might be even more sensitive for the detection and classification of lung cancer and mediastinal metastases than dwi [ 3537 ] .
one potential role of dwi might be to predict tumour invasiveness for clinical stage ia non - small - cell lung cancer and to separate the mass from atelectasis [ 38 , 39 ] .
the role of dwi sequences for the differentiation of malignant or benign lung lesions or for the discrimination of subtypes of lung cancer remains controversial [ 37 , 4042 ] . in the authors own experience
thus , it makes sense to include a fast dwi acquisition in the protocol recommendations for mri of the lung [ 43 , 44].fig .
3diffusion - weighted imaging highlighting pleural metastases of hepatocellular carcinoma at the right diaphragm ( left , open arrow ) .
the same spots are only hardly visible on the post - contrast fat - saturated breath - hold t1-weighted 3d gre sequence ( right ) .
diffusion - weighted imaging highlighting pleural metastases of hepatocellular carcinoma at the right diaphragm ( left , open arrow ) .
the same spots are only hardly visible on the post - contrast fat - saturated breath - hold t1-weighted 3d gre sequence ( right ) . thus far ,
approaches for disorders of pulmonary perfusion have been aimed at either the visualisation of the pulmonary arterial tree ( mr angiography ) or at the assessment of lung parenchyma signal changes associated with perfusion on contrast - enhanced or non - contrast - enhanced scans . mr angiography and mr perfusion have mainly been applied for the study of acute pulmonary embolism , a key clinical entity to demonstrate diagnostic accuracy .
many approaches include direct visualisation of the thrombus inside the pulmonary artery either with positive or negative contrast against the signal of the flowing blood .
presently , fast steady state free precession gradient echo sequences ( ssfp - gre ) appear to be one of the most effective techniques .
they display the lung vessels with bright signal , against which thrombotic material is contrasted with low signal intensity . a sensitivity of 90% and a specificity of 97%
another approach has used double inversion recovery , demonstrating stagnant blood clot as bright signal , but insufficient data exist as to the diagnostic accuracy at this time [ 48 , 49 ] .
the presently most powerful technique , however , appears to be high spatial resolution mr angiography with t1-weighted contrast - enhanced 3d gradient echo acquisitions with k - space centred contrast bolus in a breath - hold . for optimum contrast , it is recommended to use a power injector and selected injection protocols .
several studies have shown very encouraging results for mr angiography ( mra ) in the workup of patients with suspected pulmonary embolism [ 5255 ] .
most recently , the pioped iii study involving seven centres and 371 patients with suspected pulmonary embolism demonstrated sufficient image quality in only 75% of the patients . sensitivity and
the most frequent reason for insufficient image quality was dyspnoea , coughing or insufficient timing of contrast material injection . to overcome the problem of bolus timing , other approaches favoured time - resolved mra with multiple acquisitions of lung volumes using very fast 3d gradient echo techniques .
extremely short acquisition times of 1.5 s or less were achieved by combining parallel imaging and data sharing . with a so - called 4d mra or dynamic first - pass perfusion mri
[ also known as dynamic contrast enhanced ( dce)-mri ] , ersoy et al .
the development of dynamic first pass perfusion mri has opened further perspectives in studying lung parenchyma perfusion in other disease conditions than pulmonary embolism as well .
limited to one plane , the temporally resolved so - called two - dimensional dynamic ( 2d + t ) perfusion mri reaches excellent temporal resolution of up to 10 images / s with reasonable spatial resolution .
however , volume coverage needs multiple series and contrast injections , which are usually not feasible .
other techniques such as arterial spin labeling ( asl ) based on intrinsic contrast of magnetised , inflowing blood into the imaging plane or volume have been investigated and applied for scientific studies , but have not yet found their way into clinical applications [ 60 , 61 ] .
the visual evaluation of 4d mri image sets is facilitated by subtraction of the non - enhanced from the contrast - enhanced image signal , which results in a bright display of the contrast - enhanced lung vessels and parenchyma .
the clinical value of lung perfusion studies with visual and semi - quantitative evaluation is being tested in the assessment of lung perfusion deficits in cystic fibrosis patients who suffer from mucus retention and hypoxic vasoconstriction ( fig .
4 ) [ 6264 ] . the perfusion series allows indirect visualisation of lung parenchyma abnormalities due to emphysema or conditions such as pneumothorax due to the absence of perfused lung tissue.fig .
4an 18-year - old male cystic fibrosis patient , coronal t2-weighted half fourier fast spin echo sequence ( a ) and coronal subtraction perfusion image ( b ) .
the subtraction perfusion image shows correspoding areas with perfusion loss due to hypoxic vasoconstriction . due to redistribution of perfusion
both lower lobes show a high perfusion signal an 18-year - old male cystic fibrosis patient , coronal t2-weighted half fourier fast spin echo sequence ( a ) and coronal subtraction perfusion image ( b ) .
the subtraction perfusion image shows correspoding areas with perfusion loss due to hypoxic vasoconstriction . due to redistribution of perfusion
both lower lobes show a high perfusion signal direct visualisation of the airways with mri is limited to airways in excess of 3 mm diameter , unless filled with bright materials such as retained mucus in cystic fibrosis patients [ 65 , 66 ] ( fig . 5 ) .
in young healthy subjects , lung mri depicted airways down to the first subsegmental level ; however , in parts of the lung subject to cardiac pulsation , detection rates were significantly lower . as expected from the higher spatial resolution , high resolution ct is still superior to mri in the depiction of small peripheral airways.fig .
coronal t2-weighted , respiration triggered and transverse breath - hold t1-weighted 3d gre images show peripheral airways with enhanced signal due to mucus plugging .
sign similar to the typical appearance on ct ( dashed circles ) lung mri of a 37-year - old male patient with cystic fibrosis .
coronal t2-weighted , respiration triggered and transverse breath - hold t1-weighted 3d gre images show peripheral airways with enhanced signal due to mucus plugging .
sign similar to the typical appearance on ct ( dashed circles ) however , mri is capable of studying dynamic processes , e.g. to analyse respiratory motion of the lung , diaphragm and relationships of tumours to chest wall boundaries .
the technical advances described above for 2d + t mri or 3d + t mri with different variants of t1-weighted gradient echo or steady state free precession sequences have been applied for this purpose [ 68 , 69 ] .
one of the most important clinical applications will be radiotherapy planning for organs with respiration - correlated motion [ 70 , 71 ] .
since air has no signal on mri , ventilation can only be visualised directly with hyperpolarised noble gases , sulphur hexafluoride ( sf6 ) or tracked indirectly by signal changes after inhalation of 100% oxygen or inhalation of aerosol of a paramagnetic contrast agent . despite the fascinating scientific publications obtained with these approaches , most of them are still remote from clinical application .
presently , the use of dynamic image acquisitions in single 2d planes ( 2d + t ) to study respiratory motion appears to be closest to routine use .
apart from the conditions mentioned above , the spectrum of findings to be covered comprises a wide range of disorders , ranging from pleural pathology ( effusion , empyema , tumour with chest wall infiltration , pneumothorax ) to mediastinal involvement ( masses , lymphnodes , vascular pathologies ) and the assessment of the adjacent upper abdomen ( e.g. adrenal and liver metastases in lung cancer ) .
it would be beyond the scope of this article to discuss the role of mri in all of these conditions , since this is well covered by standard textbooks .
nevertheless , any suggested standard protocol for lung diseases should offer sufficient coverage of the surrounding structures , which may then be further examined with dedicated protocols . a wide field , for instance ,
is the interaction between the heart and the lung . to keep within the frame of this article
, the possible useful combinations of lung mri protocol components with heart mri protocols will not be discussed explicitly
. however , their clinical value is obvious and building flexibility into the protocol trees is suggested , which would allow the user to combine protocols as required .
quite a lot of experience exists for detection of pathological conditions that result in an increase of lung proton density .
experimental work has shown the high sensitivity of mri with t2-weighted and proton - density weighted sequences for fluid accumulation inside the lung [ 1214 ] .
one can conclude that the sensitivity of mri for pulmonary infiltrates is at least as good as with chest radiography and ct [ 2 , 12 , 1517 ] .
the majority of the applied protocols are based on t2-weighted or proton - density - weighted fast spin echo sequences , either with respiration gating or triggering or in breath - hold acquisition modes ( fig .
the plain chest x - ray ( a ) demonstrates a dense infiltrate in the left lower lung lobe which is confirmed on non - contrast - enhanced low dose ct ( b ; arrows ) .
multi - breath - hold coronal t2-weighted fast spin echo ( c ) and single breath - hold t1-weighted 3d gre imaging ( d ) as well as free breathing coronal steady state ssfp ( e ) and multi - breath - hold fat - saturated t2-weighted fast spin echo series ( f ) clearly demonstrate the infiltrates with particularly high signal on t2-weighted images a 66-year - old male patient with fever and coughing , clinically suspected pneumonia . the plain chest x - ray ( a ) demonstrates a dense infiltrate in the left lower lung lobe which is confirmed on non - contrast - enhanced low dose ct ( b ; arrows ) .
multi - breath - hold coronal t2-weighted fast spin echo ( c ) and single breath - hold t1-weighted 3d gre imaging ( d ) as well as free breathing coronal steady state ssfp ( e ) and multi - breath - hold fat - saturated t2-weighted fast spin echo series ( f ) clearly demonstrate the infiltrates with particularly high signal on t2-weighted images another key clinical demand is the detection of small solid or soft tissue lesions ( nodules ) .
the sensitivity of mri for lung nodules larger than 4 mm ranges between 80 and 90% and reaches 100% for lesions larger than 8 mm .
depending on the sequence technique and the signal intensity of the lesions and given that conditions are optimal ( i.e. patient can keep a breath - hold for 20 s or perfect gating / triggering ) , a threshold size of 3 - 4 mm can be assumed for lung nodule detection with mri [ 19 , 20 ] . in comparison with ct
, it might be even faster and more efficient to read lung mri for pulmonary nodules , since they appear with bright signal against the dark background of the healthy lung tissue ( fig .
calcified nodules tend to disappear in the background , as they have no inherent signal , whereas contrast - filled vascular lesions will be highly visible on t1-weighted images .
so far , a variety of sequence types has been evaluated for lung nodule detection with mri .
the spectrum comprises t2-weighted fast spin echo imaging with and without fat saturation [ 2326 ] , inversion recovery techniques , t1-spin echo [ 26 , 28 ] and gradient echo sequences [ 29 , 30].fig .
2a 64-year - old woman with the incidental finding of an unspecific , 4-mm nodule in the right middle lobe .
the nodule ( open arrow ) is clearly depicted on the coronal multi - breath - hold t2-weighted ( a ) and transverse contrast - enhanced , fat - saturated 3d gre images ( b ) a 64-year - old woman with the incidental finding of an unspecific , 4-mm nodule in the right middle lobe .
the nodule ( open arrow ) is clearly depicted on the coronal multi - breath - hold t2-weighted ( a ) and transverse contrast - enhanced , fat - saturated 3d gre images ( b ) the implications for protocol design are to include at least one t2-weighted or proton - density - weighted or short tau inversion recovery ( stir ) sequence to cover infiltrates and nodular lesions with high fluid content .
this should be combined with a second sequence to cover nodules with high signal on t1-weighted images as well .
in particular , for the detection of malignant lesions with hyperperfusion and intense enhancement , the i.v .
not yet clarified is the role of diffusion - weighted imaging ( dwi ) of lung lesions .
dwi is recommended for the whole - body staging of lung cancer , including mediastinal metastases [ 31 , 32 ] ; however , in the chest a clear advantage of dwi over other mri protocols has not been confirmed so far [ 33 , 34 ] .
stir sequences might be even more sensitive for the detection and classification of lung cancer and mediastinal metastases than dwi [ 3537 ] .
one potential role of dwi might be to predict tumour invasiveness for clinical stage ia non - small - cell lung cancer and to separate the mass from atelectasis [ 38 , 39 ] .
the role of dwi sequences for the differentiation of malignant or benign lung lesions or for the discrimination of subtypes of lung cancer remains controversial [ 37 , 4042 ] . in the authors own experience
3 ) , assess mediastinal extension and may serve as a second reader for detection of small nodules .
thus , it makes sense to include a fast dwi acquisition in the protocol recommendations for mri of the lung [ 43 , 44].fig .
3diffusion - weighted imaging highlighting pleural metastases of hepatocellular carcinoma at the right diaphragm ( left , open arrow ) .
the same spots are only hardly visible on the post - contrast fat - saturated breath - hold t1-weighted 3d gre sequence ( right ) .
diffusion - weighted imaging highlighting pleural metastases of hepatocellular carcinoma at the right diaphragm ( left , open arrow ) .
the same spots are only hardly visible on the post - contrast fat - saturated breath - hold t1-weighted 3d gre sequence ( right ) .
thus far , approaches for disorders of pulmonary perfusion have been aimed at either the visualisation of the pulmonary arterial tree ( mr angiography ) or at the assessment of lung parenchyma signal changes associated with perfusion on contrast - enhanced or non - contrast - enhanced scans .
mr angiography and mr perfusion have mainly been applied for the study of acute pulmonary embolism , a key clinical entity to demonstrate diagnostic accuracy .
many approaches include direct visualisation of the thrombus inside the pulmonary artery either with positive or negative contrast against the signal of the flowing blood .
presently , fast steady state free precession gradient echo sequences ( ssfp - gre ) appear to be one of the most effective techniques .
they display the lung vessels with bright signal , against which thrombotic material is contrasted with low signal intensity .
a sensitivity of 90% and a specificity of 97% have been reported for acute segmental pulmonary embolism [ 4547 ] .
another approach has used double inversion recovery , demonstrating stagnant blood clot as bright signal , but insufficient data exist as to the diagnostic accuracy at this time [ 48 , 49 ] .
the presently most powerful technique , however , appears to be high spatial resolution mr angiography with t1-weighted contrast - enhanced 3d gradient echo acquisitions with k - space centred contrast bolus in a breath - hold . for optimum contrast , it is recommended to use a power injector and selected injection protocols .
several studies have shown very encouraging results for mr angiography ( mra ) in the workup of patients with suspected pulmonary embolism [ 5255 ] .
most recently , the pioped iii study involving seven centres and 371 patients with suspected pulmonary embolism demonstrated sufficient image quality in only 75% of the patients . sensitivity and specificity for acute pulmonary embolism were 78% and 99% , respectively .
the most frequent reason for insufficient image quality was dyspnoea , coughing or insufficient timing of contrast material injection . to overcome the problem of bolus timing , other approaches favoured time - resolved mra with multiple acquisitions of lung volumes using very fast 3d gradient echo techniques .
extremely short acquisition times of 1.5 s or less were achieved by combining parallel imaging and data sharing . with a so - called 4d mra or dynamic first - pass perfusion mri [ also known as dynamic contrast enhanced ( dce)-mri ] , ersoy et al . realised a sensitivity of 98% for lobar and 92% for segmental embolism .
the development of dynamic first pass perfusion mri has opened further perspectives in studying lung parenchyma perfusion in other disease conditions than pulmonary embolism as well .
limited to one plane , the temporally resolved so - called two - dimensional dynamic ( 2d + t ) perfusion mri reaches excellent temporal resolution of up to 10 images / s with reasonable spatial resolution .
however , volume coverage needs multiple series and contrast injections , which are usually not feasible .
other techniques such as arterial spin labeling ( asl ) based on intrinsic contrast of magnetised , inflowing blood into the imaging plane or volume have been investigated and applied for scientific studies , but have not yet found their way into clinical applications [ 60 , 61 ] .
the visual evaluation of 4d mri image sets is facilitated by subtraction of the non - enhanced from the contrast - enhanced image signal , which results in a bright display of the contrast - enhanced lung vessels and parenchyma .
the clinical value of lung perfusion studies with visual and semi - quantitative evaluation is being tested in the assessment of lung perfusion deficits in cystic fibrosis patients who suffer from mucus retention and hypoxic vasoconstriction ( fig .
4 ) [ 6264 ] . the perfusion series allows indirect visualisation of lung parenchyma abnormalities due to emphysema or conditions such as pneumothorax due to the absence of perfused lung tissue.fig .
4an 18-year - old male cystic fibrosis patient , coronal t2-weighted half fourier fast spin echo sequence ( a ) and coronal subtraction perfusion image ( b ) .
due to redistribution of perfusion both lower lobes show a high perfusion signal an 18-year - old male cystic fibrosis patient , coronal t2-weighted half fourier fast spin echo sequence ( a ) and coronal subtraction perfusion image ( b ) .
the subtraction perfusion image shows correspoding areas with perfusion loss due to hypoxic vasoconstriction . due to redistribution of perfusion
direct visualisation of the airways with mri is limited to airways in excess of 3 mm diameter , unless filled with bright materials such as retained mucus in cystic fibrosis patients [ 65 , 66 ] ( fig .
lung mri depicted airways down to the first subsegmental level ; however , in parts of the lung subject to cardiac pulsation , detection rates were significantly lower .
as expected from the higher spatial resolution , high resolution ct is still superior to mri in the depiction of small peripheral airways.fig .
coronal t2-weighted , respiration triggered and transverse breath - hold t1-weighted 3d gre images show peripheral airways with enhanced signal due to mucus plugging .
sign similar to the typical appearance on ct ( dashed circles ) lung mri of a 37-year - old male patient with cystic fibrosis .
coronal t2-weighted , respiration triggered and transverse breath - hold t1-weighted 3d gre images show peripheral airways with enhanced signal due to mucus plugging .
sign similar to the typical appearance on ct ( dashed circles ) however , mri is capable of studying dynamic processes , e.g. to analyse respiratory motion of the lung , diaphragm and relationships of tumours to chest wall boundaries .
the technical advances described above for 2d + t mri or 3d + t mri with different variants of t1-weighted gradient echo or steady state free precession sequences have been applied for this purpose [ 68 , 69 ] .
one of the most important clinical applications will be radiotherapy planning for organs with respiration - correlated motion [ 70 , 71 ] .
since air has no signal on mri , ventilation can only be visualised directly with hyperpolarised noble gases , sulphur hexafluoride ( sf6 ) or tracked indirectly by signal changes after inhalation of 100% oxygen or inhalation of aerosol of a paramagnetic contrast agent . despite the fascinating scientific publications obtained with these approaches , most of them are still remote from clinical application .
presently , the use of dynamic image acquisitions in single 2d planes ( 2d + t ) to study respiratory motion appears to be closest to routine use .
apart from the conditions mentioned above , the spectrum of findings to be covered comprises a wide range of disorders , ranging from pleural pathology ( effusion , empyema , tumour with chest wall infiltration , pneumothorax ) to mediastinal involvement ( masses , lymphnodes , vascular pathologies ) and the assessment of the adjacent upper abdomen ( e.g. adrenal and liver metastases in lung cancer ) .
it would be beyond the scope of this article to discuss the role of mri in all of these conditions , since this is well covered by standard textbooks . nevertheless , any suggested standard protocol for lung diseases should offer sufficient coverage of the surrounding structures , which may then be further examined with dedicated protocols .
a wide field , for instance , is the interaction between the heart and the lung . to keep within the frame of this article
, the possible useful combinations of lung mri protocol components with heart mri protocols will not be discussed explicitly
. however , their clinical value is obvious and building flexibility into the protocol trees is suggested , which would allow the user to combine protocols as required .
more than in x - ray or ct , image quality in mri depends on patient compliance .
as discussed above , it can be expected that some sequences may produce unsatisfactory results in individual patients .
therefore , the use of fast imaging protocols is advocated , with additional sequences to allow for with a certain degree of redundancy to compensate for any failed acquisitions .
excellent results will be obtained in young , compliant subjects with good breath - hold capability .
in contrast to this , it may become most difficult to obtain diagnostic image quality in non - compliant , obese patients unable to hold their breath or unable to understand and follow the breathing commands .
for the latter , parts of the protocol can be acquired in free breathing , either due to their fast acquisition scheme or with respiration gated or triggered acquisition modes .
respiration - triggered versions of the t2-weighted fast spin echo sequences are available for uncooperative patients who have difficulties with breath - holding ( their application increases the total in - room time by 10 min ) .
technicians will test patient compliance early on in the study , and can adjust the sequences accordingly .
however , it needs to be emphasised that coaching of patients is very important to gain most information from any mri scan .
respiration belts may be helpful , since this allows for monitoring patient compliance even during image acquisition . as discussed in the previous article of this series in detail [ mri of the lung ( 1/3 ) ] ,
the following protocol suggestions can be transferred from 1.5- to 3-t mr scanners . while most sequences , in particular 3d gradient echo techniques , profit from a higher lesion - to - background contrast to a certain degree , artefacts may deteriorate the image quality of steady state gradient echo sequences [ 17 , 21 , 77 ] .
overall , the changes of image quality with transfer of the concept to 3 t are acceptable or even positive for most sequence types .
the lack of radiation exposure makes mri of the lung particularly attractive for paediatric radiology . depending on experience with the technology and the availability of scanner time
, mri has become the first - line cross - sectional imaging technique for pulmonary disease in many departments .
the available sequence techniques are the same as for adult patients , but characteristic features of the paediatric setting influence the choice of protocols .
first of all , breath - hold imaging is frequently not possible in young children up to 8 years .
depending on the size of the patients and their ability to comply with the procedure and breathing instructions ( sometimes even 6-year - old or even younger children are capable of holding their breath on command ) , it appears useful to prepare a separate protocol tree not only with motion compensated protocols but also with adjusted fields of view , slice thickness and in - plane resolution with optimised signal - to - noise ratios for smaller subjects .
two basic strategies have been pursued for motion compensation : fast single shot imaging with very short acquisition time and respiratory gating / triggering of fast spin echo techniques .
for the first approach , steady state ( ssfp ) or partial fourier single shot sequences ( e.g. haste ) have been successfully implemented .
ssfp sequences allow for a rapid acquisition of ten slices with breath - hold times below 10 s , even on low - field mri systems .
typically , these fast and robust sequences would be used for an initial overview with further high - resolution acquisitions in the second part of the examination . the second approach , gated or triggered acquisition , increases imaging time but provides better spatial resolution and soft tissue contrast ( figs .
6 , 7 ) [ 79 , 83 ] . the higher respiration frequencies of young children are of a certain advantage since they help speeding up the acquisition . in most cases ,
the difference to non - gated acquisitions is much less than in adult subjects with low respiration rates . t2-weighted
fast spin echo sequences can be applied with repetition times of 2000 ms or less , usually triggered to the expiratory phase , which is around 2 s , depending on the individual respiration frequency .
this time frame allows for excellent t2-weighted images without relevant motion artefacts . depending on the available hardware and specific experience of the team ,
both mechanical ( respiratory belt or cushion technique ) or image - based ( e.g. navigator ) devices for the detection of respiratory motion can be applied with good results .
a radial read - out scheme of the k - space further improves the robustness against motion artefacts .
the application of additional cardiac triggering may be helpful in specific cases , but paid for with a significant increase of acquisition time .fig .
both acquisitions , the free breathing steady state free precession series ( a ) and the respiration triggered ( navigator triggered ) series ( b ) show a large mass with high signal intensity in the right upper lung lobe in expirationfig . 7pneumonia ( asterisk ) , chambered pleural effusion ( arrowheads ) and abscess ( arrow ) in the right lower chest of a 6-year - old child , images acquired in t2-weighted triggered fast spin echo technique a 6-year - old child with lung metastases of osteosarcoma .
both acquisitions , the free breathing steady state free precession series ( a ) and the respiration triggered ( navigator triggered ) series ( b ) show a large mass with high signal intensity in the right upper lung lobe in expiration pneumonia ( asterisk ) , chambered pleural effusion ( arrowheads ) and abscess ( arrow ) in the right lower chest of a 6-year - old child , images acquired in t2-weighted triggered fast spin echo technique a second characteristic feature of the paediatric setting is the need for sedation or general anaesthesia in many cases .
sedation will normally be avoided as much as possible , but may be indispensable . in low - field lung mri it remains a matter of debate ( rupprecht et al .
versus sanborn et al . ) . for propofol sedation , an incidence of up to 42% of dorsal atelectasis has been described .
other groups use chloral hydrate or phenobarbital and report less frequent atelectases ( personal communication ) .
however , it is important to know this condition , since it may mask relevant pathology . in case of doubt ,
exact correlation with ct is needed , e.g. when switching follow - up examinations from ct to mri , it may be useful to acquire the mri examination with elevated arms . however , this position is usually not tolerated by children for more than 15 - 20 min and can not be generally recommended .
the lack of radiation exposure makes mri of the lung particularly attractive for paediatric radiology . depending on experience with the technology and the availability of scanner time
, mri has become the first - line cross - sectional imaging technique for pulmonary disease in many departments .
the available sequence techniques are the same as for adult patients , but characteristic features of the paediatric setting influence the choice of protocols .
first of all , breath - hold imaging is frequently not possible in young children up to 8 years .
depending on the size of the patients and their ability to comply with the procedure and breathing instructions ( sometimes even 6-year - old or even younger children are capable of holding their breath on command ) , it appears useful to prepare a separate protocol tree not only with motion compensated protocols but also with adjusted fields of view , slice thickness and in - plane resolution with optimised signal - to - noise ratios for smaller subjects .
two basic strategies have been pursued for motion compensation : fast single shot imaging with very short acquisition time and respiratory gating / triggering of fast spin echo techniques .
for the first approach , steady state ( ssfp ) or partial fourier single shot sequences ( e.g. haste ) have been successfully implemented .
ssfp sequences allow for a rapid acquisition of ten slices with breath - hold times below 10 s , even on low - field mri systems .
typically , these fast and robust sequences would be used for an initial overview with further high - resolution acquisitions in the second part of the examination .
the second approach , gated or triggered acquisition , increases imaging time but provides better spatial resolution and soft tissue contrast ( figs .
6 , 7 ) [ 79 , 83 ] . the higher respiration frequencies of young children are of a certain advantage since they help speeding up the acquisition . in most cases ,
the difference to non - gated acquisitions is much less than in adult subjects with low respiration rates . t2-weighted
fast spin echo sequences can be applied with repetition times of 2000 ms or less , usually triggered to the expiratory phase , which is around 2 s , depending on the individual respiration frequency .
this time frame allows for excellent t2-weighted images without relevant motion artefacts . depending on the available hardware and specific experience of the team ,
both mechanical ( respiratory belt or cushion technique ) or image - based ( e.g. navigator ) devices for the detection of respiratory motion can be applied with good results .
a radial read - out scheme of the k - space further improves the robustness against motion artefacts .
the application of additional cardiac triggering may be helpful in specific cases , but paid for with a significant increase of acquisition time .fig .
both acquisitions , the free breathing steady state free precession series ( a ) and the respiration triggered ( navigator triggered ) series ( b ) show a large mass with high signal intensity in the right upper lung lobe in expirationfig . 7pneumonia ( asterisk ) , chambered pleural effusion ( arrowheads ) and abscess ( arrow ) in the right lower chest of a 6-year - old child , images acquired in t2-weighted triggered fast spin echo technique a 6-year - old child with lung metastases of osteosarcoma .
both acquisitions , the free breathing steady state free precession series ( a ) and the respiration triggered ( navigator triggered ) series ( b ) show a large mass with high signal intensity in the right upper lung lobe in expiration pneumonia ( asterisk ) , chambered pleural effusion ( arrowheads ) and abscess ( arrow ) in the right lower chest of a 6-year - old child , images acquired in t2-weighted triggered fast spin echo technique a second characteristic feature of the paediatric setting is the need for sedation or general anaesthesia in many cases .
sedation will normally be avoided as much as possible , but may be indispensable . in low - field lung mri
it remains a matter of debate ( rupprecht et al . versus sanborn et al . ) . for propofol sedation
other groups use chloral hydrate or phenobarbital and report less frequent atelectases ( personal communication ) .
however , it is important to know this condition , since it may mask relevant pathology . in case of doubt ,
exact correlation with ct is needed , e.g. when switching follow - up examinations from ct to mri , it may be useful to acquire the mri examination with elevated arms . however ,
this position is usually not tolerated by children for more than 15 - 20 min and can not be generally recommended .
based on the published experience and matching the above - stated expectancies , table 1 summarises a selection of available sequences and their potential diagnostic yield for lung mri . for the overview of concept , details on sequence technology and parameters
are left out here , since dedicated protocols are described in the literature and may vary in between different vendors [ 8891 ] .
adjusted to the size of the patient , the fields of view ( fovs ) would be typically 450 - 500 mm in coronal and approximately 400 mm in transverse acquisitions with matrices of 256 - 384 pixels ( for triggered fast spin echo series up to 512 ) resulting in pixel sizes smaller than 1.8 1.8 mm .
three - dimensional acquisitions for imaging lung morphology in transverse orientation would use slice thicknesses of 4 mm or less , pulmonary angiography in coronal orientation 2 mm or less .
this is in line with the qa guidelines for thoracic mri published by the german board of medicine .
a basic or general study combines t1-weighted and t2-weighted images based on gradient echo and fast spin echo sequences , respectively .
t1-gre sequences are available as 3d acquisitions and may , therefore , be limited to a volume acquisition of the chest in one breath - hold .
fast t2-weighted spin echo sequences should cover at least two planes , e.g. with a half fourier breath - hold acquisition in coronal and a transverse orientation .
this results in a high sensitivity of the protocol for infiltrates and small nodular lesions . to improve the sensitivity of the protocol for mediastinal lymph nodes and bone lesions ( e.g. metastases ) , a stir or fat saturated t2-fast spin echo sequence
since rib metastases are easier to detect on transverse slices , this orientation should be preferred ( fig .
the list of must sequences ( in the table indicated by g for general protocol )
is concluded with a coronal steady - state free precession sequence in free breathing , which contributes to a high sensitivity for central pulmonary embolism and gross cardiac or respiratory dysfunction . as an option ( but at the cost of additional imaging time exceeding the intended limitation to 15 min ) , motion - compensated t2-weighted fast spin echo sequences can be added to improve the depiction of masses with chest - wall invasion [ 1 , 5].fig .
8recent fracture of the left 5th rib as incidental finding in a 29-year - old female volunteer with left chest pain , hardly visible on the non - contrast enhanced t1-weighteg breath - hold 3d gre series ( a ) but with bright signal on the t2-weighted fat saturated image from an multiple breath - hold series ( b , arrow ) recent fracture of the left 5th rib as incidental finding in a 29-year - old female volunteer with left chest pain , hardly visible on the non - contrast enhanced t1-weighteg breath - hold 3d gre series ( a ) but with bright signal on the t2-weighted fat saturated image from an multiple breath - hold series ( b , arrow ) with this selection of non - contrast - enhanced sequences , the study covers some of the most common potential findings , including pneumonia , atelectasis , pulmonary nodules or masses , mediastinal masses ( lymphoma , goiter , cyst , thymoma ) and acute pulmonary embolism . depending on the initial findings following the basic protocol , additional contrast - enhanced acquisitions may be required , which would use the same type of volume interpolated 3d - gre sequence , but now with fat saturation to improve the visibility of contrast - enhanced tissues and mediastinal lymph nodes ( t tumour protocol ) .
although the 3d sequences cover the whole chest , in - plane resolution is optimised in either transverse or coronal section ( fig .
are just one breath - hold , it appears to be feasible to acquire the 3d gre studies in at least transverse and coronal planes . in particular for the staging of lung cancer
, it might be helpful for the detection of small lymph nodes metastases to add a diffusion - weighted sequence as well .
9a 77-year - old male patient with adenocarcinoma in segment 6 of the right lower lung lobe ( arrow ; transverse contrast - enhanced breath - hold 3d gre study ) a 77-year - old male patient with adenocarcinoma in segment 6 of the right lower lung lobe ( arrow ; transverse contrast - enhanced breath - hold 3d gre study ) the available options for imaging disorders of lung vasculature comprise three components : first of all , the free breathing steady state gradient echo ( ssfp - gre ) study which is also part of the general protocol
. then two variations of 3d gradient echo based contrast enhanced mra : ( 1 ) a time - resolved , low spatial resolution acquisition for first pass perfusion imaging and ( 2 ) a high spatial resolution acquisition for a breath - hold angiogram ( fig .
depending on the performance of the mr scanner , the dynamic study produces a comprehensive lung perfusion study with excellent temporal resolution and at the same time serves for the determination of optimum contrast bolus timing for the acquisition of the high resolution angiogram .
( v in table 1 ) optimises the sensitivity for acute and chronic pulmonary embolism , arterio - venous ( av ) malformation ( e.g. osler s disease ) , lung sequestration , pulmonary arterial aneurysm , abnormalities of pulmonary venous drainage and any other pathology of lung vasculature . as in other parts of the protocol recommendations
, it is suggested to combine different fast imaging sequences to increase sensitivity and specificity of the examination .
therefore , kluge et al . suggested combinations of different available mri techniques for the detection of pulmonary embolism .
the lung vessel imaging branch of the protocol tree can be used just for a study of vascular pathology , e.g. in suspected acute pulmonary embolism or in combination with the tumour protocol for the comprehensive evaluation of a central mass with vessel invasion.fig .
10an 18-year - old female patient with clinical suspicion ( dyspnoea and elevated d - dimers ) of acute pulmonary embolism .
the steady state free precession study shows an embolus inside the right pulmonary artery ( a , arrow ) that is also clearly depicted in the subtraction images form the contrast enhanced 3d flash mra ( b ) .
the subtraction of the first pass perfusion study ( c ) confirm large perfusion deficits in the right lower lobe and a posterior segment of the left upper lobe ( arrowheads ) an 18-year - old female patient with clinical suspicion ( dyspnoea and elevated d - dimers ) of acute pulmonary embolism .
the steady state free precession study shows an embolus inside the right pulmonary artery ( a , arrow ) that is also clearly depicted in the subtraction images form the contrast enhanced 3d flash mra ( b ) .
the subtraction of the first pass perfusion study ( c ) confirm large perfusion deficits in the right lower lobe and a posterior segment of the left upper lobe ( arrowheads ) these protocol suggestions cover all expected clinical questions with different branches of the protocol tree for specific problems .
they are a good point to start from and allow users to make up their own branches based on the suggested components .
with a comprehensive protocol approach as proposed , mri of the lung can be readily performed on most state - of - the - art 1.5-t mri scanners .
breath - hold imaging or triggered acquisitions , together with advanced sequence technology ( e.g. parallel imaging and rotating phase encoding ) , make image quality reasonably robust against artefacts induced by respiratory motion and heart action .
this allows for appreciation of the specific features of lung mri related to its excellent soft tissue contrast and functional imaging capacities .
the sensitivity of these protocols for infiltrates is at least similar to x - ray and ct . in lung
nodule detection , mri is superior to x - ray and almost as sensitive as ct . a dedicated selection of sequences for imaging lung vasculature allows for the detection of pulmonary embolism with high sensitivity and specificity . in respect to lung perfusion and respiratory motion , lung mri offers additional functional imaging capacities beyond the scope of x - ray and ct . with this
, lung mri offers not only solutions for tricky problems of daily routine but also is a good option for paediatrics and science or any situation where ct would be ( relatively ) contra - indicated .
a set of dedicated protocols , as suggested in this article , may help new users to get started and to stimulate the further development of this powerful , third modality for lung imaging besides x - ray and ct .
further details on how to use the suggested toolbox or sequence buffet may be used and modified for specific clinical applications and how future perspectives for further protocol developments would look like will be discussed in the subsequent article of this series .
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### Summary:
: backgroundamong the modalities for lung imaging , proton magnetic resonance imaging ( mri ) has been the latest to be introduced into clinical practice . its value to replace x - ray and computed tomography ( ct )
when radiation exposure or iodinated contrast material is contra - indicated is well acknowledged : i.e. for paediatric patients and pregnant women or for scientific use .
one of the reasons why mri of the lung is still rarely used , except in a few centres , is the lack of consistent protocols customised to clinical needs.methodsthis article makes non - vendor - specific protocol suggestions for general use with state - of - the - art mri scanners , based on the available literature and a consensus discussion within a panel of experts experienced in lung mri.resultsvarious sequences have been successfully tested within scientific or clinical environments .
mri of the lung with appropriate combinations of these sequences comprises morphological and functional imaging aspects in a single examination .
it serves in difficult clinical problems encountered in daily routine , such as assessment of the mediastinum and chest wall , and even might challenge molecular imaging techniques in the near future.conclusionthis article helps new users to implement appropriate protocols on their own mri platforms.main messages mri of the lung can be readily performed on state - of - the - art 1.5-t mri scanners. protocol suggestions based on the available literature facilitate its use for routine mri offers solutions for complicated thoracic masses with atelectasis and chest wall invasion. mri is an option for paediatrics and science when ct is contra - indicated
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: fractures of the zygomatic complex are common after facial trauma and are frequently associated with additional traumatic injury .
early diagnosis of zygomatic complex fractures is essential for optimal treatment and is directly dependent on appropriate initial evaluation , correct injury assessment , and timely initiation of the chosen therapy .
surgical intervention is the treatment of choice for dislocated zygomatic complex fractures , unless patients are medically unfit to undergo surgery if patients refuse surgery , or if patients present with none or minimal functional and/or aesthetic problems . in the literature
, many of the studies can be found concerning the evaluation of the surgical treatment management of the fractured zygomatic complex .
literature concerning the pre - operative assessment of zygomatic complex fractures , in particular the epidemiological differences between the surgically and non - surgically indicated treatment groups , is lacking . to the best of our knowledge ,
specifically investigated the non - surgically treated patients . however , the study by back et al . included all facial fractures and therefore did not in particular focus on patients with solely zygomatic complex fractures .
the purpose of the present retrospective study was to provide physicians a more complete view of the epidemiological characteristics of the surgically and non - surgically treated patients with zygomatic complex fractures .
a retrospective review was performed from all hospital and out - patient records of 283 patients diagnosed with a fractured zygomatic complex , from january 2007 to january 2012 .
data collection consisted of age , gender , fracture site , fracture displacement , cause of the trauma injury ( assault , traffic accident , sport accident , fall or other ) , date of the trauma , date of the first consultation , and treatment management ( surgical or non - surgical ) .
diagnosis ( and the presence of fracture displacement ) of all patients was established at the same day of initial assessment by plain radiographic analysis ( submentovertex and occipitomental radiographs ) and/or computed tomography - scan ( ct - scan ) .
exclusion - criteria were the presence of a le fort fracture , or other facial bone fractures that were associated with the ( four - sided ) fractured zygomatic complex ( e.g. , isolated lateral orbital rim and/or wall , orbital floor or zygomatic arch ) , and/or a bilaterally fractured zygomatic complex .
furthermore , patients were excluded if the initial clinical assessment was more than 1 week after the trauma and if radiographical analyses ( e.g. , plain radiographs or ct - scans ) were not available . after data retrieval patients were divided into a group in which patients underwent surgical treatment and a non - surgical treatment group .
furthermore , patients in the non - surgical treatment group were subdivided into groups based on displacement of the fractured zygomatic complex ( displacement vs. non - displacement ) .
nominal data were presented as absolute and relative frequencies , metric data as mean and standard deviation ( sd ) .
comparisons between the groups were done by the chi - square test for nominal data and the mann - whitney u - test for age .
all calculations were made using statistical package for the social sciences ( ibm ) v 19.0 .
a retrospective review was performed from all hospital and out - patient records of 283 patients diagnosed with a fractured zygomatic complex , from january 2007 to january 2012 .
data collection consisted of age , gender , fracture site , fracture displacement , cause of the trauma injury ( assault , traffic accident , sport accident , fall or other ) , date of the trauma , date of the first consultation , and treatment management ( surgical or non - surgical ) .
diagnosis ( and the presence of fracture displacement ) of all patients was established at the same day of initial assessment by plain radiographic analysis ( submentovertex and occipitomental radiographs ) and/or computed tomography - scan ( ct - scan ) .
exclusion - criteria were the presence of a le fort fracture , or other facial bone fractures that were associated with the ( four - sided ) fractured zygomatic complex ( e.g. , isolated lateral orbital rim and/or wall , orbital floor or zygomatic arch ) , and/or a bilaterally fractured zygomatic complex .
furthermore , patients were excluded if the initial clinical assessment was more than 1 week after the trauma and if radiographical analyses ( e.g. , plain radiographs or ct - scans ) were not available . after data retrieval patients were divided into a group in which patients underwent surgical treatment and a non - surgical treatment group .
furthermore , patients in the non - surgical treatment group were subdivided into groups based on displacement of the fractured zygomatic complex ( displacement vs. non - displacement ) .
nominal data were presented as absolute and relative frequencies , metric data as mean and standard deviation ( sd ) .
comparisons between the groups were done by the chi - square test for nominal data and the mann - whitney u - test for age .
all calculations were made using statistical package for the social sciences ( ibm ) v 19.0 .
as you can see in table 1 , the patient demographics are listed the study population consisted of 283 patients of which 133 surgically treated and 150 non - surgically treated .
subdivided by gender , 201 male ( 71% ) and 82 female ( 29% ) patients were included .
there was a significant ( p < 0.05 ) difference in age between male patients ( mean age : 40.6 years , sd : 17 ) and female patients ( mean age : 48.2 years , sd : 23.6 ) . compared with the surgically treated patients group
the patients of the non - surgically treated group were significantly older ( p < 0.05 ) .
concerning the non - surgically treated patients group , the 55 patients with a displaced fractured zygomatic complex differed from the 95 patients with a non - displaced zygomatic complex fracture .
the mean age of those with displaced zygomatic complex fractures was higher ( 51.2 years , sd : 23.6 ) , compared with those with the non - displaced fractures ( 43.4 years , sd : 20.6 ) , especially with regard to the female patients ( mean age of 59.5 years , sd : 27.4 ) .
as demonstrated in table 2 , the main cause of zygomatic complex fractures was traffic accidents ( 43.1% ) , followed by falls ( 27.2% ) and assaults ( 20.5% ) .
cause of injury according to age groups in all patients with a fractured zygomatic complex the main causes differed substantially between male and female patients [ tables 2a and b ] . in male patients , traffic accidents accounted for 43.3% , followed by assaults ( 26.4% ) and falls ( 20.9% ) . in female patients both traffic accidents ( 42.7% ) and falls ( 42.7% ) were the most common causes , whereas assaults were not seen frequently ( 6.1% ) .
falls accounted significantly more for the older ages , whereas traffic accidents and assaults accounted for the younger ages ( p < 0.000 ) . the male patients were mainly in their 20 year of age , whereas the females were mainly older than 70 years of age .
cause of injury according to age for male patients cause of injury according to age for female patients for both groups traffic accidents mainly consisted of bicycle and motorcycle accidents with relative more bicycle accidents for the female patients [ figure 1 ] .
the main cause of injury in the surgically treated patients accounted for almost 50% of traffic accidents , followed by assaults ( 24.1% ) and falls ( 13.5% ) [ table 3a ] . in the non - surgically treated patient group
falls formed the main cause ( 39.3% ) , closely followed by traffic accidents ( 37.3% ) .
traffic accidents divided by mode of transport for male and female patients cause of injury for surgically treated patients cause of injury for non - surgically treated patients the relative share of male patients was almost equally divided between the displaced fracture group ( 65.5% ) and the non - displaced fractures ( 66.3% ) .
displaced zygomatic complex fractures were mainly caused by falls [ table 4a ] , whereas non - displaced fractures were mostly caused by traffic accidents , followed by falls [ table 4b ] .
causes of injury for the displaced fractures in the non - surgically treated patients group causes of injury for the non - displaced fractures in the non - surgically treated patients group
as you can see in table 1 , the patient demographics are listed the study population consisted of 283 patients of which 133 surgically treated and 150 non - surgically treated .
subdivided by gender , 201 male ( 71% ) and 82 female ( 29% ) patients were included .
there was a significant ( p < 0.05 ) difference in age between male patients ( mean age : 40.6 years , sd : 17 ) and female patients ( mean age : 48.2 years , sd : 23.6 ) . compared with the surgically treated patients group
the patients of the non - surgically treated group were significantly older ( p < 0.05 ) .
concerning the non - surgically treated patients group , the 55 patients with a displaced fractured zygomatic complex differed from the 95 patients with a non - displaced zygomatic complex fracture .
the mean age of those with displaced zygomatic complex fractures was higher ( 51.2 years , sd : 23.6 ) , compared with those with the non - displaced fractures ( 43.4 years , sd : 20.6 ) , especially with regard to the female patients ( mean age of 59.5 years , sd : 27.4 ) .
as demonstrated in table 2 , the main cause of zygomatic complex fractures was traffic accidents ( 43.1% ) , followed by falls ( 27.2% ) and assaults ( 20.5% ) .
cause of injury according to age groups in all patients with a fractured zygomatic complex the main causes differed substantially between male and female patients [ tables 2a and b ] . in male patients , traffic accidents accounted for 43.3% , followed by assaults ( 26.4% ) and falls ( 20.9% ) . in female patients both traffic accidents ( 42.7% ) and falls ( 42.7% ) were the most common causes , whereas assaults were not seen frequently ( 6.1% ) .
falls accounted significantly more for the older ages , whereas traffic accidents and assaults accounted for the younger ages ( p < 0.000 ) . the male patients were mainly in their 20 year of age , whereas the females were mainly older than 70 years of age .
cause of injury according to age for male patients cause of injury according to age for female patients for both groups traffic accidents mainly consisted of bicycle and motorcycle accidents with relative more bicycle accidents for the female patients [ figure 1 ] .
the main cause of injury in the surgically treated patients accounted for almost 50% of traffic accidents , followed by assaults ( 24.1% ) and falls ( 13.5% ) [ table 3a ] . in the non - surgically treated patient group
falls formed the main cause ( 39.3% ) , closely followed by traffic accidents ( 37.3% ) .
traffic accidents divided by mode of transport for male and female patients cause of injury for surgically treated patients cause of injury for non - surgically treated patients
the relative share of male patients was almost equally divided between the displaced fracture group ( 65.5% ) and the non - displaced fractures ( 66.3% ) .
displaced zygomatic complex fractures were mainly caused by falls [ table 4a ] , whereas non - displaced fractures were mostly caused by traffic accidents , followed by falls [ table 4b ] .
causes of injury for the displaced fractures in the non - surgically treated patients group causes of injury for the non - displaced fractures in the non - surgically treated patients group
this retrospective study aimed at the documentation of a more complete view of epidemiological data , as well as analysis of the differences between the surgically and non - surgically treated patients with zygomatic complex fractures .
the mean age of all 286 patients was 42.8 years ( sd : 19.8 ) .
surgically treated and non - surgically treated patients differed substantially in presentation and , in particular , the females of the non - surgically treated group . as expected ,
the non - surgically treated patients had a higher mean age ( 46.2 years , sd : 22.0 ) , especially within the group of fracture displacement .
this latter group almost consisted of symptomatic patients and will mainly consist of patients with treatment refusal or patients that are medically unfit .
strikingly , only female patients of the non - surgically treated patients group and not of the surgically treated patients group were much older ( mean age of 52.3 years , sd : 26.3 ) and especially for those within the displaced fractures ( mean age of 59.5 years , sd : 27.4 ) .
the age of our surgically treated patients group had similar results with other publications , in which predominance of younger patients , aged between 21 and 30 years and , moreover , no large differences in age between male and female patients were reported .
we found an overall higher mean age and this was due to our non - surgically treated patients that consisted of an old aged female population .
as in line with other previous studies the sex distribution was markedly higher for males than for females with a ratio of 2.4:1 of all patients . in our study ,
the main causes in all patients were mainly attributed to traffic accidents , assaults and falls . in many other studies ,
traffic accidents and assaults were main causes , which was in accordance with our surgically treated population but not with the non - surgically treated population .
fall ( 40% ) was the main cause in the non - surgically treated patients group and in particular in those with displaced zygomatic complex fractures ( 47% ) , followed by traffic accidents .
this is not in accordance with back et al . , who reported a high incidence of assaults ( 46% ) , followed by falls ( 20% ) in their non - surgically treated patients .
however , the study of back et al . included all facial fractures and was conducted in australia with a lower mean age of 38 years . our higher incidence of falls is partially due to old aged ( above 50 years ) female patients who have a higher risk on and are more prone to falls and have other living and/or social habits .
assaults happen much more in young male adults , as in accordance with our surgically treated population .
additional explanation for our higher incidence of falls might be due to our governmental safety measurements that could have decreased traffic ( car ) accidents and citizen safety ( less alcohol abuse , assaults ) in our country .
this study was a retrospective analysis , which means that it was automatically subject to measurements and registration styles by physicians and might therefore have a subjective bias .
another shortcoming of our study is , whether our epidemiological data is representative for whole amsterdam as there are four other hospitals treating patients with trauma injury .
however , to our knowledge this is the first report for the netherlands , which includes the non - surgically treated patients group .
there are several differences between the non - surgically treated and the surgically treated patients , and even within the non - surgically treated patients group , based on the presence of fracture displacement . from an epidemiological point of view neglecting , this non - surgically treated group in studies and solely describing the surgically treated patients can be considered a data gap and may be also an explanation for the large variability of incidence and etiology between different countries .
standardized and comparable studies including non - surgically treated patients and more specifically comparing the non - surgical group with the surgical group are therefore highly required .
this retrospective analysis provides us important data for a detailed view of all patients with zygomatic complex fractures and shows several epidemiological differences between the surgically and non - surgically treated patient groups and even differences within the latter group .
the surgically treated group mainly consisted of young male adults and the assault - related cause highly contributed , as in accordance with previous studies . on the contrary ,
the non - surgically treated group had a high proportion of elderly female patients , especially for the group with displaced zygomatic complex fractures .
epidemiological studies should be based on surgically as well as non - surgically treated patient groups and will help us to provide the importance of the differences between these groups and perhaps future plans for injury prevention .
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### Summary:
: introduction : this retrospective study is aimed at the documentation of a more complete view of epidemiological data with particular focus on the characteristics of the surgically and non - surgically treated patients with zygomatic complex fractures.materials and methods : a total of 133 surgically and 150 non - surgically patients were treated with zygomatic complex fractures in vu university medical center amsterdam from january 2007 to january 2012 were analyzed .
these patient groups were further subdivided into displaced or non - displaced fractures and compared with each other according to age , gender and trauma etiology.results:the mean age of all 286 patients was 42.8 years ( standard deviation [ sd : 19.8 ] ) . surgically and non - surgically treated patients differed in presentation with a significantly overall higher age of females , especially within the non - surgically treated patient group with displaced fractures ( mean age of 59.5 years , sd : 27.4 ) .
the mean ages of males from the different subgroups were more consistent with the overall mean age .
the main causes were traffic accidents , whereas the contribution of falls and assaults depended on age group , gender , treatment management and even fracture displacement.conclusions:this report provides us important epidemiological data of all patients with zygomatic complex fractures .
the non - surgically treated patient group contained patients of higher age , more females and a fall - related cause , compared to the surgically treated patient group .
the surgically treated patient group showed the same epidemiological characteristics as were demonstrated in previous studies .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: on march 30 , 2012 , a local health department notified the north carolina division of public health ( ncdph ) of 5 persons who had laboratory - confirmed infection with s. enterica ser .
all 8 ill persons ate or worked at the same restaurant in buncombe county , north carolina ; 5 ( 63% ) were food handlers .
on april 24 , ncdph was notified of 10 additional persons with laboratory - confirmed s. enterica ser .
l(+ ) tartrate(+ ) infection ; all had visited or resided in buncombe county during the infection s incubation period .
pulsed - field gel electrophoresis ( pfge ) patterns of isolates from all 15 laboratory - confirmed case - patients were indistinguishable and represented a pattern not previously reported to the national database of enteric pfge patterns , pulsenet , coordinated by cdc ( www.cdc.gov/pulsenet ; outbreak strain identification xba1 jkxx01.1228 ) .
ncdph initiated an investigation to determine the extent of the outbreak , identify the transmission source , and implement control measures .
a confirmed case was defined as laboratory identification of the outbreak strain from a person s clinical specimen , regardless of illness onset date or exposure location .
a probable case was defined as gastroenteritis in a person epidemiologically linked to a confirmed case .
patients were interviewed by using the standard ncdph salmonellosis reporting form to assess clinical symptoms ; travel history ; and food , water , and animal exposures .
a total of 89 cases ( 87 confirmed , 2 probable ) were identified among residents of 5 states ; illness onset dates were february 29may 8 , 2012 ( figure 1 ) .
of the 89 case - patients , 81 were residents of north carolina ; 80 reported travel to or residence in buncombe county during the incubation period .
ten self - identified as food service workers , 2 as health care providers , and 39 as students of or visitors to university a , located in buncombe county .
all 86 patients for whom data were available experienced diarrhea ( > 3 loose stools in a 24-hour period ; median duration 7 days , range 224 ) ; 30 ( 37% ) of 82 reported bloody diarrhea ( denominator reflects the number of case - patients who responded to the question ) .
eighty - three patients sought medical care ; 8 were hospitalized ; and none died ( table ) .
cases of salmonella enterica serovar paratyphi b variant l(+ ) tartrate(+ ) gastroenteritis , by date of symptom onset , north carolina , usa , february 29may 8 , 2012 . for comparison , the date that the manufacturer of brand a tempeh changed rhizopus spp .
consumption of vegetarian cuisine was commonly reported by case - patients . because meat substitutes ( e.g. , tofu and tempeh ) were not included on the standard reporting form
of these , 18 ( 44% ) indicated that they had eaten tempeh , a fermented bean product that is usually pasteurized and cooked before consumption .
of these 18 patients , 12 had eaten tempeh at a restaurant , 4 had eaten it at university a , and 2 had sampled it at a grocery store .
two of the 18 persons who consumed tempeh also regularly handled it at a restaurant .
site visits were conducted at the 3 restaurants most frequently identified in patient interviews ( 12%40% of patient reports ) .
interviews with managerial staff and observation of food preparation identified multiple opportunities for cross - contamination , including preparation of uncooked , unpasteurized tempeh on the same surfaces used to prepare ready - to - eat ( rte ) foods ; failure to perform handwashing after handling uncooked tempeh ; and bare - hand contact with rte foods .
on april 26 , the north carolina department of agriculture and consumer services ( ncda&cs ) notified ncdph that salmonellae had been presumptively identified from samples of brand a tempeh , which had been collected for routine food product testing before this outbreak was reported .
brand a produced unpasteurized tempeh in buncombe county and distributed it to 34 restaurants in north carolina .
additional distribution sites included grocery stores in several southeastern states and university a s cafeteria .
all 41 case - patients who completed the outbreak - specific questionnaire had eaten at a restaurant or venue that served brand a tempeh .
ncda&cs and ncdph visited brand a tempeh s production facility to interview staff , review tempeh production , and obtain food samples .
production of the tempeh began in october 2009 and involved combining beans ( e.g. , soybeans , black beans , or black - eyed peas ) , vinegar , and rhizopus spp .
the starter culture was added after cooking ; the bean product was then fermented until it formed a dense cake , and the unpasteurized product was packaged , frozen , and shipped .
were not recovered from raw soybeans or black - eyed peas , black beans were unavailable for sampling , and vinegar was not tested , but the outbreak strain was identified in opened and unopened bags of rhizopus spp . starter culture ( figure 2 ) .
pulse - field gel electrophoresis dendrogram showing xba1 enzyme band patterns for 8 case - patients , tempeh , and rhizopus spp . starter culture associated with outbreak of salmonella enterica serovar paratyphi
b variant l(+ ) tartrate(+ ) gastroenteritis , by date of symptom onset , north carolina , usa , 2012 .
culture was recalled voluntarily , domestically and internationally , on may 22 , 2012 ( 5 ) .
culture used in brand a tempeh , which then acted as a novel vehicle for spreading salmonellae to consumers , probably through cross - contamination of rte foods .
ncdph confirmed the association between illness and brand a tempeh through patient interviews and laboratory testing .
the contaminated starter culture was distributed internationally ; it is unclear why cases related to other tempeh brands did not occur , but a hypothesis is that , unlike other commercial tempeh products , brand a tempeh is unpasteurized , and thus pathogens remained in the finished product .
the role of cross - contamination in foodborne outbreaks is well established ( 611 ) .
bacteria can be transferred from surfaces to food products hours after surface contamination ( 6,7,9 ) .
rte foods typically do not include a heating or cooking step to kill pathogens ; consequently , raw vegetables and salads are commonly associated with foodborne outbreaks caused by cross - contamination ( 7,1012 ) . in this outbreak ,
all case - patients who responded to an outbreak - specific questionnaire reported eating at a venue that served brand a tempeh . although fewer than half recalled eating or handling tempeh , other case - patients might have been exposed during handling or consumption of cross - contaminated rte foods .
control measures addressing bare - hand contact with rte foods , sanitation of food contact surfaces , and separation of raw and rte foods were provided to restaurants that received brand a tempeh and to the local independent restaurant association .
although tempeh can be part of a healthy diet ( 13 ) , public health considerations should focus on safe handling of unpasteurized tempeh to prevent illness .
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### Summary:
: during an investigation of an outbreak of gastroenteritis caused by salmonella enterica serovar paratyphi b variant l(+ ) tartrate(+ ) , we identified unpasteurized tempeh as a novel food vehicle and rhizopus spp .
starter culture as the source of the contamination .
safe handling of uncooked , unpasteurized tempeh should be emphasized for prevention of foodborne illnesses .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: amyloid can affect any site in the
head and neck including the orbit , sinuses , oral cavity , salivary glands ,
pharynx , and larynx .
amyloid involvement of tongue is almost always secondary
to systemic amyloidosis and localized involvement is extremely rare [ 1 , 2 ] .
the etiology , treatment , and
outcome of systemic amyloidosis are totally different from localized
amyloidosis .
the mean survival of patients with systemic amyloidosis is between
5 to 15 months , whereas patients with localized amyloidosis have excellent
prognosis . to rule out a systemic amyloidosis
for these patients is extremely critical because this can markedly change the
expected morbidity and mortality .
abdominal fat aspirate is a risk - free
procedure and is the most specific test available as it is positive in 7080% of patients
with amyloidosis ; however , the sensitivity is low and is very technique
sensitive [ 2 , 3 ] .
the purpose of this article is to
present a rare case of localized , solitary amyloid tumor of tongue base and
emphasize some of the characteristic features of challenging histopathologic
diagnosis .
a 61-year - old male patient
presented with pyrosis of tongue and a nodular mass in tongue base . head and
neck examination revealed a 1 1 cm well - circumscribed , rubbery , nodular mass
at the right side of the tongue base .
a computed tomography was performed
and a possible granulomatous or inflammatory mass with calcification was
reported ( figure 1 ) .
the lesion appeared to be under normal
mucosa , within hyalinized muscular and connective tissue which includes focal
chondroid differentiation areas .
rough and irregular mass , 2 cm in diameter , was dissected from surrounding normal tissue with
minimal tissue loss and en
bloc excision could be achieved via transcervical suprahyoid approach
( figure 2 ) .
postoperative microscopic examination of the specimen
revealed a well - circumscribed submucosal lesion characterized with
structureless eosinophilic material deposition .
the amorphous , more or
less homogenous eosinophilic material
resembled amyloid histologically and on congo red staining , exhibited the classical apple - green
birefringence under polarized
light .
deposits of amyloid were also found in and around the walls of small
blood vessels .
immunohistochemical examination of the matrix with monoclonal
antibody aa - congo ( aac )
( dako , denmark 1/100 dilution ) revealed a non - aa - type amyloid deposition ( figure 3 ) . at the
periphery of the lesion
, there was a prominent chronic inflammatory reaction
rich in mixed kappa and lambda immunoreactive ( neomarkers , barcelona ,
spain 1/3000 , 1/100 dilutions ) plasma cells .
focal chondroid differentiation
was also observed either neighboring
the osseous tissue or spread as single chondrocytes in the amyloid matrix
( figure 4 ) .
thus , the lesion was reported as localized amyloid tumor of tongue
base with focal osseous and chondroid metaplasia .
diagnostic workup including
complete blood count , liver and renal function tests , urine analysis ,
esophagography , chest x - ray , electrocardiography , echocardiography , bone - marrow
biopsy , esr , rf , ana , and abdominal fat biopsy was carried out .
all examinations for exclusion of
systemic amyloidosis , including bone - marrow and abdominal fat biopsies , were
found to be negative for congo red staining and amyloid deposition .
bone - marrow
aspiration biopsy was found to be free of any type of infiltrations .
thus , the
patient was determined to be free of systemic amyloidosis and diagnosed as
localized , solitary amyloid tumor of the tongue base .
the differential diagnosis of the mass in tongue base includes
neoplastic processes and also lingual thyroid .
because the mass was settled
under normal appearing mucosa , a preoperative incisional biopsy was performed
in order to rule out thyroid tissue and malignancy .
we could not achieve a
definitive pathology with preoperative biopsy so we planned total excision of
the mass .
when amyloidosis is the histopathologic diagnosis in the patients
presenting with a localized mass in head and neck region , the main diagnostic
dilemma of the surgeon becomes the extension of the disease .
histopathologic
examinations of these lesions may help clinicians about the necessity of the
diagnostic examinations .
amyloid tumor of tongue base is a rare condition and
may not be predicted preoperatively , therefore there is little information on
the clinical and histopathologic features of the disease . in this paper
, we
focused on the clinical and pathological specifications of this rare tumor , so
any unnecessary examinations or measures may be spared and patient may be
informed clearly about the disease .
also , in the literature there is no consensus on terminology of the
disease .
we did not prefer to use the term localized amyloidosis of tongue
base for this disease because diffuse involvement of tongue with systemic
amyloidosis may be mistaken with well - circumscribed amyloid tumor .
the terms
localized primary amyloid tumor and solitary amyloid tumor were both used
for localized amyloid deposits without systemic amyloidosis or multiple myeloma
in the literature , and better distinguish from the systemic form and better
defines the disease .
so we decided to use the term solitary amyloid tumor for
the diagnosis after ruling out systemic involvement of the disease because it
briefly underlines the nature of the disease .
bone - marrow examination revealed no evidence of a plasma
cell dyscrasia . also , abdominal fat biopsy was free of amyloid deposits . to
date ,
the patient has not developed clinical or laboratory evidence of systemic
amyloidosis or multiple myeloma for a four - year follow - up period .
although , negative staining with
aac and osseous metaplasia which is noted in histopathological examination
supports non - aa - type amyloidosis , we performed these examinations to support
our diagnosis .
negative staining of amyloid material with aac is mostly seen in
primary type of amyloidosis .
also , osseous metaplasia noted in the histopathologic
examination may not be thought as definite criteria for localized amyloidosis , but a supporter of
localized , solitary amyloid tumor diagnosis .
there is data about osseous
metaplasia in the literature regarding the solitary amyloid tumor of other tissues
, and to our knowledge this is the first case in tongue .
a submucosal , surgically well - defined ,
well - circumscribed , and rubbery mass in tongue base with calcifications on
radiologic studies may not be surgically differentiated from other tumors of
tongue .
when histopathology reveals amyloid deposits on light microscopy , these
clinical findings may come out as important features in order to differentiate
local disease from involvement of tongue by a systemic disease . with this little information
regarding the clinical and histopathologic features of localized
, solitary
amyloid tumor of tongue base , we may not discuss the necessity of the
examinations in order to rule out systemic disease including abdominal fat and
bone - marrow biopsy .
therefore , the publication of more cases or series of the
disease may yield better characterization of the histopathologic , radiologic ,
and clinical features of solitary amyloid tumor of tongue base .
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### Summary:
: the purpose of this article is to present a rare case of localized , solitary amyloid tumor of tongue base and emphasize some of the characteristic features of challenging clinical and histopathologic diagnosis . in this paper , we focused on the clinical and pathological specifications of this rare tumor , so any unnecessary examinations or measures may be spared .
negative staining of amyloid material with aac and osseous metaplasia noted in the histopathologic examination may not be thought as definite criteria for localized amyloidosis , but a supporter of localized , solitary amyloid tumor diagnosis .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: a 30-year - old woman was referred to our clinic for evaluation of an intraocular mass lesion in her right eye .
her best corrected visual acuity was 30/50 in the right eye and 20/20 in the left eye .
although the anterior segment showed no pathologic findings , including the absence of an afferent pupillary defect , ophthalmoscopy revealed a 311 cm - sized nonpigmented choroidal mass with subretinal fluid in the superonasal quadrant of the fundus , extending from the equator to the ora serrata ( fig .
the mass showed relatively medium internal reflectivity and contained a cystic portion on ultrasonography ( fig .
1 ) . magnetic resonance imaging ( mri ) showed high signal intensity in t1-weighted images with enhancement and low signal intensity in t2-weighted images ( fig .
1 ) . a pet ( 18-fdg ) whole body scan was performed to rule out a metastatic lesion ; the scan showed no remarkable fdg uptake .
we subsequently decided to perform a fine needle aspiration biopsy of the lesion with a 25 g pars plana vitrectomy .
approximately 20% of cytological biopsy results can be errorneous due to inadequate selection of the aspiration site ; therefore , we did not exclusively rule out choroidal melanoma .
however , because of several atypical characteristics , including the presence of cystic portions and amelanotic nonpigmented lesions , and the relatively infrequent occurrence of malignant melanoma in korea , our differential diagnosis contained benign masses such as schwannomas and leiomyomas .
although the patient 's central vision was only mildly affected , the extent of subretinal fluid could have eventually involved the macula .
we decided to surgically excise the lesion to obtain a definitive diagnosis and to prevent further visual deterioration .
the gross specimen was approximately 311 cm in size and contained a cystic portion ( fig .
interrupted sutures were places at the scleral flaps and cryotherapy was performed at the margins of excision .
light microscopy revealed that the tumor was composed of spindle cells with bland palisading nuclei in an antoni a pattern .
intraocular schwannomas are very rare , benign , peripheral nerve neoplasms that usually appear as solitary , amelanotic lesions of the ciliary body or choroid .
although schwannomas are cytologically benign , they may progressively enlarge at a rate similar to or greater than that of choroidal melanomas.1 ophthalmoscopic , mri , and ultrasonographic findings are not helpful in differentiating schwannomas from uveal melanomas.2 in two reported cases of anterior uveal schwannomas , the tumors were noted to transilluminate brightly.3,4 this may be a helpful clinical finding because it is unusual for anterior uveal melanomas to transilluminate in this way .
most previously reported schwannoma cases have been diagnosed after enucleations performed because of the possibility of malignant melanoma.5,6 in some reported cases , early diagnosis was made using anterior chamber biopsy techniques for ciliary body masses.7 other cases have utilized local block excision of ciliary body tumors to confirm the diagnosis of a schwannoma.8 however , it is not known if this can always be done to confirm the presence of a schwannoma . as was illustrated in our case
, it is difficult to differentiate between an amelanotic melanoma , metastatic carcinoma , a choroidal schwannoma , or a medulloepithelioma using ancillary techniques . immunohistochemical staining techniques were not utilized in this case . when clinical features exist that are not typical of melanoma , such as the presence of cystic components or amelanotic nonpigmented lesions ( amelanotic melanoma is very rare in korea ) , we recommend performing an aspiration biopsy or even surgical excision to first rule out the presence of a benign neoplasm before performing enucleation .
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### Summary:
: schwannomas rarely present as intraocular tumors and are often misdiagnosed as malignant melanoma .
we describe a choroidal schwannoma confirmed by sclerouvectomy.a 30-year - old woman presented with a large nonpigmented intraocular mass of the choroid in the right eye and underwent surgical excision by sclerouvectomy .
histologically , the tumor was composed of a mixture of cellular solid components ( antoni a ) and loose myxoid components ( antoni b ) .
the tumor was eventually diagnosed as a schwannoma .
currently available ancillary studies are still of little value in definitively differentiating schwannomas from other choroidal tumors . in the case of atypical findings for a malignant melanoma , a benign neoplasm
should be included in the differential diagnosis .
this patient avoided enucleation by first having the mass excised .
we are unaware of previous reports in which a choroidal schwannoma was diagnosed by surgical excision .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: we report a case of major and early ossifications after synthesis of a fracture dislocation of the shoulder .
a 57-year - old man , right - handed , bipolar schizophrenic , presented after a fall , a fracture of the head and metaphysis of the humerus from the anterior notch of posterior dislocation of the right humerus .
the postoperative period was complicated because of early ossifications and painless stiffness of the shoulder .
the importance of local trauma , the long consultation period , the operative difficulties and the heparin therapy are factors that could have favored the occurrence of ossifications .
ossifications were described for the first time in the shoulder , according to erggelet et al . by smith in 1835 and are rather the consequence of arthroplasty .
they are rare after synthesis of the proximal humerus and compromise little the functional prognosis of the shoulder .
our objective is to report the observation of major and early ossifications after osteosynthesis of a fracture dislocation of the humeral head and make a review of the literature .
mr . k. f. a 57-year - old man , right - handed , bipolar schizophrenic , was the victim of a mechanical fall from standing height . on admission ,
radiography objectified anterior marginal fracture of the distal radius and fracture of the proximal humerus with suspected posterior dislocation associated ( fig .
1 ) . the computed tomography scan confirmed the diagnosis of complex proximal humeral fracture associated with posterior dislocation of the humeral head .
this was a fracture in four fragments of neer associated with posterior dislocation or fracture of the head and metaphysis of the humerus from the anterior notch of posterior dislocation in reference to duparc classification .
( a and b ) scanner of the shoulder : fracture - dislocation , fracture of the glenoid , and anterior notch of the humeral head .
ten days later , the synthesis of the humeral fracture was performed by the extended deltopectoral approach .
the minor tubercle held up , the long biceps broken is resected and undergoes tenodesis in its groove .
the humeral cap united to the metaphyseal - diaphyseal posteromedial beak is reduced then screwed in compression .
we fix again the fragment of the major tubercle fractured by osteosuture and the minor tubercle is screwed into the cephalic notch .
the synthesis is carried out by a small fragment locking compression plate . the incision is closed over a suction drain .
rehabilitation started on the 4 day by assisted passive and active mobilization , joint and muscle maintenance .
three weeks later , the radiography showed ossifications with grade 3 glenoid starting point according to kjaersgaard - andersen et al .
six months later , the shoulder was stiff and painless with active anterior elevation to 70 , active abduction to 45 , external rotation nil and thumb to the right buttock in internal rotation .
the hand - mouth was possible , and the hand - head was the limit .
( a ) to 3 weeks , ( b ) to 6 weeks , ( c ) to 3 months , ( d ) to 6 months .
ossifications after osteosynthesis of the proximal humerus are reported in a proportion of 0 - 10% [ 4 , 7 ] .
males would be predisposed to them [ 3 , 8 ] without any preferred age unlike the hip where the 60s are more exposed .
hereditary and acquired factors , trauma and certain treatments such as heparin therapy might predispose to their formation [ 1 , 3 , 4 , 7 , 9 , 10 , 11 , 12 ] .
the operative difficulties and the intervention beyond 10 days due to the transformation of the hematoma around the fracture may increase the risk [ 1 , 12 ] . we still ignore the possible role of immobilization and rehabilitation in the process of periarticular ossification after surgery .
the intervention was carried out within 10 days and was quite difficult with enlargement of the approach .
moreover , the neurological origin can not be discussed because there is no notion of head trauma or coma .
what is important is to find the indication that adapts to the patient s needs and to obtain the support of the latter for the treatment chosen .
the lesion in our patient is a particular form because of low risk of necrosis according to favard et al . .
in addition , ossifications are more frequent in prosthetic shoulder with rates ranging up to 45% than in synthesis .
pre- and post - operative external radiotherapy and nonsteroidal anti - inflammatory drugs ( nsaids ) are two preventive methods of postoperative ossifications . for the nsaids , indomethacin molecule
is usually used in three daily doses of 25 mg from the 1 operative day to 6 - 12 weeks . according to zouhair
, it was used for the first time in 1975 by dalh in higher doses .
its prescription is limited by its gastrointestinal complications and contra - indication in renally impaired subjects . for radiotherapy , protocols are quite varied . however , in recent studies , two patterns seem to be accepted .
this is , on the one hand , the single preoperative irradiation of seven to eight grays , 4 h before surgery , and on the other hand , the single irradiation at the same dose until the 4 postoperative day .
the major complication of radiotherapy is the occurrence of cancer that single doses seem to minimize .
they prevent the formation of osteoblastic cells by inhibiting the differentiation of mesenchymal cells , thereby preventing the formation of ectopic bone . with very different side effects , external radiotherapy and nsaids are equally effective [ 3 , 8 , 10 , 14 , 15 ] . the choice of one or other of the methods depends on the therapist and takes into account the patient s organism and the therapeutic cost . on this latter criterion
indomethacin was the most accessible means that we should have prescribed in the prevention of the postoperative period .
the biological process of their formation starts as soon as the 16 posttraumatic hour , peaking between 36 and 48 h [ 8 , 10 ] . their diagnosis is accessible on the radiography between 3 and 6 weeks . in our patient , they formed very early , as they were already visible on radiographies 3 weeks postoperatively .
sanders et al . advocate their surgical resection and arthrolysis coupled to a preventive treatment of recurrences when they are aggressive either through pain or by mechanical action on the joint . for plausinis et al .
, surgical treatment is licit , provided that the patient has objective limitations of joint mobility .
our patient presents a fairly limited articular mobility , but he seems to adapt to it from the point of view of the gestures of everyday life .
it is important to know the contributing factors and seek them faced with a complex fracture of the shoulder to institute a prophylactic treatment .
their surgical resection is discussed if they are aggressive and painful and is subject to a morphological assessment and a careful surgical planning to maturity .
even if heterotopic ossifications following osteosynthesis of the proximal humerus are poorly reported , precautions to avoid them must be taken , when the contributing factors exist .
when diagnosed , the surgical resection of heterotopic ossifications needs a careful surgical planning and must respect functional needs of the patient .
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### Summary:
: introduction : ossifications after osteosynthesis of the proximal humerus are poorly described .
we report a case of major and early ossifications after synthesis of a fracture dislocation of the shoulder.case report : a 57-year - old man , right - handed , bipolar schizophrenic , presented after a fall , a fracture of the head and metaphysis of the humerus from the anterior notch of posterior dislocation of the right humerus .
an osteosynthesis was performed after reduction on the tenth posttraumatic day .
the postoperative period was complicated because of early ossifications and painless stiffness of the shoulder.conclusion:the importance of local trauma , the long consultation period , the operative difficulties and the heparin therapy are factors that could have favored the occurrence of ossifications .
preventive treatment could have prevented them or limited their extent .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: carinal resection is associated with high rates of morbidity , making the procedure challenging task for both thoracic surgeons and anesthesiologists ( 1 ) .
it is essential to provide adequate ventilation and oxygenation during airway manipulation without disturbing the surgical field .
this may be accomplished using high frequency jet ventilation ( hfjv ) with a suction catheter ( 2 ) .
this case report describes the successful use of a bronchial blocker of a univent tube ( fuji systems corporation , japan ) for hfjv of one lung in a patient undergoing carinal resection .
he has suffered from cough and sputum for about 3 months before visiting our hospital .
his preoperative electrocardiogram , chest radiography , and laboratory findings were all within normal limits .
the chest computed tomogram revealed a protruding lesion in the posterior portion of the trachea , which was suspected to be malignant ( fig .
anesthesia was induced with etomidate 14 mg , rocuronium 50 mg , and glycopyrrolate 0.2 mg , and was uneventful .
total intravenous anesthesia with propofol ( diprivan , astrazeneca , london , uk ) and remifentanil ( ultiva , glaxosmithkline , london , uk ) using a target controlled infusion pump ( orchestra , fresenius vial , paris , france ) under bispectral index ( a2000xp monitor , aspect , norwood , usa ) monitoring was carried out with 100% o2 .
after the induction , the arterial blood gas analysis under two lung ventilation with a tidal volume of 10 ml / kg and a respiratory rate of 10 breaths / min was acceptable ( table 1 ) .
after the right main bronchus was severed from the trachea , the balloon of the bronchial blocker was deflated and withdrawn up to the trachea .
the tumor on the carina was removed by separating the left main bronchus from the trachea .
the bronchial blocker of a univent tube was immediately advanced without difficulty to the surgical field , and the surgeon introduced the proximal tip of the bronchial blocker into the left main bronchus without ballooning .
the distal tip of the bronchial blocker was connected to a high frequency jet ventilator and hfjv was commenced ( fig .
the jet ventilator delivered 100% o2 with a respiratory rate of 2 hz , a driving pressure of 15 psi ( pound per square inch ) and an inspiratory time of 25% .
under hfjv of the left lung , the left main bronchus was anastomosed end - to - end with the trachea , and the right main bronchus was anastomosed end - to - side with the lateral wall of the trachea .
no adverse events were observed , and both vital signs and o2 saturation ( measured using pulse oximeter ) were maintained without disturbance of the surgical field . after completing the anastomoses ,
we removed the bronchial blocker and ventilated both lungs with the univent tube . the patient was kept in a position of head flexion from the time that construction of anastomoses commenced .
the hfjv and one lung ventilation using bronchial blocker were performed for about 30 min and 155 min , respectively .
the operation took a total of 390 min , at the end of which the patient was extubated after it was confirmed that he was fully awake and showed adequate muscle strength .
the patient was cared in the intensive care unit for 3 days without any complications .
on the eighth day , good healing of anastomoses and good patency of distal bronchi were verified by bronchoscope .
first , the use of cardiopulmonary bypass ( cpb ) is feasible but there is a risk of bleeding after terminating cpb ( 3 , 4 ) .
it is advanced into the left main bronchus for one lung ventilation during separating the right main bronchus from the trachea and withdrawn to the trachea during separating the left main bronchus from the trachea ( 3 , 4 ) . after separating the airway , one or two secondary sterile tubes from surgical field
are inserted at dissected bronchial stump during anastomoses while single lumen endotracheal tube is remained at the trachea ( 3 , 5 ) .
bronchial lumen of double lumen tube is used during anastomoses instead of single lumen tube .
the second and third one have some disadvantages that the tube may interfere the surgical field and repeated insertion and removal of tube may cause stump injury ( 2 ) .
hfjv has been shown to be appropriate in patients with disrupted major airways , including patients with tracheal and bronchial problems ( 3 , 6 - 8 ) . because of the continuous high frequency outflow of gases , hfjv provides the surgeon with an uninterrupted surgical field and lessens the risk of aspiration of blood into the airways distal to the resection ( 2 ) . however , air trapping and barotraumas are potential risks of hfjv ( 9 , 10 ) .
moreover , air trapping can cause catastrophic complication such as tension pneumothorax resulting in cardiopulmonary compromise ( 10 ) . in our case , we chose hfjv instead of differential lung ventilation because the former hinders surgical field less than the latter .
we planned to change to the latter method if we could not achieve adequate ventilation and oxygenation using the former method .
an attempt to ventilate one lung with high frequency positive pressure ventilator with a single plastic catheter was made by el - baz et al .
( 11 ) and simultaneous ventilation of both lungs using two separate catheters , one inserted into each main bronchus , and two ventilators , has been reported by perera et al .
( 2 ) however , they pointed out the flexibility of a plastic catheter could cause the difficulty with manipulation .
we applied a bronchial blocker instead of the previously used suction catheter for hfjv . because of its stiffness , a bronchial blocker may be managed more easily and positioned more stably in the bronchus than a suction catheter , reducing the risks of hypercapnia and hypoxemia . using this system
, we were able to maintain ventilation and oxygenation , and easily and safely alternate between one and two lung ventilation without cardiopulmonary compromise .
a sterile endotracheal tube must be prepared in advance in surgical field so that it can be used immediately at any time when neither ventilation nor oxygenation is accomplished adequately using hfjv .
independent hfjv at each lung is another possible method ( 2 ) . in conclusion ,
a bronchial blocker of a univent tube may be a useful tool for hfjv of one lung during carinal resection , in that this approach may provide more convenience without the need for additional catheter to perform hfjv and more stable position of the stiffer bronchial blocker in univent tube in airway management .
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### Summary:
: airway management during carinal resection should provide adequate ventilation and oxygenation as well as a good surgical field , but without complications such as barotraumas or aspiration .
one method of airway management is high frequency jet ventilation ( hfjv ) of one lung or both lungs .
we describe a patient undergoing carinal resection , who was managed with hfjv of one lung , using a de - ballooned bronchial blocker of a univent tube without cardiopulmonary compromise .
hfjv of one lung using a bronchial blocker of a univent tube is a simple and safe method which does not need additional catheters to perform hfjv and enables the position of the stiffer bronchial blocker more stable in airway when employed during carinal resection .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: obesity is a causative factor in the development of several pathologies including diabetes and other metabolic diseases , cardiovascular diseases , and cancer .
the liver is a major organ regulating glucose and lipid metabolism , and hence it plays a key role in the development of obesity .
nonalcoholic fatty liver disease ( nafld ) is the liver condition most commonly associated with obesity , and it includes a spectrum of liver disorders ranging from steatosis without inflammation to nonalcoholic steatohepatitis , which in turn is a significant cause of more serious diseases such as liver cirrhosis and hepatocellular carcinoma [ 2 , 3 ] .
there is a clear relationship between the degree of obesity and nafld prevalence , with this prevalence being greater than 80% in the presence of morbid obesity .
autophagy is a highly regulated process involved in the turnover of long - lived proteins , cytosolic components , and damaged organelles .
autophagy and endoplasmic reticulum ( er ) stress have recently been considered as key regulators of insulin resistance in peripheral tissues , especially in the liver .
for example , the levels of autophagy indicators have been found to be markedly decreased in the liver of obese mice , while suppression of autophagy resulted in insulin resistance and er stress .
consistent with this , atg7 and atg5 knockout in hepatocytes resulted in the accumulation of lipid droplets and the activation of er stress , accompanied by decreased insulin signaling and impaired glucose tolerance , further supporting the associations among abnormal autophagy , activation of er stress , and insulin resistance in the liver .
several authors have also speculated that autophagy can be beneficial for cells by disposing of damaged cell structures caused by er stress , whereas that defective autophagy may lead to the failure of restoration of cellular homeostasis , including organelle function [ 79 ] , thus exacerbating insulin resistance and possibly other metabolic pathologies associated with obesity .
tauroursodeoxycholic acid ( tudca ) is one of the chemical chaperones that constitute a group of low - molecular - weight compounds known to modulate er function , stabilize protein conformation , improve the folding capacity of the er , and facilitate the trafficking of mutant proteins .
a recent study found that tudca could alleviate the increased er stress seen in obesity and reverse insulin resistance and type 2 diabetes in experimental models [ 11 , 12 ] , suggesting tudca as a promising new regulator for mediating autophagy , er stress , and insulin resistance via certain signaling pathways in the liver of obese mice .
however , the intracellular events responsible for tudca - mediated effects in autophagy , er stress , and insulin resistance remain elusive .
the present study provides evidence that tudca can reverse abnormal autophagy , reduce er stress , and restore insulin sensitivity in the liver of the mice fed the high - fat diet .
these results support the hypothesis that tudca improves the defective hepatic autophagy , activation of er stress , and impaired insulin signaling induced by obesity , thereby offering novel opportunities for the treatment of obesity .
all chemicals used were of analytical grade and were purchased from sigma ( st . louis , mo ) unless otherwise stated .
the following antibodies were used : anti - atg7 , anti - lc3 , anti - p - perk , anti - perk , anti - p - ir , and anti - ir ( cell signaling technology inc . , danvers , ma ) ; anti - g6pase , anti - pck1 , anti - p62 , anti - p - akt , anti - akt , anti - p - eif2 , anti - eif2 , anti - gapdh , and peroxidase goat anti - rabbit igg and peroxidase goat anti - mouse igg from santa cruz biotechnology ( santa cruz biotechnology inc .
this study was carried out in strict accordance with the recommendations in the guide for the care and use of laboratory animals of the national institutes of health .
the protocol was approved by the committee on the ethics of animal experiments of medical school of xi'an jiaotong university ( permit number : 2014 - 009 ) .
all surgery was performed under sodium pentobarbital anesthesia ( 40 mg / kg ) , and all efforts were made to minimize suffering .
c57bl/6j mice ( 4-week - old ) were housed under standard conditions with a 12 h light / dark cycle ( darkness from 7:30 p.m. to 7:30 a.m. ) .
mice were distributed into four groups ( n = 15 per group ) : ( 1 ) vehicle ( normal chow diet , 4% of energy as fat , 3.85 kcal / g , plus 10 l / g of 0.9% nacl i.p . injection ) ; ( 2 ) tudca ( normal chow plus 500 mg / kg of tudca i.p
. injection ) ; ( 3 ) high - fat + vehicle ( diet containing 60% of energy as fat , 5.24 kcal / g , plus 10 l / g of 0.9% nacl i.p . injection ) ; ( 4 ) high - fat + tudca ( high - fat diet plus 500 mg / kg of tudca i.p .
daily injections of tudca or normal saline solution ( vehicle ) were initiated after mice were fed a high - fat diet for 8 weeks .
mice were injected once a day ( 6 p.m. ) intraperitoneally ( i.p . ) with 500 mg / kg of tudca or with vehicle for a further 8 weeks .
additionally , adenovirus carrying atg7 or gfp was delivered into the mice which had been fed a high - fat diet for 8 weeks via orbital venous plexus at a titer of 3 10 vp / mice for a further 10 days . at the end of the study period ,
half of mice in each group were randomly selected and received an intraperitoneal injection of insulin at a dosage of 2 iu / kg ; 15 minutes after the injection , all mice were euthanized and the liver tissue was obtained and stored at 80c for subsequent analysis .
glucose tolerance testing ( gtt ) and insulin tolerance testing ( itt ) were performed as previously described .
superficial gastrocnemius muscles were fixed in 4% paraformaldehyde/2% glutaraldehyde/0.1 m sodium cacodylate ph 7.3 ,
ultrathin sections ( 80 nm ) were stained with aqueous uranyl acetate and lead citrate and examined with a jeol 2000fx transmission electron microscope ( jeol , peabody , ma ) .
sixteen electron micrographs per mouse were digitized and the area and number of clearly distinguishable mitochondria were analyzed using osteomeasure software ( osteometrics , decatur , ga ) .
for quantification of autophagolysosome - like vacuoles , the numbers of autophagolysosomal - like vacuoles were counted in each field and normalized by the surface area .
liver samples ( 5 5 5 mm ) were fixed in paraformaldehyde 4%/1x pbs , washed three times with 1x pbs , and equilibrated in sucrose 20%/1x pbs , before being embedded in oct ( optimal cutting temperature ) compound .
the sections were air - dried , postfixed in formalin , rinsed with 60% isopropanol , stained with oil red o ( in 60% isopropanol ) , and counterstained with hematoxylin .
the oil red o positive area over total area was quantified using quantity one software .
the real - time pcr was applied to dnasei - treated total rna converted into cdna using primers ( superarray bioscience , frederick , md ) and the taq sybr green supermix with rox ( bio - rad , hercules , ca ) on a pcr system ( mx3000 , agilent technologies , santa clara , ca ) .
tissues and cells under various treatments were lysed in lysis buffer containing 25 mm tris hcl ( ph 6.8 ) , 2% sds , 6% glycerol , 1% 2-mercaptoethanol , 2 mm phenylmethylsulfonyl fluoride , 0.2% bromophenol blue , and a protease inhibitor cocktail for 20 min .
the results were analyzed by two - way anova ( two variables ) , one - way anova followed by dunnett 's post hoc test ( one variable , more than two groups ) , or two - tailed student 's t - test ( two groups ) .
given the potential therapeutic relevance of tudca in vivo , we investigated its effects on glucose metabolism and insulin sensitivity in mice with obesity induced by consuming a high - fat diet .
the administration of tudca was initiated after mice consumed a high - fat diet or a normal diet for 8 weeks .
as expected , those mice consuming a high - fat diet had elevated body weight , blood glucose level , and insulin level and developed glucose intolerance and insulin insensitivity as measured by glucose tolerance testing ( gtt ) and insulin tolerance testing ( itt ) ( figures 1(a)1(g ) ) .
the obese mice that were subsequently injected with tudca displayed significantly lower body weight , blood glucose level , and serum insulin level and improved glucose tolerance and insulin sensitivity in comparison with the mice consuming the high - fat diet that were injected with vehicle ( figures 1(a)1(g ) ) .
these findings demonstrate that tudca exerts positive effects on systemic glucose homeostasis and insulin sensitivity in obese mice .
nafld is known to be strongly associated with obesity , which is due to the accumulation of lipids in the liver of mice that consume a high - fat diet , which in turn eventually results in the development of liver steatosis . as shown in figures 2(a)2(c ) , the liver of obese mice injected with tudca was lighter than that of the mice consuming a high - fat diet that were injected with vehicle , and little lipid accumulation was found in liver sections stained with oil red o in the tudca - treated obese mice .
in addition , the rna and protein expressions of tumor necrosis factor ( tnf ) , interleukin- ( il- ) 6 , and il-8 , which are a group of inflammatory factors , were significantly increased in the liver of obese mice but were normalized after injecting tudca ( figures 2(d)2(h ) ) .
this indicates that the inflammation typically associated with liver steatosis was absent in the liver of obese mice treated with tudca . as a major organ regulating glucose and lipid metabolism
, the liver plays a key role in the synthesis and degradation ( oxidation ) of fatty acids . to determine the effects of tudca on hepatic glucose homeostasis
as shown in figures 3(a)3(d ) , the rna and protein levels of glucose-6-phosphatase ( g6pase ) and phosphoenolpyruvate carboxykinase 1 ( pck1 ) were lower in obese mice receiving tudca than in the mice consuming the high - fat diet that were injected with vehicle , indicating that tudca improved hepatic gluconeogenesis in the obese mice .
we therefore also evaluated -oxidation by measuring the release of co2 after administering [ 114 ] oleic acid .
the -oxidation rate and -oxidation - related genes such as peroxisome proliferator - activated receptor ( ppar ) and carnitine palmitoyltransferase 1 ( cpt1 ) were markedly downregulated in mice consuming a high - fat diet , while tudca treatment partially restored the expression levels of -oxidation rate and related genes ( ppar and cpt1 ) in obese mice ( figures 3(e)3(g ) ) .
in contrast , the expression of lipogenic genes ( fas and scd1 ) was upregulated in the liver of obese mice , and those mice injected with tudca showed significant downregulation of lipogenic genes compared to the mice consuming the high - fat diet that were injected with vehicle ( figures 3(h ) and 3(i ) ) . to determine the role of autophagy and er stress in the liver of obese mice , we used western blotting to measure the protein expressions of autophagy and er stress indicators in the liver .
autophagic indicators such as atg7 and light chain 3 ii ( lc3-ii ) were significantly reduced in the liver of obese mice .
in contrast , p62 ( also called sqstm1 , which is involved in aggresome formation and degraded through autophagy ) was increased in the liver of obese mice compared to mice consuming the normal diet ( figures 4(a ) and 4(b ) ) .
however , autophagy indicators such as atg7 and lc3-ii were increased significantly while p62 was decreased in the liver of obese mice injected with tudca by comparison with obese mice injected with vehicle ( figures 4(a ) and 4(b ) ) .
electron microscopy ( em ) examinations of the liver demonstrated a slight reduction in autophagosome / autolysosome formation in obese mice by comparison with mice consuming the normal diet , whereas autophagosome / autolysosome formation was elevated in obese mice injected with tudca compared to obese mice injected with vehicle ( figures 4(c ) and 4(d ) ) , supporting the biochemical alterations in key autophagy molecules .
moreover , we found a significant increase in phosphorylated protein - kinase - like endoplasmic reticulum kinase ( perk ) and eukaryotic initiation factor 2 ( eif2 ) in the liver of obese mice , while the liver of the mice consuming the high - fat diet that were injected with tudca displayed reduced er stress , based on the downregulation of phosphorylated perk and eif2 proteins in comparison to obese mice injected with vehicle ( figures 4(e ) and 4(f ) ) .
we next used western blotting to measure the protein expressions of indicators of insulin receptor signaling .
the liver of mice consuming the high - fat diet and injected with vehicle displayed impaired insulin signaling , as evidenced by insulin - stimulated tyrosine 1162/1163 phosphorylation of insulin receptor ( ir ) subunit and serine 473 phosphorylation of akt compared with mice that consumed the normal diet ( figures 4(g ) and 4(h ) ) . meanwhile ,
insulin signaling was restored in the liver of obese mice injected with tudca , based on the upregulation of phosphorylated ir and akt by comparison with obese mice injected with vehicle ( figures 4(g ) and 4(h ) ) .
this indicates that tudca improved glycolipid metabolism disorder partially by recovering the abnormal autophagy and er stress in the liver of obese mice . to further check
whether the defects in hepatic autophagy in obesity are the cause of insulin resistance in vivo , we restored atg7 via an adenoviral system in the liver of obese mice . after delivering the adenovirus
, we found that the expression of atg7 was significantly elevated in the liver tissue of obese mice compared to vector controls , which resulted in increased autophagosome / autolysosome formation and autophagy indicators , as evident by a higher lc3-ii and a decreased p62 expression level in the liver .
these observations indicated that atg7 and autophagic activity in the liver of obese mice were restored successfully in vivo ( figures 5(a)5(d ) ) .
meanwhile , restoration of atg7 expression resulted in a significant reduction in obesity - induced er stress in the liver of obese mice , as evidenced by decreased levels of phosphorylated perk and eif2 ( figures 5(e ) and 5(f ) ) .
moreover , insulin stimulation in the liver of atg7-expressing obese mice led to markedly enhanced phosphorylated ir and akt levels by comparison with controls ( figures 5(g ) and 5(h ) ) and improved glucose tolerance and insulin sensitivity as measured by gtt and itt ( figures 5(i)5(l ) ) , indicating that the restoration of atg7 rescued the defects in insulin receptor signaling and improved glucose homeostasis .
this study has demonstrated that tudca can improve glycolipid metabolism disorder in the liver of obese mice via the restoration of defective hepatic autophagy , which causes impaired hepatic insulin sensitivity and glucose homeostasis in obesity .
the present results indicate that autophagic dysfunction in the liver may be a relevant mechanism for the two main pathological arms of insulin resistance in obesity : activation of er stress and impaired insulin signaling .
we found that impaired autophagy could contribute to er stress in obese mice and that the restoration of autophagy via treatment with tudca or an adenovirus carrying atg7 resulted in improvements in er stress , insulin signaling , and glycolipid metabolism in vivo .
it is therefore plausible that autophagy can facilitate the elimination or repair of damaged organelles and assist their adaptive responses in restoring metabolic homeostasis .
actually , er stress can induce autophagy to participate in the degradation of unfolded proteins and in the removal of superfluous er membranes .
er function could be impaired if this is not achieved , which creates a vicious cycle resulting in metabolic deterioration , insulin resistance , and type 2 diabetes .
future studies should address whether other mechanisms are also involved in the interaction between autophagy and er stress .
there is a strong relationship between defective autophagy and insulin resistance in obese mice , which has a major effect on glycolipid metabolism .
this study has shown that suppressing autophagy not only results in insulin insensitivity , but also influences hepatic gluconeogenesis and -oxidation in obese mice .
consistent with our results , another study showed that suppressing atg7 expression in the liver tissue of lean mice treated with adenovirus carrying atg7 shrna reduced the autophagy deficiency by 80% , in turn resulting in er stress in the liver tissue of lean mice , as evident by the induction of eif2 and perk phosphorylation and of chop , which are three well - known er stress indicators .
meanwhile , the lean mice treated with adenovirus carrying atg7 shrna developed glucose intolerance and insulin insensitivity as measured by gtt and itt , thereby also demonstrating the importance of autophagy in maintaining glucose homeostasis . in line with our results , recent studies found that tudca administration significantly improved the in vivo responses to insulin in ob / ob mice and that the impaired glucose tolerance seen in vehicle - treated ob / ob mice was corrected upon treatment with tudca via inhibiting the activation of er stress and restoring impaired insulin signaling [ 11 , 12 ] .
however , another study found that the effects of an er protectant on glucose homoeostasis varied in different models of type 2 diabetes : while pba ( a kind of chemical chaperone ) normalized hyperglycemia in ob / ob mice , it did not exert a glucose - lowering effect in goto - kakizaki rats and had no preventive or therapeutic effects on insulin resistance or hyperglycemia in mice treated with hydrocortisone [ 19 , 20 ] .
our results also differ from previous findings in elegant experiments involving the foz / foz mice model , wherein er stress was not a feature associated with insulin resistance and steatohepatitis in the foz / foz model and that altering or protecting er functions had no effect on insulin resistance and liver disease propagation [ 2123 ] .
we therefore consider that at least some of the previous findings could be model - specific .
the progressive liver disease of the hfd - fed foz / foz mice including hepatocellular injury with ballooning , apoptosis , and inflammation and later accompanied by pericellular fibrosis indicates that this model differs from the diet - induced obese mice model and the ob / ob mice model , inferring that tudca may improve liver steatosis in the early stage of nafld . in conclusion
, we found that tudca reversed abnormal autophagy , reduced er stress , and restored insulin sensitivity in the liver of obese mice .
additionally , glycolipid metabolism disorder was improved in the liver of obese mice via the restoration of defective hepatic autophagy .
the results of this study suggest not only a new concept for the treatment of obesity involving autophagy , but also the novel potential of tudca as an effective therapeutic candidate for liver steatosis in the early stage of nafld .
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### Summary:
: objective .
tauroursodeoxycholic acid ( tudca ) has been considered an important regulator of energy metabolism in obesity .
however , the mechanism underlying how tudca is involved in insulin resistance is not fully understood .
we tested the effects of tudca on autophagic dysfunction in obese mice .
material and methods .
500 mg / kg of tudca was injected into obese mice , and metabolic parameters , autophagy markers , and insulin signaling molecular were assessed by western blotting and real - time pcr .
results .
the tudca injections in the obese mice resulted in a reduced body weight gain , lower blood glucose , and improved insulin sensitivity compared with obese mice that were injected with vehicle .
meanwhile ,
tudca treatment not only reversed autophagic dysfunction and endoplasmic reticulum stress , but also improved the impaired insulin signaling in the liver of obese mice .
additionally , the same results obtained with tudca were evident in obese mice treated with the adenoviral atg7 .
conclusions .
we found that tudca reversed abnormal autophagy , reduced er stress , and restored insulin sensitivity in the liver of obese mice and that glycolipid metabolism disorder was also improved via the restoration of defective hepatic autophagy .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: one of the major challenges in caring for men with newly diagnosed prostate cancer ( cap ) is deciding between the many treatment options available .
in fact , short of encouraging participation in clinical trials , it is difficult to define the optimal way to treat localized cap .
this controversy is highlighted by a recent specialist survey on the optimal treatment of a hypothetical patient with localized cap : approximately 29% favored expectant management , 33% favored radiotherapy and 39% chose radical prostatectomy.1 the lack of consensus amongst experts underscores how important it is for men diagnosed with cap to make an informed treatment decision through an objective discussion of the risks and benefits of each approach . in planning a treatment
, the burden typically falls upon the primary diagnosing physician , most commonly the urologist , to discuss with the patient both the choice of intervention and also the concerns of quality of life and longevity .
each treatment often carries unique potential for side effects , variable long term cancer control data .
the long time course of cap intervention outcomes combined with continuing modifications in treatments further complicate the matter .
this article will discuss surgical and nonsurgical options available for the treatment of newly diagnosed localized cap and will highlight some of the advances in each area . for patients with low - volume and low - grade cancer ,
characteristics typically associated with minimal risk of cancer progression , a considerable controversy exists regarding the optimal treatment , including whether to treat at all . finding the right approach for treating high risk cap is also difficult .
however , while monotherapy with radical prostatectomy or radiation may be adequate for some men , there are randomized trials suggesting the need for a multi - modal approach to a more aggressive high risk cancer .
damico and colleagues developed the concept of risk stratification , allowing the classification of men into low- , intermediate- , and high - risk pretreatment groups using a combination of clinical data : prostate - specific antigen ( psa ) , gleason sum , and clinical stage ( table 1).2 the classification was originally developed to estimate the risk of biochemical recurrence following treatment for localized cap and has become an important component in treatment recommendations .
other methods such as the partin tables or kattan nomograms may help guide therapy as they suggest the probability of organ confined disease or if the cancer has spread outside the prostate.3 in the current era of multimodality therapy , this data may help guide treatment choices as well as create realistic expectations on the probability that a single treatment would be successful or if a combined approach is likely to be necessary .
additional patient specific data may aid in determining the aggressiveness of cap and guide recommendations towards the best treatment option .
for example , a rise of psa > 2.0 ng / ml / year before radical prostatectomy was a predictor for cap mortality with a 15% cap mortality rate at 7 years .
no patients with a psa rise of < 2.0 ng / ml / year before surgery died from cap .
this rise of > 2.0 ng / ml / year identifies a group of patients with aggressive and potentially life threatening cap.4 a psa density > 0.15 ng / ml / cm predicted those more likely to receive active treatment after active surveillance ( as).5 these studies suggest that clinical data including psa kinetics may identify patients at elevated risk of disease progression and have a potential role in patient counseling in favor or against specific therapy .
growing in popularity are treatment approaches for localized , asymptomatic cap that do not involve an active intervention : active surveillance and watchful waiting ( ww ) . while similar , there are distinct differences .
watchful waiting is now considered the intent to treat only if , or when , metastases or symptomatic progression appears .
this is usually limited to asymptomatic men with limited life expectancy who often have high grade tumors .
contemporary as protocols aim to treat , with curative intent , those prostate cancers that develop more aggressive features during a period of surveillance and while the cap is still amenable to definitive therapy such as surgery or radiotherapy .
while there is no uniform consensus at present , as generally involves periodic follow up examinations , psa testing and repeat biopsy .
there is a glaring discrepancy between the number of patients diagnosed with cap and the number of men that will die from this disease .
there is a 16% lifetime risk of being diagnosed with cap but only a 3% lifetime risk of dying from it.6 autopsy data shows that despite the presence of cap in one - third of men over age 60 and up to 50% of men over 70 , men in the united states are more likely to die of other comorbid conditions.7 knowledge of the natural history of low - risk cap has also improved .
parker , et al estimated that the 15-year cap specific mortality for conservative management of screen detected cap was 0%2% if the gleason score were < 7.8 data from the recently completed european randomized study of screening for prostate cancer , estimated the lead time associated with psa screening to be 10.3 years and the over diagnosis rate to be 54%.9 these studies highlight the need to identify more definitive factors to distinguish insignificant disease from that which will result in disease specific morbidity and mortality .
one of the challenges of an as protocol is the concern of under sampling and inadequate mapping of the volume of cancer present .
an as study from md anderson cancer center demonstrated very low upstaging at the time of prostatectomy and that all specimens had organ confined tumor .
the transition zone was involved in 29% of unifocal and 71% of multifocal tumors.10 therefore when instituting an as program , a repeat biopsy is usually recommended . despite these findings , van den bergh et al
have shown that delayed intervention within 2 years does not have worse pathologic features compared to patients who undergo immediate radical prostatectomy.11 only a small percentage of patients on as will show signs of disease progression , with an estimated risk of metastasis of < 1% at 2 to 8 years while on surveillance.11,12,13 also , patients with low - risk features ( psa < 10 ng / ml , clinical stage t1t2a , and biopsy gleason sum 6 or less ) who select as have an estimated disease - specific mortality of 1% at 8 years.14 ( see table 2 ) if a patient progresses on an as protocol , early intervention can be offered .
as noted , delayed intervention does not appear to significantly compromise successful outcomes compared to immediate intervention .
several other studies have also demonstrated that low - risk patients who delayed prostatectomy for medians of 6 and 22 months did not experience more adverse pathologic outcomes nor a compromised curability.15,16 patients need to be counseled that as , as the name implies , is an active approach to following cancer and to reassure them that , if their tumor shows any sign of biochemical or pathologic progression during follow - up , intervention can be undertaken safely at that time with minimal added risk . as allows close follow - up of disease and intervention with curative intent triggered by early signs of disease progression .
an accepted definition of suitable candidates for as has been offered by epstein and associates .
based on the hopkins radical prostatectomy experience , preoperative parameters were assessed to predict which patients were likely to harbor cancers with low risk , favorable features . a psa density ( psad )
< 0.15 ng / ml , clinical stage t2a or less , and no biopsy gleason grade 4 or 5 led to a 73% predictive accuracy for favorable disease.17 the as strategy is appropriate for patients who have a life expectancy of less than 10 years and for healthy men 65 years of age or older who have low - volume , low - grade cap as noted by epstein.18 this approach avoids the potential complications of definitive therapy . from a quality of life standpoint , possible adverse effects of as include increased anxiety and patient compliance with repeated prostate biopsies . clinical progression and loss of the opportunity for definitive
patient eligibility into active surveillance , subsequent follow - up , and when to intervene is summarized in figure 1 .
one very clear advantage of radical prostatectomy ( rp ) over other treatment options is precise pathologic staging . as noted
, prostate needle biopsy is not entirely accurate , and therefore non - surgical treatment decisions are often made based on partin or kattan nomograms . at times , these nomograms may under stage the extent of cap . for example , extracapsular extension ( ece ) has been found in up to 15% of patients with presumed low risk organ - confined disease .
in addition , roughly a third of the patients undergoing prostatectomy will experience a significant upgrade of their gleason score ( upstaging of pattern gleason 3 to a diagnosis of pattern gleason 4 or 5).19 following rp , a urologist has clear pathologic data on determining whether the local cancer has been removed , and reassure the patient of a 10-year disease - free survival of well above 90%.20 from a quality of life concern , rp provides the added benefit of an unambiguous interpretation of post - operative psa , so that a patient can often be reasonably assured that his cancer was removed based on an undetectable psa level ( standard psa assay of < 0.2 ng / ml ) . if the patient s disease is upstaged to pathologic t3 or t4 disease after rp , the patient can be counseled on the use of adjuvant radiation therapy in a timely fashion , which has been shown to reduce the risk of metastasis and improve overall survival.21,22 in addition , an inability to achieve an undetectable psa or a psa recurrence following rp ( psa > 0.2 ng / ml ) , allows for early therapy in a salvage or an adjuvant fashion .
boorjian et al showed that adjuvant radiotherapy was associated with significantly improved 10-year biochemical recurrence - free survival , local recurrence - free survival and a decreased need for late hormone therapy.23 also , in patients who received salvage radiation , the risk of local recurrence was decreased and systemic progression and hormonal therapy was delayed . once again , there is a paucity of clinical trials comparing radical to other treatment modalities .
the american college of surgeons oncology group attempted a trial that randomized low risk men between brachytherapy and radical prostatectomy . due to very poor accrual
, the trial was never completed.24 one prospective randomized trial has shown a distinct survival advantage of rp over watchful waiting . at 12 years
, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of cap , and at 12 years , 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases.25 a retrospective cohort analysis compared oncologic cure rates for rp , external beam radiation therapy ( ebrt ) and brachytherapy in low - risk cap .
follow - up of up to 8 years after therapy showed a significant psa failure - free survival advantage for rp over ebrt ( 88% vs 78% ) .
however , the study has been criticized , as the ebrt patients received on average rt dose of 70 gy , which is currently considered a low dose , as dose escalation above this level has shown to improve biochemical disease specific survival.26 regardless , long term outcomes after rp are strong with rp considered by most to be the gold standard in the treatment of localized cap .
a recent multi - institutional study of prostate cancer specific mortality ( pcsm ) after rp at 15 years was 12%.27 results from this study helped establish a nomogram that predicts that only 4% in the modern psa era of contemporary patients , had a predicted 15-year pcsm of greater than 5% .
the authors concluded that few patients will die from cap within 15 years of radical prostatectomy , even with adverse clinical features.28 excellent outcomes after rp have been reported in older men as well . in patients > 70 years of age , 10-year cancer - specific survival rates for low , intermediate and high risk were 99.5% , 97.5% and 94% , respectively.28 postoperative complications in men aged 7074 years were comparable to the younger cohort of men aged 6569 years .
outcome of rp is related much more to the preoperative comorbidity than to age alone.29 a life expectancy > 10 years is the most frequently used benchmark for prostatectomy as definitive therapy for patients with localized cap.30 with its introduction over a decade ago , laparoscopic radical prostatectomy ( lrp ) challenged the standard retropubic and perineal approaches .
lrp has been criticized for its difficult learning curve and its long operating times , allowing only limited centers of excellence to perform this technically demanding operation .
robotic - assisted technology has further allowed the transition of the lrp into the robotically assisted radical prostatectomy rarp.31 now nine years after its approval by the fda , sixty - three percent of tier i hospitals own a davinci surgical system , and the robotic approach accounted for 81% of all prostate - removal procedures in the us last year.32 there are several potential advantages of the robotic approach .
rarp also appears to afford faster convalescence when compared to the rp , while still achieving similar oncologic outcomes.33 although , long term oncologic data is not available yet with rarp , there are numerous series evaluating positive margin rate ( psm ) , an independent predictive factor for biochemical recurrence . in a review of a comparison of matched - pair analysis of open rp versus rarp , no difference in the psm rates between rarp and open rp was noted , and the intermediate biochemical progression - free survival was also not significantly different.34 by contrast with these results , in a cumulative analysis of six comparative studies reporting data on margins , ficarra et al showed a statistically significant difference in favor of rarp over open rp.20 a recent multicenter analysis published in jama reviewed the outcomes of about 2,000 men treated with minimally invasive surgical techniques from 2003 to 2007.35 they were compared with approximately 6,900 men who had standard open radical prostatectomy .
the minimally invasive surgical group had shorter hospital stays and fewer immediate surgical complications compared with open surgery .
however , 18 months post operatively , there was a greater risk of incontinence and erectile dysfunction in comparison to the open surgery group .
when adjusted for both patient and tumor characteristics , men in both groups required similar amounts of adjuvant therapy .
additional long term studies will be necessary if the claims of improved outcomes of minimally invasive surgery for cap will be validated . as more surgeons learn and perform rarp , it is likely that further modifications will be made at improving outcomes .
kaouk et al have described using laparo - endoscopic single - site surgery ( less ) to perform rp .
this technique is performed via a single umbilical incision , with all instruments used through the single site .
this is illustrative of the recent shift in surgery to more even more minimally invasive approaches.36
lastly , a comment should be made concerning the major shift in the management of node positive cap at the time of radical prostatectomy .
although the classic teaching is that the procedure should be abandoned in the setting of lymph node involvement , recent data including prospective clinical trials and retrospective analysis suggests that this is no longer considered proper management.37,38 overall survival may in fact be improved with the removal of both the prostate , lymph nodes and the immediate use of hormonal therapy.38 data from messing et al also suggests that a subset of men with positive nodes may have long term disease free survival without additional hormonal therapy.37 in conclusion , in order to fully counsel a patient about which surgical modality to choose with regards to complications , oncologic and functional outcomes , a large randomized controlled trial comparing open vs laparoscopic vs robotic - assisted prostatectomy are required but none are currently planned .
one factor that has been shown to improve both the cancer control and functional results of radical prostatectomy is the experience of the surgeon , regardless of the technique.39
damico and colleagues developed the concept of risk stratification , allowing the classification of men into low- , intermediate- , and high - risk pretreatment groups using a combination of clinical data : prostate - specific antigen ( psa ) , gleason sum , and clinical stage ( table 1).2 the classification was originally developed to estimate the risk of biochemical recurrence following treatment for localized cap and has become an important component in treatment recommendations .
other methods such as the partin tables or kattan nomograms may help guide therapy as they suggest the probability of organ confined disease or if the cancer has spread outside the prostate.3 in the current era of multimodality therapy , this data may help guide treatment choices as well as create realistic expectations on the probability that a single treatment would be successful or if a combined approach is likely to be necessary .
additional patient specific data may aid in determining the aggressiveness of cap and guide recommendations towards the best treatment option .
for example , a rise of psa > 2.0 ng / ml / year before radical prostatectomy was a predictor for cap mortality with a 15% cap mortality rate at 7 years .
no patients with a psa rise of < 2.0 ng / ml / year before surgery died from cap .
this rise of > 2.0 ng / ml / year identifies a group of patients with aggressive and potentially life threatening cap.4 a psa density > 0.15 ng / ml / cm predicted those more likely to receive active treatment after active surveillance ( as).5 these studies suggest that clinical data including psa kinetics may identify patients at elevated risk of disease progression and have a potential role in patient counseling in favor or against specific therapy .
growing in popularity are treatment approaches for localized , asymptomatic cap that do not involve an active intervention : active surveillance and watchful waiting ( ww ) . while similar , there are distinct differences .
watchful waiting is now considered the intent to treat only if , or when , metastases or symptomatic progression appears .
this is usually limited to asymptomatic men with limited life expectancy who often have high grade tumors .
contemporary as protocols aim to treat , with curative intent , those prostate cancers that develop more aggressive features during a period of surveillance and while the cap is still amenable to definitive therapy such as surgery or radiotherapy . while there is no uniform consensus at present , as generally involves periodic follow up examinations , psa testing and repeat biopsy
there is a glaring discrepancy between the number of patients diagnosed with cap and the number of men that will die from this disease .
there is a 16% lifetime risk of being diagnosed with cap but only a 3% lifetime risk of dying from it.6 autopsy data shows that despite the presence of cap in one - third of men over age 60 and up to 50% of men over 70 , men in the united states are more likely to die of other comorbid conditions.7 knowledge of the natural history of low - risk cap has also improved .
parker , et al estimated that the 15-year cap specific mortality for conservative management of screen detected cap was 0%2% if the gleason score were < 7.8 data from the recently completed european randomized study of screening for prostate cancer , estimated the lead time associated with psa screening to be 10.3 years and the over diagnosis rate to be
54%.9 these studies highlight the need to identify more definitive factors to distinguish insignificant disease from that which will result in disease specific morbidity and mortality .
one of the challenges of an as protocol is the concern of under sampling and inadequate mapping of the volume of cancer present .
an as study from md anderson cancer center demonstrated very low upstaging at the time of prostatectomy and that all specimens had organ confined tumor .
the transition zone was involved in 29% of unifocal and 71% of multifocal tumors.10 therefore when instituting an as program , a repeat biopsy is usually recommended . despite these findings , van den bergh et al
have shown that delayed intervention within 2 years does not have worse pathologic features compared to patients who undergo immediate radical prostatectomy.11 only a small percentage of patients on as will show signs of disease progression , with an estimated risk of metastasis of < 1% at 2 to 8 years while on surveillance.11,12,13 also , patients with low - risk features ( psa < 10 ng / ml , clinical stage t1t2a , and biopsy gleason sum 6 or less ) who select as have an estimated disease - specific mortality of 1% at 8 years.14 ( see table 2 ) if a patient progresses on an as protocol , early intervention can be offered .
as noted , delayed intervention does not appear to significantly compromise successful outcomes compared to immediate intervention .
several other studies have also demonstrated that low - risk patients who delayed prostatectomy for medians of 6 and 22 months did not experience more adverse pathologic outcomes nor a compromised curability.15,16 patients need to be counseled that as , as the name implies , is an active approach to following cancer and to reassure them that , if their tumor shows any sign of biochemical or pathologic progression during follow - up , intervention can be undertaken safely at that time with minimal added risk . as allows close follow - up of disease and intervention with curative intent triggered by early signs of disease progression .
an accepted definition of suitable candidates for as has been offered by epstein and associates .
based on the hopkins radical prostatectomy experience , preoperative parameters were assessed to predict which patients were likely to harbor cancers with low risk , favorable features . a psa density ( psad ) < 0.15 ng / ml , clinical stage t2a or less , and no biopsy gleason grade 4 or 5 led to a 73% predictive accuracy for favorable disease.17 the as strategy is appropriate for patients who have a life expectancy of less than 10 years and for healthy men 65 years of age or older who have low - volume , low - grade cap as noted by epstein.18 this approach avoids the potential complications of definitive therapy . from a quality of life standpoint , possible adverse effects of as include increased anxiety and patient compliance with repeated prostate biopsies .
clinical progression and loss of the opportunity for definitive cure , while rare in properly selected men , remains a concern .
patient eligibility into active surveillance , subsequent follow - up , and when to intervene is summarized in figure 1 .
one very clear advantage of radical prostatectomy ( rp ) over other treatment options is precise pathologic staging .
as noted , prostate needle biopsy is not entirely accurate , and therefore non - surgical treatment decisions are often made based on partin or kattan nomograms . at times , these nomograms may under stage the extent of cap . for example , extracapsular extension ( ece ) has been found in up to 15% of patients with presumed low risk organ - confined disease .
in addition , roughly a third of the patients undergoing prostatectomy will experience a significant upgrade of their gleason score ( upstaging of pattern gleason 3 to a diagnosis of pattern gleason 4 or 5).19 following rp , a urologist has clear pathologic data on determining whether the local cancer has been removed , and reassure the patient of a 10-year disease - free survival of well above 90%.20 from a quality of life concern , rp provides the added benefit of an unambiguous interpretation of post - operative psa , so that a patient can often be reasonably assured that his cancer was removed based on an undetectable psa level ( standard psa assay of < 0.2 ng / ml ) . if the patient s disease is upstaged to pathologic t3 or t4 disease after rp , the patient can be counseled on the use of adjuvant radiation therapy in a timely fashion , which has been shown to reduce the risk of metastasis and improve overall survival.21,22 in addition , an inability to achieve an undetectable psa or a psa recurrence following rp ( psa > 0.2 ng / ml ) , allows for early therapy in a salvage or an adjuvant fashion .
boorjian et al showed that adjuvant radiotherapy was associated with significantly improved 10-year biochemical recurrence - free survival , local recurrence - free survival and a decreased need for late hormone therapy.23 also , in patients who received salvage radiation , the risk of local recurrence was decreased and systemic progression and hormonal therapy was delayed .
once again , there is a paucity of clinical trials comparing radical to other treatment modalities . the american college of surgeons oncology group attempted a trial that randomized low risk men between brachytherapy and radical prostatectomy . due to very poor accrual
, the trial was never completed.24 one prospective randomized trial has shown a distinct survival advantage of rp over watchful waiting . at 12 years
, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of cap , and at 12 years , 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases.25 a retrospective cohort analysis compared oncologic cure rates for rp , external beam radiation therapy ( ebrt ) and brachytherapy in low - risk cap .
follow - up of up to 8 years after therapy showed a significant psa failure - free survival advantage for rp over ebrt ( 88% vs 78% ) .
however , the study has been criticized , as the ebrt patients received on average rt dose of 70 gy , which is currently considered a low dose , as dose escalation above this level has shown to improve biochemical disease specific survival.26 regardless , long term outcomes after rp are strong with rp considered by most to be the gold standard in the treatment of localized cap .
a recent multi - institutional study of prostate cancer specific mortality ( pcsm ) after rp at 15 years was 12%.27 results from this study helped establish a nomogram that predicts that only 4% in the modern psa era of contemporary patients , had a predicted 15-year pcsm of greater than 5% .
the authors concluded that few patients will die from cap within 15 years of radical prostatectomy , even with adverse clinical features.28 excellent outcomes after rp have been reported in older men as well . in patients > 70 years of age , 10-year cancer - specific survival rates for low , intermediate and high risk were 99.5% , 97.5% and 94% , respectively.28
postoperative complications in men aged 7074 years were comparable to the younger cohort of men aged 6569 years .
outcome of rp is related much more to the preoperative comorbidity than to age alone.29 a life expectancy > 10 years is the most frequently used benchmark for prostatectomy as definitive therapy for patients with localized cap.30 with its introduction over a decade ago , laparoscopic radical prostatectomy ( lrp ) challenged the standard retropubic and perineal approaches .
lrp has been criticized for its difficult learning curve and its long operating times , allowing only limited centers of excellence to perform this technically demanding operation .
robotic - assisted technology has further allowed the transition of the lrp into the robotically assisted radical prostatectomy rarp.31 now nine years after its approval by the fda , sixty - three percent of tier i hospitals own a davinci surgical system , and the robotic approach accounted for 81% of all prostate - removal procedures in the us last year.32 there are several potential advantages of the robotic approach .
rarp also appears to afford faster convalescence when compared to the rp , while still achieving similar oncologic outcomes.33 although , long term oncologic data is not available yet with rarp , there are numerous series evaluating positive margin rate ( psm ) , an independent predictive factor for biochemical recurrence . in a review of a comparison of matched - pair analysis of open rp versus rarp
, no difference in the psm rates between rarp and open rp was noted , and the intermediate biochemical progression - free survival was also not significantly different.34 by contrast with these results , in a cumulative analysis of six comparative studies reporting data on margins , ficarra et al showed a statistically significant difference in favor of rarp over open rp.20 a recent multicenter analysis published in jama reviewed the outcomes of about 2,000 men treated with minimally invasive surgical techniques from 2003 to 2007.35 they were compared with approximately 6,900 men who had standard open radical prostatectomy .
the minimally invasive surgical group had shorter hospital stays and fewer immediate surgical complications compared with open surgery .
18 months post operatively , there was a greater risk of incontinence and erectile dysfunction in comparison to the open surgery group .
when adjusted for both patient and tumor characteristics , men in both groups required similar amounts of adjuvant therapy .
additional long term studies will be necessary if the claims of improved outcomes of minimally invasive surgery for cap will be validated . as more surgeons learn and perform rarp , it is likely that further modifications will be made at improving outcomes .
kaouk et al have described using laparo - endoscopic single - site surgery ( less ) to perform rp .
this technique is performed via a single umbilical incision , with all instruments used through the single site .
this is illustrative of the recent shift in surgery to more even more minimally invasive approaches.36
lastly , a comment should be made concerning the major shift in the management of node positive cap at the time of radical prostatectomy .
although the classic teaching is that the procedure should be abandoned in the setting of lymph node involvement , recent data including prospective clinical trials and retrospective analysis suggests that this is no longer considered proper management.37,38 overall survival may in fact be improved with the removal of both the prostate , lymph nodes and the immediate use of hormonal therapy.38 data from messing et al also suggests that a subset of men with positive nodes may have long term disease free survival without additional hormonal therapy.37 in conclusion , in order to fully counsel a patient about which surgical modality to choose with regards to complications , oncologic and functional outcomes , a large randomized controlled trial comparing open vs laparoscopic vs robotic - assisted prostatectomy are required but none are currently planned .
one factor that has been shown to improve both the cancer control and functional results of radical prostatectomy is the experience of the surgeon , regardless of the technique.39
the field of radiation oncology for the treatment of localized cap is constantly being reevaluated to optimize delivery and optimize cancer control but also to minimize damage to surrounding normal tissues .
development of better cancer - targeting therapies in the form of three - dimensional conformal radiation therapy ( 3dcrt ) and intensity - modulated radiotherapy ( imrt ) and the use of image guided ( igrt ) techniques such as fiducial markers theoretically decrease the side effects seen with ebrt.40 similarly , during this same time frame , other advances in the field have supported the use of higher doses of radiation for organ - confined disease and the use of androgen deprivation therapy ( adt ) concurrent with ebrt with higher risk tumors .
data from retrospective analyses suggest that the noted technical improvements translate into decreased rates of local failure and distant metastases , as well as better overall survival .
an example of these findings is shown in an analysis of 1,465 men treated in four randomized trials conducted by the radiation therapy oncology group ( rtog ) .
radiation doses > 66 gy were associated with a 29% lower relative risk of death from cap compared to lower doses.41 it is clear that for the treatment of intermediate to high - risk cap with radiotherapy high doses are needed for high tumor control . in randomized studies of low dose compared to high dose , a better biochemical control , expressed as psa - control , was found in favor of the high - dose groups.42,43 multiple trials have demonstrated that doses of 78 to 80 gy are needed to obtain definitive therapy for cap , which is a great increase from the 70 to 74 gy that was previously the standard of care.43,44 as the technology to deliver more accurate rt develops even higher radiation doses are being considered .
the rtog 0126 , a large randomized dose escalation trial to look at doses in excess of 81 gy , recently completed accrual.45 given the fact that dose escalation of rt has shown a survival benefit for men , there is optimism that further dose escalation may benefit patients with high - risk localized disease .
although it is feasible to administer doses in excess of 81 gy using these techniques , whether doses above 78 gy provide added benefit for men with low - risk disease remains controversial .
the use of rt in combination with adt for cap patients is clearly supported by multiple randomized trials.46,47 however , several questions remain unanswered , including the optimal sequencing and duration of androgen deprivation . in the rtog 8610 , 471 men were randomly assigned to rt with or without zoladex plus flutamide .
adt was administered for 2 months before and 2 months during rt . at a median follow - up of 12.5 years
, adt significantly decreased the rates of disease - specific mortality , distant metastases , and biochemical failure ( 23% vs 36% , 35% vs 47% , and 65% vs 80% with and without adt , respectively ) while increasing the rate of disease - free survival ( 11% vs 3%).48 damico et al reported a survival benefit with neoadjuvant ( nadt ) of 6 months in patients with intermediate risk cap.47 the major endpoint of the study was overall survival and the time to psa > 1.0 ng / ml and an increase in the psa by > 0.2 ng / ml on two consecutive occasions .
patients randomized to receive nadt had a significantly improvement in overall survival , cause specific survival and survival without salvage adt .
one drawback in these studies is that the dose of rt delivered would be considered suboptimal by today s standards , and therefore would adt provide benefit in current patients receiving higher radiation doses ?
therefore , some investigators have argued that if adequate local doses are given adt may not be required.49 another area of advancement has been with the use of prostate markers to allow for an accurate guide in delivering rt .
our experience from the kimmel cancer center has shown that placement of gold fiducial markers can easily be placed in an outpatient setting , more importantly , these markers allowed accurate delivery of rt while limiting acute toxicity.40 investigators at the university of california san francisco ( ucsf ) have shown that prostate markers provide an accurate guide such that treatments can be delivered within 2 mm , without the risk of seed migration.50 this progression has allowed the development in the field of image guided radiotherapy ( igrt ) and 4d crt .
fourth dimension in this setting refers to the impact of time on the position and/or shape of the target volume allowing tight margins that can be placed around the target tissues .
monotherapy with radioactive seeds is preferably reserved for patients with low - risk disease , many groups are combining seed brachytherapy with ebrt for patients with intermediate to high - risk disease .
the goal of this approach is to aim at higher tumor dose and better coverage of the target volume because of presumed extension of cancer cells beyond the prostate boundaries .
the advantage of multi - modal rt is also seen in high - dose - rate brachytherapy in conjunction with imrt over imrt alone .
the 3-year biochemical disease - free survival rates in high - risk patients treated with imrt alone was 67% as opposed to 93% in the high dose rate ( hdr ) brachytherapy and imrt group.51 the same benefit has also been shown in intermediate and high - risk patients who received 3dcrt with a single hdr brachytherapy implant over 3dcrt . the 5- and
7-year biochemical control rates for intermediate were 82.5% and 80.3% , respectively , for the combined group and 81.3% and 71% , respectively , for 3dcrt alone .
in addition , there was minimal toxicity in patients with unfavorable cap who underwent combination therapy.52 stereotactic body radiotherapy is being rapidly deployed in the treatment of localized cap .
the prostate target is usually localized in space using an external frame of reference which can be related to the treatment machine .
stereotactic positioning can be precise and as a result , stereotactic radiotherapy commonly employs higher doses per fraction and fewer fractions ( hypofractionation ) than conventional radiation .
stereotactic body radiotherapy typically consists of a total course of therapy comprising five or fewer treatments .
many commercially available systems are currently used that typically incorporate some type of sophisticated image guidance and most also have patient immobilization devices ( eg , cyberknife robotic radiosurgery system , accuray , inc . , sunnyvale , ca and many others ) .
the utility of hypofractionation in the treatment of cap is not conclusive and awaits the results of ongoing randomized trials to confirm any of the hypofractionation advantages over routinely administered ( normofractionated ) radiotherapy.53 proton beam , or charged - particle beam , radiotherapy for cap was first used at massachusetts general hospital in the 1970s , but recently has received increased attention in press for the treatment of cap . in theory ,
proton particles have better depth penetration than traditional photon or electron beam therapy and therefore , should deposit most of their energy near the tumor site rather than at the skin level .
in addition , very little of the prescribed dose travels past the site of tumor , whereas , photons continue to deposit the dose of radiation in normal tissues beyond the tumor .
this phenomenon is known as bragg peak , where the pattern of delivery is localized with a sharp drop off past the projected site of delivery.54 in a phase ii trial comparing the dosimetric characteristics of protons and imrt , vargas et al showed a decrease of 59% and 35% of the rectal and bladder dose , respectively.54 proton beam therapy is expected to deliver biologically equivalent doses more precisely and with less radiation - induced morbidity than conventional photon radiation therapy .
it is unclear whether the claimed high precision in dose delivery is beneficial , let alone necessary , for the treatment of cap when compared to contemporary radiation techniques .
cryotherapy has been used for surgical lesions since the 1850 s , when it was first introduced by dr james arnot.55 the american urologic association ( aua ) recognized cryotherapy first in 1996 for the treatment of cap .
although , only recently , the aua has accepted cryosurgery as a primary modality in treatment of localized cap , published in best practice statement on cryosurgery for the treatment of localized prostate cancer.56 cryotherapy is currently indicated in low - risk patients as an alternative to prostatectomy or radiotherapy , in higher - surgical - risk patients as primary therapy , and in patients who have not responded to radiation therapy as a salvage procedure .
historically , cryosurgery was associated with relatively high risks , such as urethral sloughing , rectal injury and urinary fistulas .
a significant development was the introduction of cryotherapy probes that use argon gas rather than liquid nitrogen .
argon rapidly cools the probe tip to 187c ( 304.6f ) and can be rapidly exchanged with helium at 67c ( 152.6f ) for an active thawing phase , producing a faster response to operator input and significantly speeding 2-cycle treatment.57 moreover , argon - based probes have a much smaller diameter , thus permitting direct , sharp transperineal insertion , facilitating more conformal cryosurgery . gland volume is an important factor : larger prostates may be more difficult to treat because of the difficulty in achieving a uniformly cold temperature throughout the gland .
neoadjuvant therapy for downsizing the gland may be considered in such patients , although there are no published studies on this topic . with the newer generation of cryoprobe needles , urethral and rectal warming catheters , real - time temperature monitoring ,
the rates of complications have been drastically improved . in a review of current literature ,
the rates of incontinence , urethral fistula , and urethral sloughing are reported to be 2%7% , 0%2% , and 2%6% , respectively.58,59,60 han et al reported good outcomes in a series of 106 patients with only 3% incontinence requiring pads ,
5% urge incontinence requiring no pads , 3.3% transient urinary retention , and 2.6% rectal pain.59 this demonstrates the relatively low complication profile of cryotherapy .
short of any head to head trials , in terms of being minimally invasive , the side - effect profile of cryoablation is comparable to ebrt and brachytherapy . moreover , in a study by hubosky et al at 18-month follow - up , cryosurgery patients had better urinary function compared with a series of brachytherapy patients , and this improvement was still present at 24 months.58 robinson et al presented quality of life ( qol ) outcomes from a single institution randomized trial comparing ebrt with cryotherapy for localized cap .
cryoablation patients reported lower urinary function scores ( 69.4 vs 90.7 ) , similar bowel function , and lower sexual function scores ( 7.2 vs 32.9 ) . at 36 months
ebrt men had slightly lower urinary function scores but no difference in bowel function scores .
the cryoablation patients had lower sexual function scores at 36 months ( 16 vs 36.7).61 one major downside to cryosurgery is the high risk of erectile dysfunction .
this occurs primarily because the effective kill zone to ensure adequate prostatic coverage extends to the periprostatic tissue , which includes the neurovascular bundle , necessary for erection .
hubosky et al reported that only 20% of the entire cohort was able return to baseline sexual function at 12-month followup.58 this is similar to other published studies that report the incidence of ed after total gland cryosurgery , to be nearly 90 percent of patients at 1 year of follow - up.59,60 therefore , patients for whom preservation of erectile function is a high priority are probably less - than - ideal candidates .
one of the drawbacks of cryotherapy , similar to rt , is that post intervention monitoring of recurrent disease or failure of treatment can be difficult .
most commonly , similar to post rt patients , psa is followed but the definition of biochemical failure is not universally defined .
the two definitions , astro criteria and the phoenix criteria , described in ebrt data are implemented in the cryotherapy literature .
others have used a strict psa cutoff . however , the nadir psa cutpoint that should represent the absence of cancer remains uncertain .
long - term retrospective data from cohen et al reported 10-year biochemical disease free survival ( bdfs ) of 56.01% according astro criteria and 62.36% using the phoenix criteria ( nadir plus 2 ng / ml ) . when stratified by risk groups ( low , medium , and high ) , bdfs using the phoenix criteria was 80.56% , 74.16% , and 45.54% ,
respectively.62 jones et al recently published the largest series of patients undergoing whole gland cryotherapy as primary treatment , all of whom were included in the cryo on - line database ( cold ) registry the largest cohort published regarding whole gland cryotherapy for localized cap .
the median pretreatment psa level was 6.8 ng / ml ( mean , 9.6 8.6 ng / ml ) , and various gleason scores were represented ( median , 7 ) .
the mean follow - up period was 24.4 25.9 months . applying the phoenix definition to the data from men accumulated in that registry , 91 percent of men with low - risk , 78 percent of men with intermediate - risk , and 62 percent of men with high - risk , localized cap experienced biochemical recurrence.63
the cold registry is a multicenter collaboration , was developed and incorporates data from four academic medical centers and 34 community urologists , so that control of the generation of cryosystem used and treatment protocols varied among different centers .
this inherently weakens the data as there is no standardization in delivering the treatment modality . more importantly
, 49.5% of these men received hormone therapy prior to cryoablation , perhaps giving a false undetectable psa.63 regardless , published data from the cold registry report 5-year bdfs of 77.1% using the astro criteria and 72.9% using the phoenix criteria . using risk stratification ,
the 5-year bdfs was 84.7% , 73.4% , and 75.3% ( astro ) and 91.1% , 78.5% , and 62.2% ( phoenix ) for low- , medium- , and high - risk groups , respectively.63
as discussed earlier , incidence of ed is high in patients undergoing whole gland ablation .
although still in experimental stages , focal cryoablation , or commonly coined term the male lumpectomy of the prostate is developing as a potential option for patients with unilateral , low - risk cancer .
the goal behind focal therapy is to allow effective tumor ablation while sparing the neurovascular bundle .
onik et al reported their result of forty - eight patients with a mean follow - up of 4.5 years , who had focal cryoablation .
forty - five of 48 patients ( 94% ) had stable psas , using the astro criteria , with no evidence for cancer .
twenty - four patients who underwent routine biopsy had no evidence of disease.64 focal cryoablation may therefore have a potential role for low - risk patients with unilateral disease on biopsy who are desirous of preserving erectile function .
a study by ward et al reviewed prostate specimens with unilateral positive prostate biopsy to characterize the location , volume and grade of each tumor focus , in determining if focal therapy templates could eradicate tumor burden . despite only 17% of patients having a single focus of cancer , hemi - prostate treatment templates that would have been used in focal therapy would have successfully treated all clinically significant prostate tumor foci in 81% of patients .
most out - of - field cancers were clinically insignificant tumors not identified by prostate biopsy ( low - volume , 0.5 ml ; and low grade , gleason score < or = 6).65 contemporary results of focal cryotherapy demonstrate high - potency rates of approximately 90%.64,66 high intensity focused ultrasound ( hifu ) is approved in the eu and in canada but is not commercially available in the us .
high dose rate radiation ( hdr ) employs temporary prostate implantation that requires a short hospital stay .
is limited on this approach and the number of facilities that perform prostate cancer hdr in the us is limited .
however , the benefit of hormonal monotherapy ( lhrh analogue alone , lhrh in combination with antiandrogens or with antiandrogens alone ) in localized cancer is not clear and can be associated with severe toxicities in some men.67 treatment guidelines do not recommend its use as a first - line therapy at earlier disease stages . despite limited evidence to date for the impact on clinical outcomes , the use hormonal monotherapy therapy in patients with localized or locally advanced cap has increased in many countries , most notably japan.68 hormonal therapy , either using lhrh analogues alone or in combination with antiandrogens is currently controversial in localized cap as a monotherapy and should not be used routinely until additional data is available .
high intensity focused ultrasound ( hifu ) is approved in the eu and in canada but is not commercially available in the us . high dose rate radiation ( hdr ) employs temporary prostate implantation that requires a short hospital stay .
is limited on this approach and the number of facilities that perform prostate cancer hdr in the us is limited .
however , the benefit of hormonal monotherapy ( lhrh analogue alone , lhrh in combination with antiandrogens or with antiandrogens alone ) in localized cancer is not clear and can be associated with severe toxicities in some men.67 treatment guidelines do not recommend its use as a first - line therapy at earlier disease stages . despite limited evidence to date for the impact on clinical outcomes , the use hormonal monotherapy therapy in patients with localized or locally advanced cap has increased in many countries , most notably japan.68 hormonal therapy , either using lhrh analogues alone or in combination with antiandrogens is currently controversial in localized cap as a monotherapy and should not be used routinely until additional data is available .
as illustrated in this paper , there are numerous treatment options available for the management of localized cap . at the present time
the limited availability of head to head randomized trials makes picking the right treatment option more difficult .
the trend for patients seeking multidisciplinary clinical consultations are often facilitated at cancer centers with a commitment to these patient centric efforts.69 as noted by the aua , various factors must be taken into consideration when making a collective decision in the man with clinically localized cap.70 consideration for enrolling the patient in a randomized trial is always a top priority as we move the care of our patients ahead .
the comparisons of the risks and benefits of treatments for localized cap and aua recommendations are summarized in tables 3 and 4 .
quality of life factors such as potency , urinary , or rectal bother should play an important role in any patient s treatment decision and a detailed discussion of these specific issues is beyond the scope of this paper . a recent publication by sanda
, et al provides excellent objective data on the potential major quality of life effects of primary cap treatment.71 outcomes for men with low risk disease treated by radiation or surgery appear to have similar cancer outcomes out to at least 1015 years . perhaps , the younger patient with greater than ten year life expectancy may benefit from accurate staging and an undetectable psa offered by rp . with high risk disease , adjuvant radiation administered as part of a multimodality treatment plan following
radiation combined with hormonal therapy is currently considered standard of care for those men with high risk features who opt for external beam radiation therapy .
finally , a suitable patient for as may choose this less invasive route to monitor his cap .
in the end , the treatment of cap needs to be individualized for each patient , after weighing in the current information available to each patient s expectations , overall health and quality of life .
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### Summary:
: widespread screening with prostate - specific antigen ( psa ) has led to a significant increase in the detection of early stage , clinically localized prostate cancer ( cap ) .
various treatment options for localized cap are discussed in this review article including active surveillance , radical prostatectomy , radiation therapy , and cyrotherapy .
the paucity of high - level evidence adds a considerable amount of controversy when choosing the optimal intervention , for both the treating physician and the patient .
the long time course of cap intervention outcomes , combined with continuing modifications in treatments , further complicate the matter . lacking randomized trials that compare treatment options , this review article attempts to summarize the different treatment options and associated side - effects , including effects on health - related quality of life , from current published literature .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: full term newborn babies tend to be hypermetropic at birth [ 1 , 2 ] whereas preterm babies have been found to be either hypermetropic or myopic ; even very preterm babies with severe rop are slightly hyperopic at birth [ 35 ] . to date , refractive status at birth and its relation to birth weight ( bw ) , birth length , head circumference , and gestational age ( ga ) have been studied and refractive error has been reported to correlate better with birth weight more than it did with ga .
on the one hand , another study on preterms from 2 weeks to 6 months of age reported no correlation of refractive error to ga or bw .
babies born prematurely , with low birth weight or with retinopathy of prematurity , usually develop myopia [ 3 , 8 ] .
numerous studies have been carried out to find out the relations of refractive error and ocular biometric measures with birth parameters in preterm or low birth weight child at birth and in the long term [ 6 , 913 ] .
a few studies investigated the association of birth parameters and refraction or biometric parameters in the general population of children [ 1416 ] . in this cohort study , we aimed to investigate the association of birth parameters ( bw , ga , and appropriateness for ga ) with refractive status in different age groups of caucasian children .
this cross - sectional study included children aged 4 to 17 years who had been examined at the department of ophthalmology in 2013 .
the children with neurologic sequela such as mental retardation and cerebral palsy and those who had ocular diseases such as glaucoma , cataract , and history of treatment for retinopathy of prematurity and those who had undergone any ocular surgery were excluded .
written informed consent was taken from the parents of the children who were involved in the study .
the study was in accordance with the standards of the local ethics committee and conformed to the tenets of the declaration of helsinki .
the parents of the children provided the information regarding bw and ga based on the child 's hospital delivery record .
all children underwent complete ophthalmologic examination including measurement of snellen visual acuity as decimals , refraction , and dilated funduscopy .
after 30 minutes , the cycloplegic refraction measurement was performed with an autorefractor ( topcon a6300 , topcon corporation , tokyo , japan ) .
the average value was recorded and the refraction was expressed as spherical equivalent ( se ) .
the children were divided into three groups according to their refractive status : emmetropia , myopia , and hyperopia .
emmetropia was defined between 0.5 and + 0.5 d , myopia as less than 0.5 , and hyperopia as more than + 0.5 , respectively .
they were further divided into age groups : 47 , 8 - 9 , 1012 , and > 13 years .
they were also divided into small for gestational age ( sga ) , appropriate for gestational age ( aga ) , and large for gestational age ( lga ) according to their birth weights for the gestational age .
the international standardized average fetal growth tables were considered to calculate appropriateness for gestational age . for statistical analysis ,
multinominal logistic regression analysis was used to evaluate the effect of bw , ga , and age at examination on refractive error .
the mean age of the children was 9.2 2.8 ( age range 417 years ) .
of 282 children , 155 were male ( 55% ) and 127 were female ( 45% ) .
the mean se was + 0.3 1.7 ( range : ( 10.0)(+10.0 ) diopters ) and the mean snellen visual acuity was 0.9 0.1 ( 0.21.0 ) .
the mean bw and ga were 2681.1 930.8 grams ( 7505000 grams ) and 37.2 3.7 weeks ( 2542 weeks ) .
the mean age , bw , and ga distribution according to age groups and refractive status are given in table 1 . according to multinominal logistic regression analysis ,
children with myopia were more likely to have higher bws than emmetropic children ( or : 1.0 , 95% ci : 1.0001.001 , and p = 0.028 ) .
myopia is also more likely to be found in older age groups than emmetropia ( or : 1.119 , 95% ci : 1.271.219 , and p = 0.010 ) and hypermetropia ( or : 1.39 , 95% ci : 1.2361.565 , and p < 0.0001 ) .
number of aga , sga , and lga children and number of children under and over 2500 grams , according to refractive states in each age group , are given in table 2 .
emmetropic children aged between 47 and 8 - 9 years of age had significantly lower bws under 2500 grams whereas myopic children aged between 4 and 7 years of age had significantly higher bws over 2500 grams .
the hypermetropes were found to be significantly sga between 13 and 17 years of age .
birth weight , as one of the indicators of intrauterine development , may be associated with several systemic disorders in the long term .
since it also affects the eye size , it may have an impact on refractive status or development of refractive error along with gestational age .
likewise , another parameter , appropriateness for gestational age , as sga , aga , and lga may have an impact on refraction .
therefore , in our study , we also grouped the children as sga , aga , or lga .
we found that children with myopia were more likely to have higher bws than emmetropic children . also , when the cut - off for birth weight is chosen as 2500 grams , the myopes had significantly higher bws above 2500 grams than the others in children aged 7 .
a comprehensive study in 1413 singapore chinese children reported an association between birth size and ocular dimensions .
another study on australian children found that axial length and corneal radius were related to bw , birth length , and head circumference but showed no trend or associations for spheric equivalent refractions in relation to birth parameters .
apart from our study , they analysed children aged 6 years , in whom myopia can still develop , and excluded children who had been born before 36 weeks of gestational age .
similarly , a recent study also has reported that refraction is unrelated to birth size or gestational age in swedish children aged 415 years , but this study comprised 143 children and did not include children born at < 35 weeks ' gestation .
on the other hand , another twin study with an age range of 1886 years showed no association of bw with myopia . but both studies showed that bw was not a major contributor to the discordance in myopia for monozygotic twin pairs .
a cohort twin study comprising 1498 twins aged 580 years found no association between bw and refraction status .
lower bw tended to have shorter axial length and steeper corneas . in our study , hypermetropia was more common in sga children than in aga or lga children aged 13 years and older .
these results may suggest that emmetropic sga children in early ages tended to be hypermetropes in later ages .
our finding of increased hypermetropia in sga is in accordance with the study of lindqvist et al . .
they studied adolescents with very low birth weight ( < 1500 g ) , adolescents born at term but sga , and concluded that being sga may be a risk factor for hypermetropia development in adolescence , probably due to smaller eye size and other development arresting factors suggesting restricted fetal growth .
prematurity has been associated with increased refractive errors including mainly myopia [ 22 , 23 ] .
verma et al . also reported an inverse relationship between gestational age and incidence of refractive error . in a cohort study comprising low birth weight children who were born preterm ,
the prevalence of all refractive errors was reported to be higher than the control group born at term who were involved in another study [ 13 , 23 ] . in our study
, we also included both premature and sga children and found that hypermetropia is associated with being sga .
the discrepancy between our study and the others may result from other factors that have a role in inducing myopia .
myopia has been shown to be affected by environmental factors , such as near work , educational access , and urbanization as well as genetic factors [ 26 , 27 ] . to sum up
, birth weight and appropriateness as birth parameters may have an impact on development of all types of refractive errors .
therefore , delivery records of children as birth weight and gestational age may be important in determining the follow - up of them for refractive state changes .
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### Summary:
: purpose . to investigate the association of birth parameters with refractive status in different age groups of caucasian children .
materials and methods . this cross - sectional study included 564 eyes of 282 children
aged 4 to 17 years .
all children underwent complete ophthalmologic examination .
the children were divided into three groups according to their refractive status ( emmetropia , myopia , and hyperopia ) , ages ( 47 , 8 - 9 , 1012 , and 1317 ) , and appropriateness for gestational age , respectively .
results .
the mean age of the children was 9.2 2.8 ( age range 417 years ) .
the mean spheric equivalent was + 0.3 1.7 ( range : ( 10.0)(+10.0 ) diopters ) .
the mean birth weight and gestational age were 2681.1 930.8 grams ( 7505000 grams ) and 37.2 3.7 weeks ( 2542 weeks ) . according to multinominal logistic regression analysis ,
children with myopia were more likely to have higher birth weights than emmetropic children ( or : 1.0 , 95% ci : 1.0001.001 , and p = 0.028 ) .
the hypermetropes were found to be significantly small for gestational age between 13 and 17 years of age .
conclusion . birth weight and appropriateness for gestational age as birth parameters may have an impact on development of all types of refractive errors .
the hypermetropic children tended to be small for gestational age .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: a 4-year - old boy from a consanguineous marriage presented with a history of persistent eczematous rash since the age of weeks .
physical examination revealed a coarse facial appearance and growth retardation for his age ( figure 1a ) .
there were eczematous patches , plaques and cold abscesses on extremities and scalp ( figure 1b ) .
pruritic dermatitis was noted in a distribution atypical for true atopic dermatitis ( figure 1c ) .
his serum ige level was 3000iu / ml ( normal 0 - 29.2 iu / ml ) ; other immunoglobulin levels were normal . a parent 's serum ige level was markedly elevated .
based on the combination of chronic dermatitis resembling atopic dermatitis , relapsing severe bacterial infections of skin and increased ige levels , the diagnosis of hies was confirmed .
he was successfully treated with topical corticosteroids , oral oxacillin and low - dose fluconazole . during the succeeding 23 years
, he was hospitalized more times ( exacerbation of dermatitis , skin and mucosal infections , pruritis ) and treated by local and systemic corticosteroids ( 0.5 mg / kg prednisone ) , emollients , antibiotics , and antihistamines .
figure 1a ) a coarse facial appearance with eczematous lesions in a boy with hyperimmunoglobulin e syndrome .
a ) a coarse facial appearance with eczematous lesions in a boy with hyperimmunoglobulin e syndrome .
his brother ( 2-year - old boy ) presented with a history of recurrent dermatitis and furunculosis since 1 month of age .
cultures for skin abscesses and oral mucosa were positive ( s. aureus and c. albicans ) .
the level of serum ige was markedly elevated ( 10000 iu / ml ) , and anti-s.aureus specific ige was found . at 5 years of age , he developed typical juvenile dermatomyositis ( figure 2 ) and treated by oral prednisone ( 2 mg / kg / day ) .
our patients concerned the first two tunisian cases of hies , a rare primary immunodeficiency syndrome ; less than 250 cases were documented in the literature . the primary host defense defect is impaired phagocytosis .
as observed in patient 2 , serum from hie patients can inhibit the neutrophilic chemotaxis of healthy patients when added to their serum .
clinical manifestations often start with eczematous or atopic dermatitis - like eruptions within the first days of life as in our patients .
other manifestations described since then include : coarse faces as in our first observation , skeletal abnormalities , and vascular abnormalities ( table 1 ) .
the mode of inheritance appears to be autosomal dominant with incomplete penetrance ; the gene has been linked to chromosome 4q .
recently , dominant - negative mutations in the signal transducer and activator of transcription 3 ( stat3 ) gene were identified . in this report
the association of dermatomyositis with hies is extremely rare ( only 2 reports ) and may not have been coincidental . at present , no established protocol exists for the treatment of hies .
long - term chemoprophylaxis ( oral penicillin 's and low - dose fluconazole ) in patient 1 improved dramatically the course of the disease .
table 1clinical manifestations and immunologic features of hies.clinical manifestationscutaneous manifestations newborn vesicopustular eosinophilic eruption atopic eczema - like dermatitis infected dermatitis and folliculitis - staphylococcus aureus cold abscesses chronic candidiasis generalized coarsening of the skinpulmonary manifestations parenchymal lung disease pneumatoceles recurrent pneumonias - s aureus and haemophilus influenzae pulmonary abscesses - pseudomonas aeruginosa , aspergillus fumigatusmusculoskeletal findings retained primary teeth scoliosis osteopenia / osteoporosis frequent fracture of long bones midline anomalies - cleft palate , cleft tongue , high palate , hemivertebraecharacteristic facies facial asymmetry with hemihypertrophy prominent forehead broadened nasal bridge and deep - set eyes increased alar and outer canthal distancerare systemic infections ( nocardiosis , candidiasis , cryptococcosis , histoplasmosis , sporotrichinosis , herpesvirus , pneumocystis carinii ) , miscellaneous bowel perforation , giant chalazion , genu valgum , joint deformities , spinal anomalies , lymphoma , connective tissue diseaseimmunological featuresincreased serum ige , normal il-4 , abnormal neutrophil chemotaxis , decreased c3b receptors on neutrophils , decreased adhesion molecule l - selectin , decreased ifn- production , poor response to il-12 stimulation , increased gm - csf production , decreased tgf-gm - csf , granulocyte - monocyte colony - stimulating factor ; ifn , interferon ; il , interleukin ; tgf , transforming growth factor .
gm - csf , granulocyte - monocyte colony - stimulating factor ; ifn , interferon ; il , interleukin ; tgf , transforming growth factor .
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### Summary:
: hyperimmunoglobulin e recurrent infection syndrome ( hies ) is characterized by recurrent skin and lung infections , eczema , elevated serum immunoglobulin e ( ige ) levels ( > 2000 iu / ml ) , various connective tissue , skeletal , and vascular abnormalities.1 we describe herein two brothers with hies and documented the complications and management of such involvement .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: sarcophine was isolated from the soft coral sarcophyton glaucum collected from several locations of the red sea in egypt .
phenylmethylsulfonylfluoride ( pmsf ) , tween 20 , sodium chloride , ammonium persulphate , sodium lauryl sulphate , acetic acid , leupeptin and pepstatin were obtained from sigma chemical company ( st .
acrylamide was purchased from bio rad laboratories , ( hercules , ca ) , glycine , sodium dodecyl sulphate ( sds ) and tris from usb corporation ( cleveland , oh ) , and nitrocellulose membrane from bioexpress ( kaysville , ut ) .
primary antibodies against caspase-3 were purchased from cayman chemical company ( ann arbor , mi ) , primary antibody against caspase-8 , -9 , and horseradish peroxidase conjugated goat anti - rabbit secondary antibodies were purchased from bd biosciences ( rockville , md ) and p53 from abcam inc .
sarcophine was isolated from the soft coral sarcophyton glaucum by multiple extraction with petroleum ether at room temperature following the reported procedure at the laboratories of the department of pharmacognosy , faculty of pharmacy , suez canal university , ismailia , egypt .
the dried extract was evaporated under reduced pressure and chromatographed on silica gel column using hexane : ethyl acetate ( 1:2 ) as eluent .
st was synthesized according to the folowing procedure : sarcophine was reduced to its lactone ring - opened analogue ( 50 mg , 0.16 mmol ) to which selenium dioxide ( 35.5 mg , 0.32 mmol ) in dry 1,4-dioxane ( 15 ml ) was added and the reaction mixture was stirred at room temperature for 4 h. water was then added , and the product was extracted with ch2cl2 .
saturated nahco3 solution was used to wash the ch2cl2 layer which was dried over anhydrous na2so4 .
the solvent was evaporated and the residue was chromatographed on silica gel using hexane - acetone ( 1:1 ) as an eluent to obtain st ( 12 mg , 23% ) .
the uvb irradiation unit , manufactured by daavlin corporation ( ohio , usa ) consists of four uvb lamps .
female skh-1 mice ( 5 weeks old ) were purchased from charles river laboratories ( wilmington , ma ) .
the animals were housed ten per cage at 22 1c and 50 10% relative humidity and subjected to a 12h light/12h dark cycle in the college of pharmacy animal facility .
they were acclimatized for 1 week before use and provided food and water ad libitum . the tumorigenesis protocol as described by dwivedi et al .
female skh-1 mice randomly divided into two groups , control and st treated . both initiation as well as promotion was induced by uvb radiation ( 180mj / cm ) . during the initiation phase ,
control was treated with acetone ( 100 l ) and st treated with st ( 100 l , 30 g/100 l of acetone ) one hour prior to uvb treatment .
ten days after the initiation phase , promotion phase was started . during the promotion phase , both control and st
treated groups were treated in the same way as they were treated during the initiation phase .
but during the promotion phase , the treatment was done only twice a week ( tuesday and friday ) and was continued until the next 30 weeks .
mice from uvb - induced tumorigenesis protocol were sacrificed after 30 weeks by cervical dislocation and epidermis was collected from mice of control and st treated groups respectively .
the fat and tumors in the skin of these three groups were scraped by scalpel , and then epidermis was homogenized by an omni glh-115 homogenizer in 0.1 mm tris - hcl ( ph 7.4 ) containing 0.15 m sodium chloride .
the epidermal homogenate was filtered by cheesecloth and then filtrate was centrifuged at 10,000 g for 20 min in the beckman j2 - 21 centrifuge .
this pellet combined with 5% sds containing 1% 100 mm pmsf , 0.5% leupepth and 0.5% pepstatin was allowed to pass through 25 g needle and centrifuged at 13,000 g for 20 min .
the supernatant was collected , allowed to pass through 25 g needle again and heated in heating block ( 100 c ) for 5 min .
the cell pellet of mice obtained as a result of ultracentrifugation is taken in an eppendorf tube and lysed in 5% sds containing protease inhibitors leupeptin , pepstatin and phenyl methyl suphonyl floride ( pmsf ) as described by kundoor et al . and zhang et al . .
protein concentration was measured in each cell lysate by the protein assay ( pierce , illinois ) with albumin as a standard .
equal amounts of protein lysates ( 60 g ) were resolved on 12.5% sds - poly - acrylamide gels and transferred to nitrocellulose membrane .
membranes were blocked for 1 h in 5% skim milk in tbs ( 10 mm tris , 100 mm nacl ) , and then probed with primary antibodies against caspase-3 , -8 , -9 and p53 .
the secondary antibodies conjugated to horseradish peroxidase were used for development with the enhanced chemiluminescence detection ( ecl ) kit .
the western blots were quantified using a uvp biochem gel documentation system ( uvp , inc . , upland , california ) .
caspase -3 , 8- , -9 and p53 data were normalized using beta - actin as the housekeeping protein used routinely in our laboratories . the instat software package ( graph pad , san diego , ca )
student s t test was used to compare the tumor multiplicity , weight gain , caspase-3 , -8 , -9 and p53 levels in uvb - induced carcinogenesis .
sarcophine was isolated from the soft coral sarcophyton glaucum collected from several locations of the red sea in egypt .
phenylmethylsulfonylfluoride ( pmsf ) , tween 20 , sodium chloride , ammonium persulphate , sodium lauryl sulphate , acetic acid , leupeptin and pepstatin were obtained from sigma chemical company ( st .
acrylamide was purchased from bio rad laboratories , ( hercules , ca ) , glycine , sodium dodecyl sulphate ( sds ) and tris from usb corporation ( cleveland , oh ) , and nitrocellulose membrane from bioexpress ( kaysville , ut ) .
primary antibodies against caspase-3 were purchased from cayman chemical company ( ann arbor , mi ) , primary antibody against caspase-8 , -9 , and horseradish peroxidase conjugated goat anti - rabbit secondary antibodies were purchased from bd biosciences ( rockville , md ) and p53 from abcam inc .
sarcophine was isolated from the soft coral sarcophyton glaucum by multiple extraction with petroleum ether at room temperature following the reported procedure at the laboratories of the department of pharmacognosy , faculty of pharmacy , suez canal university , ismailia , egypt .
the dried extract was evaporated under reduced pressure and chromatographed on silica gel column using hexane : ethyl acetate ( 1:2 ) as eluent .
st was synthesized according to the folowing procedure : sarcophine was reduced to its lactone ring - opened analogue ( 50 mg , 0.16 mmol ) to which selenium dioxide ( 35.5 mg , 0.32 mmol ) in dry 1,4-dioxane ( 15 ml ) was added and the reaction mixture was stirred at room temperature for 4 h. water was then added , and the product was extracted with ch2cl2 .
saturated nahco3 solution was used to wash the ch2cl2 layer which was dried over anhydrous na2so4 .
the solvent was evaporated and the residue was chromatographed on silica gel using hexane - acetone ( 1:1 ) as an eluent to obtain st ( 12 mg , 23% ) .
the uvb irradiation unit , manufactured by daavlin corporation ( ohio , usa ) consists of four uvb lamps .
female skh-1 mice ( 5 weeks old ) were purchased from charles river laboratories ( wilmington , ma ) .
the animals were housed ten per cage at 22 1c and 50 10% relative humidity and subjected to a 12h light/12h dark cycle in the college of pharmacy animal facility .
they were acclimatized for 1 week before use and provided food and water ad libitum . the tumorigenesis protocol as described by dwivedi et al .
female skh-1 mice randomly divided into two groups , control and st treated . both initiation as well as promotion was induced by uvb radiation ( 180mj / cm ) . during the initiation phase ,
control was treated with acetone ( 100 l ) and st treated with st ( 100 l , 30 g/100 l of acetone ) one hour prior to uvb treatment .
ten days after the initiation phase , promotion phase was started . during the promotion phase ,
both control and st treated groups were treated in the same way as they were treated during the initiation phase .
but during the promotion phase , the treatment was done only twice a week ( tuesday and friday ) and was continued until the next 30 weeks .
the uvb irradiation unit , manufactured by daavlin corporation ( ohio , usa ) consists of four uvb lamps .
female skh-1 mice ( 5 weeks old ) were purchased from charles river laboratories ( wilmington , ma ) .
the animals were housed ten per cage at 22 1c and 50 10% relative humidity and subjected to a 12h light/12h dark cycle in the college of pharmacy animal facility .
they were acclimatized for 1 week before use and provided food and water ad libitum .
both initiation as well as promotion was induced by uvb radiation ( 180mj / cm ) . during the initiation phase ,
control was treated with acetone ( 100 l ) and st treated with st ( 100 l , 30 g/100 l of acetone ) one hour prior to uvb treatment .
ten days after the initiation phase , promotion phase was started . during the promotion phase , both control and st
treated groups were treated in the same way as they were treated during the initiation phase .
but during the promotion phase , the treatment was done only twice a week ( tuesday and friday ) and was continued until the next 30 weeks .
mice from uvb - induced tumorigenesis protocol were sacrificed after 30 weeks by cervical dislocation and epidermis was collected from mice of control and st treated groups respectively .
the fat and tumors in the skin of these three groups were scraped by scalpel , and then epidermis was homogenized by an omni glh-115 homogenizer in 0.1 mm tris - hcl ( ph 7.4 ) containing 0.15 m sodium chloride .
the epidermal homogenate was filtered by cheesecloth and then filtrate was centrifuged at 10,000 g for 20 min in the beckman j2 - 21 centrifuge . this pellet combined with 5% sds containing 1% 100 mm pmsf , 0.5% leupepth and 0.5% pepstatin
was allowed to pass through 25 g needle and centrifuged at 13,000 g for 20 min .
the supernatant was collected , allowed to pass through 25 g needle again and heated in heating block ( 100 c ) for 5 min .
the cell pellet of mice obtained as a result of ultracentrifugation is taken in an eppendorf tube and lysed in 5% sds containing protease inhibitors leupeptin , pepstatin and phenyl methyl suphonyl floride ( pmsf ) as described by kundoor et al . and
protein concentration was measured in each cell lysate by the protein assay ( pierce , illinois ) with albumin as a standard .
equal amounts of protein lysates ( 60 g ) were resolved on 12.5% sds - poly - acrylamide gels and transferred to nitrocellulose membrane .
membranes were blocked for 1 h in 5% skim milk in tbs ( 10 mm tris , 100 mm nacl ) , and then probed with primary antibodies against caspase-3 , -8 , -9 and p53 .
the secondary antibodies conjugated to horseradish peroxidase were used for development with the enhanced chemiluminescence detection ( ecl ) kit .
the western blots were quantified using a uvp biochem gel documentation system ( uvp , inc . , upland , california ) .
caspase -3 , 8- , -9 and p53 data were normalized using beta - actin as the housekeeping protein used routinely in our laboratories .
the instat software package ( graph pad , san diego , ca ) was used to analyze the data .
student s t test was used to compare the tumor multiplicity , weight gain , caspase-3 , -8 , -9 and p53 levels in uvb - induced carcinogenesis .
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### Summary:
: sarcotriol ( st ) has been shown to be chemopreventive on 7,12-dimethyl - benz(a)anthracene ( dmba ) initiated and 12-o - tetradecanoylphorbol-13-acetate ( tpa)-promoted skin tumor development in cd-1 mice in recent studies from our laboratory . the objective of this study was to determine the chemopreventive effects of st on ultraviolet b ( uvb)-induced skin tumor development in female skh-1 hairless mice , an experimental model relevant to human skin cancer development , and its possible mechanisms of action .
female skh-1 mice were divided into two groups : control and st treated .
control was topically treated with 100 l acetone and st treated group administered with 30 g st in 100 l acetone one hour before uvb exposure . for uvb - induced tumorigenesis
, carcinogenesis was initiated and promoted by uvb ( 180 mj / cm2 ) .
group weights and tumor counts were taken once every week .
after 30 weeks , mice were sacrificed and dorsal skin samples were collected .
the proteins from the skin sample were further used for sds - page and western blotting using specific antibodies against caspase-3 , caspase-8 , caspase-9 and p53 .
tumor multiplicity was found 19.6 , 5.2 in the control and st treated groups respectively .
caspase-3 , -8 , -9 and p53 were significantly ( p < 0.05 ) upregulated in st treated group compared to control group .
together , this study for the first time identifies the chemopreventive effects of st in uvb - induced carcinogenesis possibly by inducing apoptosis and upregulating p53 .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the urea cycle is the main pathway for the disposal of excess nitrogen generated from the breakdown of protein and other nitrogen - containing molecules .
urea cycle disorders , which are characterized by hyperammonemia and distorted amino acid metabolism , can have variable clinical presentations .
severe deficiencies are typically associated with neonatal hyperammonemia , presenting with poor feeding , vomiting , lethargy , tachypnea , convulsions , and coma . in milder deficiencies ,
ammonia accumulation may be triggered by illness or stress and the disease can present at almost any age . in infancy , partial deficiencies can present with poor developmental progress , behavioral disturbances , hepatomegaly , and gastrointestinal symptoms .
children and adults with partial deficiencies can develop migraine headaches , behavioral changes , confusion , and cyclic vomiting .
carbamoylphosphate synthetase 1 ( cps1 ) is the first and rate - limiting enzyme of urea cycle .
cps1 is activated by n - acetylglutamate ( nag ) , which is necessary for cps1 activity .
therefore , n - acetylglutamate synthase ( nags ) , the only enzyme that makes nag , is an essential part of the urea cycle . in this report
we describe an infant with nags deficiency who presented in neonatal period with hyperammonemia and was found to have a novel mutation in the nags gene .
in addition , we discuss the clinical and molecular spectra for previously reported individuals with nags deficiency .
her physical examination was normal and she was discharged home at 2 days old .
hours later , she developed poor sucking and decreased activity , and her parents brought her to the emergency room ( er ) at the age of 3 days . in
er she was lethargic , tachypnic , and developed convulsions in the form of abnormal movements of her right upper and lower extremities .
initial investigation showed high ammonia ( 387 m ) and respiratory alkalosis ; therefore , a urea cycle defect was highly suspected and she was transferred to a tertiary medical center . upon arrival , she was lethargic and hypotonic , and her ammonia was 809 m .
the routine management of hyperammonemia was immediately started with ammonul ( sodium phenylacetate and sodium benzoate ) , intravenous ( iv ) arginine , iv high dextrose , and continuous insulin infusion .
hemodialysis was not available , therefore , a peritoneal catheter was inserted and peritoneal dialysis was started after 4 h. at that time ammonia was 1194 m .
in addition to elevated glutamine and glycine , plasma amino acids showed undetectable citrulline level suggesting a proximal urea cycle defect , which includes nags deficiency .
therefore , n - carbamylglutamate was subsequently initiated after about 24 h. after < 48 h , ammonia normalized and dialysis and insulin infusion were discontinued , while ammonul , iv arginine , and n - carbamylglutamate were continued ( fig .
ammonia remained within normal levels while the iv medications were changed to oral medications and protein intake was gradually increased . as n - carbamylglutmate
was started after the initiation of dialysis and other medications , it was difficult to judge whether the neonate responded to the n - carbamylglutamate or the reduced ammonia was just due to the dialysis and other medications .
in addition , the rarity of nags deficiency , the limited availability of n - carbamylglutamate in the tertiary center , and the desire to have a simplified treatment regimen were also considered and a decision was made at that time to discontinue the n - carbamylglutamate while maintaining oral citrulline and sodium benzoate , and protein - restricted diet .
the infant was discharged home after two weeks on oral citrulline ( 300 mg / kg / day ) and sodium benzoate ( 300 mg / kg / day ) and protein restricted ( 2 g / kg / day ) formula composed of a mixture of essential amino acid formula and regular infant formula . a genetic panel for urea cycle disorders including the cps1 , nags , otc , ass1 , asl , and arg1 genes was sent during the hospitalization .
three weeks after discharge , the results of the genetic panel became available , demonstrating a novel homozygous mutation , c.1097 - 2a > t , in the nags gene consistent with a diagnosis of nags deficiency .
when a call was made to discuss the results and arrange for a clinic visit to initiate n - carbamylglutamate , the family mentioned that the child was not feeding well and had been less active for the past day .
therefore , the child was immediately assessed in er and found to be lethargic with ammonia of 571 m . knowing that the child has nags deficiency n - carbamylglutamate was initiated ( 200 mg / kg / day ) and ammonia normalized within 8 h ( fig .
, the child regained her normal activity and feeding was initiated using regular infant formula .
the ammonia remained normal and the infant was discharged home after 5 days with n - carbamylglutamate monotherapy and regular infant formula .
nags deficiency is the rarest and accounts for only 0.51% of urea cycle disorders ; therefore , its estimated incidence is 1:3,500,0007,000,000 . in 1981 , this disease was first described in a neonate with hyperammonemia who had undetectable nags enzyme activity in liver tissue .
subsequently , very few reports described nags deficiency , reflecting not only the rarity of the disease but also the difficulty in confirming the diagnosis which initially required enzyme assessment in liver tissue . in 2002 , the nags gene was identified and mutations found in affected individuals , . since then , the diagnosis of nags deficiency has become more common . with the infant described here , molecularly confirmed nags deficiency
however , late - onset presentations have been reported in infancy , childhood , and adulthood .
neonatal hyperammonemia was the presentation in 41 ( ~ 70% ) reported individuals with nags deficiency ( table 1 ) . neonates with this presentation
can have poor feeding , vomiting , lethargy , tachypnea , respiratory distress , respiratory alkalosis , hypothermia , hypotonia , irritability , seizures , brain edema , coma , and death .
other neonatal manifestations may include failure - to - thrive , hepatomegaly , oliguria , diarrhea , metabolic acidosis , trembling , jitteriness , and hypertonia .
these children had more variable phenotypes with common manifestations being hypotonia , developmental delay , seizures , behavioral problems , and lethargy .
less common manifestations included protein aversion , reye - like syndrome , failure - to - thrive , and hepatomegaly ( table 1 ) .
the manifestations , which were precipitated by major stressors in 3 of the 5 , included headaches , seizures , behavioral problems , confusion , lethargy , and coma ( table 1 ) .
therefore , nags deficiency presents with neonatal hyperammonemia in most cases , whereas a broad spectrum of manifestations occurring at any age beyond the neonatal period occurs in a minority of cases .
maintaining a high index of suspicion and lower threshold of doing ammonia level are needed for early diagnosis particularly for late - onset diseases . besides the hyperammonemia , the biochemical profile in nags deficiency is similar to cps1 deficiency which is characterized by low plasma citrulline and the absence of orotic aciduria . measuring enzyme activity requires liver biopsy which is difficult and not completely reliable .
therefore , molecular tests sequencing nags gene have become the practical standard for diagnosing nags deficiency .
the infant described here had the classic biochemical profile and a novel homozygous mutation , c.1097 - 2a > t , in the nags gene .
this mutation has not been previously reported ; however , it is located in the acceptor splice site of intron 4 and therefore is predicted to affect splicing . including the mutation in this infant , 41 different nags mutations have been described including 25 ( ~ 60% ) missense , 4 ( ~ 10% ) nonsense , 8 ( ~ 20% ) frameshift , and 4 ( ~ 10% ) splice - site mutations .
other than the missense mutation p.w484r , which was found in homozygous status in 6 families and heterozygous status in one , other mutations are private as they were observed in only one or two families ( table 2 ) . in contrast to the treatment of other urea cycle disorders that includes low - protein diet with essential amino acid supplements , arginine or citrulline supplementation , and the use of ammonia scavengers ; treatment of nags deficiency is with only n - carbamylglutamate , a stable structural analogous of nag that activates cps1 .
therefore , nags deficiency is the only urea cycle disorder that can be specifically and effectively treated . using stable isotope studies ,
n - carbamylglutamate successfully rescues neonates with nags deficiency when present with hyperammonemia and its long - term chronic use corrects the metabolic defects in these individuals and eliminates the need for additional medications or dietary modifications .
although mono - therapy with n - carbamylglutamate is the treatment of choice in nags deficiency , some affected individuals receiving n - carbamylglutamate may experience breakthrough hyperammonemia during episodes of acute illness or metabolic decompensation ; therefore , protein restriction and additional drugs may be needed during these episodes .
mg / kg / day ( given in 34 doses ) ; however it can be adjusted individually by progressive down - titration to the minimum dose required ( as low as 1015 mg / kg ) to maintain normal ammonia levels .
the infant reported here showed dramatic response to n - carbamylglutamate and remained only on this medication . during the initial hospitalization , using the n - carbamylglutamate with dialysis and other medications made it difficult to appreciate the contribution of n - carbamylglutamate .
however , during the second hospitalization , it was obvious how this medication resulted in normalizing the ammonia in just few hours .
although n - carbamylglutamate typically normalizes ammonia in hours , , a delayed response or no response has been reported in some neonates with nags deficiency . in conclusion ,
typically , it presents with neonatal hyperammonemia ; however , late - onset with variable manifestations can occur .
the treatment of choice in nags deficiency is n - carbamylglutamate monotherapy which can normalize ammonia in few hours .
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### Summary:
: the urea cycle is the main pathway for the disposal of excess nitrogen .
carbamoylphosphate synthetase 1 ( cps1 ) , the first and rate - limiting enzyme of urea cycle , is activated by n - acetylglutamate ( nag ) , and thus n - acetylglutamate synthase ( nags ) is an essential part of the urea cycle .
although nags deficiency is the rarest urea cycle disorder , it is the only one that can be specifically and effectively treated by a drug , n - carbamylglutamate , a stable structural analogous of nag that activates cps1 . here
we report an infant with nags deficiency who presented with neonatal hyperammonemia .
she was found to have a novel homozygous splice - site mutation , c.1097 - 2a > t , in the nags gene .
we describe the clinical course of this infant , who had rapid response to n - carbamylglutamate treatment .
in addition , we reviewed the clinical and molecular spectra of previously reported individuals with nags deficiency , which presents in most cases with neonatal hyperammonemia , and in some cases the presentation is later , with a broad spectrum of ages and manifestations . with this broad later - onset phenotypic spectrum , maintaining a high index of suspicion is needed for the early diagnosis of this treatable disease .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: systemic sclerosis ( ssc ) is an autoimmune disease having an unknown etiology characterized by microvasculopathy , immunological abnormalities , and excessive collagen deposits [ 1 , 2].endothelial dysfunction and microcirculation damage are cardinal features of systemic sclerosis ( ssc ) ; it is thought that vascular changes occur at an early stage and may include endothelial cell apoptosis , endothelium activation , inflammatory cell recruitment , intimal proliferation , and adventitial fibrosis , all of which may lead to vessel obliteration .
although ssc pathogenesis remains uncertain , increasing evidence suggests that transforming growth factor - beta ( tgf- ) plays a key role in tissue fibrosis development , a consequence of extracellular matrix accumulation in ssc pathogenesis .
tgf- regulates diverse biological activities including cell growth , apoptosis , differentiation , and extracellular matrix synthesis through interaction with tgf- receptors [ 4 , 5 ] .
endoglin ( eng ) is a glycoprotein having antiangiogenic properties that acts as a tgf- receptor complex component .
eng may act on fibroblasts to modulate tgf- signaling by acting as a molecular sink regulating or reducing the total pool of tgf- available for activating signal - transducing receptors .
increased expression in fibroblasts and endothelial cells has been demonstrated in ssc patients , suggesting that deregulating eng expression and/or function may be related to the vascular manifestation of ssc [ 6 , 7 ] .
pulmonary arterial hypertension ( pah ) is the main vascular complication in ssc , being an important cause of morbidity and the main cause of mortality , having 50% survival rate at 12 months .
this vasculopathy is caused by a number of soluble factors and involves a complex interaction between endothelial cells , smooth muscle cells , extracellular matrix , coagulation factors , and circulating cells .
there are two types of pah in ssc : pah secondary to fibrosis and severe interstitial involvement and isolated pah without fibrosis or interstitial lung disease , with the latter reflecting the illness ' vascular pathology and resulting in a more indolent pulmonary process .
cardiac catheterization is considered the gold standard for pah diagnosis , but this technique is invasive , expensive , and not available in all centers .
it can sometimes represent a high - risk factor for morbidity ; this is why its use for detecting pah and its followup are limited .
markers should thus be sought to enable detecting patient subgroups having the highest risk of developing pah as a vascular complication of ssc and allowing followup .
this would enable pah to be diagnosed as early as possible , thereby improving prognosis for pah and ssc patients .
this study examined serum levels of eng in patients with ssc and elevated spap ( ssc - spap ) and ssc without elevated spap ( ssc - non spap ) and these were compared with healthy volunteers for determining any association between eng levels and elevated spap in ssc patients .
a cross - sectional study was carried out between june and october 2008 during which 60 subjects were analyzed ; 40 patients met american college of rheumatology ( acr ) criteria for ssc ( 20 patients had elevated spap by echocardiogram and 20 patients did not ) , and 20 control healthy subjects were also included .
the patients were consecutively selected based on the available and willingness to participate in this study .
patients who presented any other connective tissue disease or a concomitant pulmonary illness from any other etiology , work , or environmental exposure for pulmonary disease were excluded .
registration forms were completed which included demographic data , clinical characteristics , antibody levels , reports from diagnostic tools such as echocardiogram and high - resolution computed tomography of the thorax ( hrctt ) .
the patients were subdivided into two groups : limited ssc ( lssc ) and diffuse ssc ( dssc ) based on the limits proposed by leroy et al . .
blood samples were drawn from the 40 ssc patients and from 20 healthy subjects matched by age and gender .
the protocol was approved by the universidad nacional de colombia 's ethics committee and all patients signed the informed consent forms agreeing to take part in this study .
all echocardiograms were taken by an expert cardiologist using standard techniques for evaluating right ventricle dimensions and tricuspid gradients after a 20-minute rest .
the spap was calculated as being the sum of the tricuspid gradient and estimated right atrial pressure .
elevated spap was defined in colombian patients living at 2,600 meters above sea level as being mean > 35 mmhg spap , >
3 m / second tricuspid regurgitation velocity , or 2.5 m / second in patients having unexplained dyspnea .
elevated spap was defined as > 35 mmhg spap with hrctt without evidence of interstitial lung disease ( such as bibasilar pulmonary fibrosis or reticulonodular densities , being most pronounced in the lung bases ) , or the presence of heterogeneous opacities such as reticular opacities , ground - glass opacities , or honeycombing in hrctt .
a commercial elisa kit ( r&d systems , minneapolis , minn , usa ) was used for serum measurement for eng from ssc patients and the control group , following the manufacturer 's protocol .
clinical data , elevated spap and eng serum values were compared by unpaired student t - test or mann - whitney u test as appropriate .
fisher 's exact test or chi - test was used for determining association between categorical variables .
odds ratios ( or ) with 95% confidence interval ( 95% ci ) were also reported .
the kruskal - wallis test or anova was used for intergroup analysis , as appropriate .
two standard deviations ( sd ) above mean were taken for calculating positive eng values .
the study included 60 subjects , 40 having a diagnosis of ssc and 20 healthy control subjects ( 20 ssc - spap patients and 20 ssc - non spap patients ) . in the ssc group ,
26 patients presented lssc and 14 patients dssc ; 28 were female and 12 were men , having an average age of 44.3 9.8 at disease onset .
disease duration was 8.57 5.2 years , measured from the point at which the first symptom appeared .
the time from the onset of raynaud 's phenomenon was 9.5 5.9 years and rodnan 's score was 21.7 10.2 .
all patients presented telangiectasias ; 12 ( 30% ) patients had calcinosis , 28 ( 70% ) patients had gastrointestinal involvement , and mean spap value was 57.75 14.5 mmhg in ssc - spap patients .
sixteen patients from the ssc - spap group ( 16/20 ) were diagnosed with > 35 mmhg spap and > 3 m / second tricuspid regurgitation velocity ; only four ( 4/20 ) had > 3 m / second tricuspid regurgitation velocity .
sixteen ssc - spap patients ( 80% ) had > 48 mmhg spap and four ( 20% ) had < 48 mmhg spap but more than 40 mmhg in spap and had no significant structural right atrial and/or ventricular damage .
forty - five percent had calcinosis in the ssc - spap group , whereas only 15% were present in ssc - non spap group ( p = .041 ) .
no abnormality was found in 12 patients ( 60% ) and pah findings such as dilatation of proximal and segmental pulmonary arteries were found in 8 ( 40% ) .
no patients had bilateral reticular linear or reticulonodular densities in the lung bases or opacities reticular , ground - glass opacities , or honeycombing in hrctt .
anticentromere antibodies ( aca ) were reported to be positive in 27 patients ( 67.5% ) and anti - scl-70 in 9 patients ( 22.5% ) .
seventy - five percent had positive aca in the ssc - spap group ( 5/7 having diffuse ssc and 10/13 having limited ssc ) , whereas antibodies anti - scl-70 were positive in 10% of that group ( 2/7 ssc - spap patients and diffuse ssc ) . a speckled antinuclear antibody ( ana ) pattern was present in 15% ( 3/13 ssc - spap patients and limited ssc ) .
serum levels of eng in ssc - spap patients tended to be higher than in ssc - non spap patients , having no significant statistical difference ( p = .2447 ) and were higher than healthy controls ( p = .0006 ) .
mean values were 6.89 ng / dl , 6.20 ng / dl , and 5.42 ng / dl and median values were 7.07 ng / dl , 6.01 ng / dl , and 5.42 ng / dl , respectively ( figure 1 ) .
there was no difference between the ssc - non spap group and healthy controls ( p = .057 ) .
intergroup analysis revealed a difference between the three groups ( kruskal - wallis test , p = .0037 ) which was mainly due to ssc - spap group compared to the healthy control group . categorized analysis of serum levels from eng reported a difference between all groups ( p = .003 ) ; however , detailed analysis revealed interesting findings . the ssc - spap group
consisted of eleven patients having positive eng ( or = 2.85 ; 0.6512.88 95% ci ; p = .11 , when was compared to the ssc - non spap group ) ; the ssc - non spap group had six patients ( or = 8.14 ; 0.8393.74 95% ci ; p = .046 , when compared to healthy controls ) and one healthy control ( or = 23.22 ; 2.461050.33 95% ci ; p = .001 when was compared to the ssc - pah group ) .
an association was reported for positive eng ( or = 14.04 ; 1.79617.05 95% ci ; p = .0028 ) when ssc - spap and ssc - non spap groups were pooled and compared to healthy controls .
there was no correlation between eng levels and spap ( rho = 0.1384 , p = .39 ) .
two clinical hallmarks for ssc are its clinical heterogeneity and the wide range of vascular and fibrotic manifestations .
organ involvement , different patterns , and internal organ manifestation severity are the global outcome 's most significant determinants .
a diagnosis of pah has occurred late in the course of the disease until now and right heart catheterization has been the gold standard for its diagnosis .
the echocardiogram is a noninvasive technique and its limitations include it being operator - dependent and its false positive rate is close to 30% .
an imbalance in circulating angiogenic factors in ssc may be associated with vascular endothelial dysfunction .
eng is one of the factors supporting vascular integrity , with this being a 180 kda homodimeric coreceptor for tgf- superfamily members which is predominantly expressed on endothelial cell surfaces .
eng may have roles in hematopoiesis , cardiovascular development , and angiogenesis and is highly expressed on vascular endothelial cells , chondrocytes , and term placenta syncytiotrophoblasts .
it is also found on monocytes , erythroid precursors , and a hematopoietic stem cell subpopulation .
although its role remains elusive , circulating soluble eng levels are raised in patients suffering from atherosclerosis and certain cancers including breast , colon , and myeloid malignancies .
eng is likely to be involved with angiogenesis in endothelial cells , since prominent eng expression has been demonstrated in neovascular states , including the enhanced vascularity of psoriasis .
previous reports have shown that the eng gene is located at 9q34.1 and that mutations of this gene having reduced eng expression are responsible for one of the two types of hereditary hemorrhagic telangiectasia , an autosomal dominant disorder characterized by multiple telangiectasia of the skin , mucous membranes , gastrointestinal tract , arteriovenous malformation , and pulmonary hypertension .
leask et al . found that the endothelial - enriched high - affinity tgf- receptor endoglin was up - regulated in dermis fibroblasts cultured from involved areas of skin taken from ssc patients related to normal fibroblasts and that eng expression increased with the disease 's progression , suggesting that eng might represent a potential marker for staging ssc .
another finding was that eng overexpression in fibroblasts blocked the accumulation of activated nuclear smads and suppressed tgf- ability to induce connective tissue growth factor ( ctgf ) profibrotic cytokine target gene promoter .
such results suggest that ssc fibroblasts induce eng expression to suppress tgf- induction of gene expression in a negative feedback loop .
examined soluble eng serum levels in ssc patients and found these levels to be higher in patients having lssc , telangiectasias , and aca .
furthermore , sppa was positively correlated with eng levels in patients having lcssc , but only two of these patients presented pah .
there was no difference in heart , esophageal , or renal involvement between patients having higher eng serum levels and those having normal levels .
. demonstrated an association between eng gene polymorphism and pah , and another study by the same authors found that eng appeared to be increased in ssc and to be particularly associated with the vascular phenotype .
they also showed a higher eng concentration in ssc patients compared to healthy controls ; they included 17 pah patients and found that eng serum levels in ssc patients with pah were similar to those of patients without pah .
higher eng levels were found in ssc patients compared to healthy controls in a previous study by the present group , having a statistical difference between the two groups in favor of ssc and pah patients . however , a correlation with spap value was not found , with a limitation of this study being the lack the comparison with patients with ssc without pah .
higher eng levels were found in the two types of ssc in the current study , contrasting with the results of fujimoto et al . .
the 20 patients in the current study presented elevated spap secondary to ssc , and eng levels in these were more raised than in controls ( ssc - non spap group and healthy controls ) .
however , there was no statistical difference when the ssc - spap group was compared to the ssc - non spap group .
these results differed from the recent ones reported by wipff et al . and suggest that eng serum levels are elevated in ssc patients and not exclusively due to pah .
endothelial activity in patients in the early stages of pah may be a potential reason for finding elevated eng serum levels .
the difference in calcinosis percentage between the groups is striking , especially since calcinosis may develop in areas of poor perfusion and be the result of vascular disease .
aca have been associated with limited ssc and anti - topoisomerase i with diffuse progressive disease ; however , 10 to 15 percent of patients with diffuse disease have these antibodies .
reported positive aca in 93% of patients studied in colombia , independent of ssc subtype .
it thus seems that the higher presence of positive aca could be related to pah ; in fact earlier reports have associated these antibodies with increased risk of pulmonary hypertension [ 36 , 37 ] .
telangiectasias were present in all patients in the present study ; it had already been reported in colombian ssc patients .
right heart catheretization ( rhc ) is now considered the gold standard for pah diagnosis due to the presence of high false positive results with echocardiogram and also because rhc allows therapeutic choices for vasoreactivity seen in pah to be evaluated .
elevated spap was assessed and diagnosed with echocardiogram in this work due to the colombian health system 's limitations regarding performing rhc .
there was a high correlation between the measurements obtained using both techniques when the cardiologist operator had broad experience in evaluating pulmonary arterial pressure and there was no change in right heart anatomical structural . besides , >
48 mmhg spap associated with > 3.0 trv was used for diagnosing moderate / severe pah , thereby reducing the possibility of false positives occurring . since our cohort had been continuously followed up , the cases were chosen during the early phases of pah development to exclude even the smallest structural damage that could have altered echocardiographic evaluation .
a second limiting concerned the fact that a relative small population was included in each branch to include biomarkers having a potentially pathophysiologic role for generating elevated spap and because not enough scientific papers have assessed it , meaning that the current paper can be considered to be a pilot - study .
raised eng serum levels were found in ssc patients ( ssc - spap patients and ssc - non spap ) compared to healthy controls , suggesting a role for eng in ssc vasculopathy and not just in pah .
however , prospective studies are needed which include a larger population to verify these observations .
serum biomarkers could detect an early stage of the disease in patients having a high risk of developing elevated spap which could afford a better outcome during these patients ' follow up .
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### Summary:
: background .
pulmonary arterial hypertension ( pah ) is the main cause of morbimortality in systemic sclerosis ( ssc ) .
increased eng expression has been demonstrated in ssc patients . objective .
ascertaining serum levels of eng in ssc patients with and without elevated systolic pulmonary arterial pressure ( spap ) and comparing them with that of healthy volunteers . methods .
a cross - sectional study was carried out .
a commercial elisa kit was used for measuring serum concentrations of eng in 60 subjects : 40 patients with ssc with and without elevated spap , compared to 20 healthy control subjects .
elevated spap was detected by echocardiogram .
results .
no association between positive eng and elevated spap was found when compared to the ssc without elevated spap group ( or = 2.85 ; 0.6512.88 95% ci ; p = .11 ) ; however , an association was found between positive eng and elevated spap compared to healthy controls ( or = 23.22 ; 2.461050.33 95% ci ; p = .001 ) , and weak association was found between the positive eng with ssc without elevated spap group compared to healthy controls ( or = 8.14 , 0.8393.74 95% ci ; p = .046 ) .
conclusion .
raised serum levels of eng in ssc patients compared to healthy controls were found , suggesting a role for eng in ssc vasculopathy and not just in elevated spap . however , prospective studies are needed to verify such observations .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
:
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### Summary:
: data relating to acute injuries of atomic bomb survivors show that the life span study cohort is biased in favor of exceptionally low levels of radiosensitivity .
these data also show that factors influencing the death rates of this cohort include irreversible damage to the immune system .
these impressions are still awaiting confirmation .
meanwhile , the oxford survey of childhood cancers and surveys of nuclear workers show that at low dose levels the cancer risk is much greater than estimates based on atomic bomb survivors ; the special association between leukemia and radiation is an exclusively high dose effect , and levels of radiosensitivity are much lower in the middle of the life span than at either extreme.imagesfigure 1figure 2figure 3figure 4figure 5
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: carbon monoxide ( co ) poisoning results in several electrical , functional , and morphological alterations of the heart .
co - associated cardiovascular damage is the result of tissue hypoxia and direct co - mediated damage at the cellular level .
the frequent occurrence of cardiac disturbances during or after exposure to co , including an increased frequency of anginal attacks , arrhythmias , and increased levels of cardiac enzymes has led to a search for morphological changes caused by co. impaired cardiac function after co poisoning is usually related to acute myocardial ischemia , and myocardial infarction induced by acute co poisoning has been reported in a patient with normal coronary arteries .
a normal carboxyhemoglobin ( cohb ) level for a non - smoker is < 2% .
even slightly elevated levels of cohb ( 2 - 6% ) have been shown to decrease exercise tolerance and worsen myocardial ischemia in patients with known coronary artery disease .
co poisoning has a complex pathophysiology that involves hypoxic stress stemming from the interference with oxygen transport to the cells and possibly also from the impairment of electron transport .
it is also possible for carbon monoxide to affect leukocytes , platelets , and the endothelium , unleashing a chain of effects that result in oxidative injury .
the amount of co that must be inhaled to induce co intoxication remains unknown . in recent years
, doppler echocardiography in combination with tissue doppler imaging has become a well - accepted , practical , safe , and non - invasive method for diagnosing left and right ventricular systolic and diastolic function in the clinical setting . in this study , considering the previous emphasis on the effects of co poisoning on the cardiovascular system , we hypothesized that even mild co poisoning would lead to impairment of left and right ventricular function .
this study included 20 consecutive patients with co intoxication ( 11 females and 9 males ; mean age , 27.45 7.80 years ) who were diagnosed in the emergency department of our university between december 2003 and march 2007 .
twenty age- and gender - matched healthy volunteers from our hospital staff served as controls [ table 1 ] .
demographic and baseline echocardiographic measurements of patient and control groups on admission to the emergency department , a complete physical examination was performed , and we searched specifically for peripheral arterial pulses and carotid bruits .
arterial and venous blood samples were obtained to determine the baseline levels of serum creatinine , blood urea nitrogen , sodium , potassium , chloride , calcium , alanine aminotransferase , aspartate aminotransferase , hemoglobin , creatinine phosphokinase - mb ( cpk - mb ) fraction , and blood glucose .
u / l , as measured with an immulite 2000 immunoassay system ( siemens medical solutions usa , inc . ,
malvern , pa , usa ) , and creatine kinase - mb ( abbott laboratories , diagnostics division , abbott park , il , usa ) levels of < 24 u / l were accepted as normal .
carboxyhemoglobin levels were measured with an osm3 hemoximeter ( radiometer , copenhagen , denmark ) .
after blood sampling , 100% oxygen was administered ( 2 - 5 l / min ) to all patients via a face mask .
a 12-lead electrocardiogram was taken at the time of admission and 1 week after poisoning .
transthoracic echocardiographic examinations , which included tissue doppler imaging , were performed on admission and 1 week after discharge from the hospital .
the study was conducted according to the recommendations set forth by the declaration of helsinki on biomedical research involving human subjects .
the ethics committee on biomedical research at our university medical school approved the study protocol .
each subject was examined using an acuson sequoia c256 echocardiography system ( acuson , mountain view , ca , usa ) equipped with 3v2c and 5v2c broadband transducers with second harmonic capability . within 30 minutes of admission to the emergency department , 2-dimensional m - mode doppler echocardiography , and standard and pulsed - tissue doppler echocardiography
m - mode images were used to measure diastolic and systolic interventricular septal thickness , posterior wall thickness , and left ventricular end - diastolic and left ventricular end - systolic diameters on the parasternal long - axis view .
early diastolic peak flow velocity ( e ) , late diastolic peak flow velocity ( a ) , e / a ratio , and e - wave deceleration time ( dt ) were measured by using trans - mitral and trans - tricuspid doppler imaging .
a 5-mm sample volume was placed at the apical 4-chamber view on the lateral corner of the mitral annulus .
the resulting velocities were recorded for 5 - 10 cardiac cycles at a sweep speed of 100 mm / s and stored on videotape for off - line analysis . as a measure of regional systolic function , peak velocity ( cm / s ) and time velocity integral of myocardial systolic ( sm ) wave were determined .
diastolic measurements including myocardial early ( em ) and atrial ( am ) peak velocities ( cm / s ) , em / am ratio , and sm - em duration ( isovolumic relaxation time [ ivrtl ] ) measured as the time interval between the end of sm and the onset of em , were performed .
left ventricular ejection time ( lvet ) was measured from the onset to the end of left ventricular ( lv ) outflow .
right ventricular ejection time ( rvet ) was measured from the onset to the end of right ventricular ( rv ) outflow .
isovolumetric contraction time of the left ventricle ( ivctl ) was the interval from the cessation of mitral inflow to the onset of lv outflow .
isovolumetric relaxation time of the right ventricle ( ivrtr ) was defined as the time interval from the cessation of rv outflow to the onset of tricuspid inflow .
the isovolumetric contraction time of the right ventricle ( ivctr ) was measured from the cessation of tricuspid inflow to the onset of rv outflow .
the myocardial performance index of the right ventricle ( mpir ) was calculated by the formula ( ivctr + ivrtr)/rvet .
the myocardial performance index of the left ventricle ( mpil ) was calculated by the formula ( ivctl + ivrtl)/lvet .
left ventricular sm and ef values were used to demonstrate left ventricular contractile ( systolic ) function .
trans - mitral and trans - tricuspid e wave velocity , a wave velocity , e / a ratios , em , am , em / am ratios , ivrt , ivct , et , and mpi values were used to demonstrate right and left ventricular relaxation ( diastolic ) function .
the echocardiography was performed by an investigator who was blinded for clinical data and the analysis of the echocardiographic recordings were performed by two cardiologists , blinded to the subjects data .
statistical analyses were performed with statistical product and services solutions software ( spss , version 10.0 ; spss inc , chicago , il , usa ) .
the difference between echocardiographic parameters obtained at the time of admission and discharge was assessed with a paired samples t - test .
the spearman rank correlation test was used to determine the correlation between the echocardiographic parameters and cohb level .
this study included 20 consecutive patients with co intoxication ( 11 females and 9 males ; mean age , 27.45 7.80 years ) who were diagnosed in the emergency department of our university between december 2003 and march 2007 .
twenty age- and gender - matched healthy volunteers from our hospital staff served as controls [ table 1 ] .
demographic and baseline echocardiographic measurements of patient and control groups on admission to the emergency department , a complete physical examination was performed , and we searched specifically for peripheral arterial pulses and carotid bruits .
arterial and venous blood samples were obtained to determine the baseline levels of serum creatinine , blood urea nitrogen , sodium , potassium , chloride , calcium , alanine aminotransferase , aspartate aminotransferase , hemoglobin , creatinine phosphokinase - mb ( cpk - mb ) fraction , and blood glucose .
u / l , as measured with an immulite 2000 immunoassay system ( siemens medical solutions usa , inc . ,
malvern , pa , usa ) , and creatine kinase - mb ( abbott laboratories , diagnostics division , abbott park , il , usa ) levels of < 24 u / l were accepted as normal .
carboxyhemoglobin levels were measured with an osm3 hemoximeter ( radiometer , copenhagen , denmark ) .
after blood sampling , 100% oxygen was administered ( 2 - 5 l / min ) to all patients via a face mask .
a 12-lead electrocardiogram was taken at the time of admission and 1 week after poisoning .
transthoracic echocardiographic examinations , which included tissue doppler imaging , were performed on admission and 1 week after discharge from the hospital .
the study was conducted according to the recommendations set forth by the declaration of helsinki on biomedical research involving human subjects .
the ethics committee on biomedical research at our university medical school approved the study protocol .
each subject was examined using an acuson sequoia c256 echocardiography system ( acuson , mountain view , ca , usa ) equipped with 3v2c and 5v2c broadband transducers with second harmonic capability . within 30 minutes of admission to the emergency department , 2-dimensional m - mode doppler echocardiography , and standard and pulsed - tissue doppler echocardiography
m - mode images were used to measure diastolic and systolic interventricular septal thickness , posterior wall thickness , and left ventricular end - diastolic and left ventricular end - systolic diameters on the parasternal long - axis view .
early diastolic peak flow velocity ( e ) , late diastolic peak flow velocity ( a ) , e / a ratio , and e - wave deceleration time ( dt ) were measured by using trans - mitral and trans - tricuspid doppler imaging .
a 5-mm sample volume was placed at the apical 4-chamber view on the lateral corner of the mitral annulus .
the resulting velocities were recorded for 5 - 10 cardiac cycles at a sweep speed of 100 mm / s and stored on videotape for off - line analysis . as a measure of regional systolic function , peak velocity ( cm / s ) and time velocity integral of myocardial systolic ( sm ) wave were determined .
diastolic measurements including myocardial early ( em ) and atrial ( am ) peak velocities ( cm / s ) , em / am ratio , and sm - em duration ( isovolumic relaxation time [ ivrtl ] ) measured as the time interval between the end of sm and the onset of em , were performed .
left ventricular ejection time ( lvet ) was measured from the onset to the end of left ventricular ( lv ) outflow .
right ventricular ejection time ( rvet ) was measured from the onset to the end of right ventricular ( rv ) outflow .
isovolumetric contraction time of the left ventricle ( ivctl ) was the interval from the cessation of mitral inflow to the onset of lv outflow .
isovolumetric relaxation time of the right ventricle ( ivrtr ) was defined as the time interval from the cessation of rv outflow to the onset of tricuspid inflow .
the isovolumetric contraction time of the right ventricle ( ivctr ) was measured from the cessation of tricuspid inflow to the onset of rv outflow .
the myocardial performance index of the right ventricle ( mpir ) was calculated by the formula ( ivctr + ivrtr)/rvet .
the myocardial performance index of the left ventricle ( mpil ) was calculated by the formula ( ivctl + ivrtl)/lvet .
all diastolic parameters were measured in three consecutive cardiac cycles and averaged . left ventricular sm and ef values
trans - mitral and trans - tricuspid e wave velocity , a wave velocity , e / a ratios , em , am , em / am ratios , ivrt , ivct , et , and mpi values were used to demonstrate right and left ventricular relaxation ( diastolic ) function .
the echocardiography was performed by an investigator who was blinded for clinical data and the analysis of the echocardiographic recordings were performed by two cardiologists , blinded to the subjects data .
statistical analyses were performed with statistical product and services solutions software ( spss , version 10.0 ; spss inc , chicago , il , usa ) .
the difference between echocardiographic parameters obtained at the time of admission and discharge was assessed with a paired samples t - test .
the spearman rank correlation test was used to determine the correlation between the echocardiographic parameters and cohb level .
all the patients were delivered 100% oxygen and none of them required additional therapy . moreover
the mean left ventricular mass index ( lvmi ) and hemoglobin values were 73.49 16.90
the mean carboxyhemoglobin levels on admission and 1 week after poisoning were 15.81% 4.87% and 1.57% 0.24% , respectively .
the mean hbo2 saturation on admission and 1 week after poisoning were 94.60% 5.09% and 97.67% 1.55% , respectively . the mean creatinine phospho - kinase - myocardial band ( cpk - mb ) level on admission and 1 week after poisoning was 16.52 6.30 u / l and 15.79 6.68
the value for troponin - i on admission and 1 week after poisoning was 0.2 0 and 0.2 0.004 , respectively .
systolic blood pressure , diastolic blood pressure , heart rate , and rate - pressure product values were only slightly affected after mild co intoxication and the differences regarding these measures between the time of admission and one week after poisoning were not significant [ table 1 ] .
mitral e / a ratios were significantly lower ( p = 0.047 ) , and mitral e wave dt ( p = 0.011 ) , tissue doppler ivrt ( p = 0.014 ) , and mpil ( p = 0.023 ) were significantly higher after co poisoning than 1 week after poisoning .
em / am values were slightly lower after co intoxication ( 1.52 0.46 ) than 1 week after poisoning ( 1.71 0.56 ) , but the difference was not statistically significant [ p = 0.233 ; table 2 ]
. left ventricular systolic and diastolic function measurements tricuspid e wave dt was significantly higher after co poisoning ( 226.10 61.53 ms ) than 1 week after poisoning ( 183.20 29.14 ms ; p = 0.008 ) .
tricuspid e / a ratios were not significantly altered after co poisoning ( 1.41 0.37 ) compared with 1 week later ( 1.56 0.32 ; p = 0.172 ) .
right ventricular ( rv ) e / a ratios and mpir did not change significantly after mild co intoxication ( p = 0.404 and p = 0.235 , respectively ) .
rv ivrt ( 101.85 27.87 ms ) was significantly higher on admission than 1 week after poisoning [ 79.95 29.23 ms ; p = 0.020 ; table 2 ] .
no significant difference was detected in left ventricular ejection fraction obtained on admission ( following co poisoning ) and 1 week later [ table 2 ] .
left ( lv sm ) and right ventricular systolic function ( rv sm ) were not significantly altered with co poisoning p = 0.766 and p = 0.332 , respectively [ tables 2 and 3 ] .
right ventricular systolic and diastolic function measurements carboxyhemoglobin levels were significantly correlated with mitral a wave ( r = 0.335 , p = 0.025 ) , mitral e wave deceleration time ( r = 0.512 , p = 0.001 ) , mpil ( r = 0.316 , p = 0.047 ) , and tricuspid deceleration time ( r = 0.344 , p = 0.030 ) .
carboxyhemoglobin levels were negatively correlated with mitral e / a ratios ( r = 0.320 , p = 0.044 ) .
all the patients were delivered 100% oxygen and none of them required additional therapy . moreover
the mean left ventricular mass index ( lvmi ) and hemoglobin values were 73.49 16.90
the mean carboxyhemoglobin levels on admission and 1 week after poisoning were 15.81% 4.87% and 1.57% 0.24% , respectively .
the mean hbo2 saturation on admission and 1 week after poisoning were 94.60% 5.09% and 97.67% 1.55% , respectively . the mean creatinine phospho - kinase - myocardial band ( cpk - mb ) level on admission and 1 week after poisoning was 16.52 6.30 u / l and 15.79 6.68
the value for troponin - i on admission and 1 week after poisoning was 0.2 0 and 0.2 0.004 , respectively .
systolic blood pressure , diastolic blood pressure , heart rate , and rate - pressure product values were only slightly affected after mild co intoxication and the differences regarding these measures between the time of admission and one week after poisoning were not significant [ table 1 ] .
mitral e / a ratios were significantly lower ( p = 0.047 ) , and mitral e wave dt ( p = 0.011 ) , tissue doppler ivrt ( p = 0.014 ) , and mpil ( p = 0.023 ) were significantly higher after co poisoning than 1 week after poisoning . em / am values were slightly lower after co intoxication ( 1.52 0.46 ) than 1 week after poisoning ( 1.71 0.56 ) , but the difference was not statistically significant [ p = 0.233 ; table 2 ] .
tricuspid e wave dt was significantly higher after co poisoning ( 226.10 61.53 ms ) than 1 week after poisoning ( 183.20 29.14 ms ; p = 0.008 ) .
tricuspid e / a ratios were not significantly altered after co poisoning ( 1.41 0.37 ) compared with 1 week later ( 1.56 0.32 ; p = 0.172 ) .
right ventricular ( rv ) e / a ratios and mpir did not change significantly after mild co intoxication ( p = 0.404 and p = 0.235 , respectively ) .
rv ivrt ( 101.85 27.87 ms ) was significantly higher on admission than 1 week after poisoning [ 79.95 29.23 ms ; p = 0.020 ; table 2 ] .
no significant difference was detected in left ventricular ejection fraction obtained on admission ( following co poisoning ) and 1 week later [ table 2 ] . left ( lv sm ) and right ventricular systolic function ( rv sm ) were not significantly altered with co poisoning p = 0.766 and p = 0.332 , respectively [ tables 2 and 3 ] .
carboxyhemoglobin levels were significantly correlated with mitral a wave ( r = 0.335 , p = 0.025 ) , mitral e wave deceleration time ( r = 0.512 , p = 0.001 ) , mpil ( r = 0.316 , p = 0.047 ) , and tricuspid deceleration time ( r = 0.344 , p = 0.030 ) .
carboxyhemoglobin levels were negatively correlated with mitral e / a ratios ( r = 0.320 , p = 0.044 ) .
a normal cohb level for a non - smoker is < 2% and even slightly elevated levels of cohb ( 2 - 6% ) have been shown to decrease exercise tolerance and worsen myocardial ischemia in patients with known coronary artery disease .
reversible cardiac failure may occur with a cohb concentration > 25% after co poisoning . in the current study ,
the mean cohb concentrations of the patients was 15.81% 4.87% , which was consistent with mild co poisoning and no clinical or laboratory findings indicating left ventricular systolic impairment was observed .
the present study has revealed that even mild co poisoning has acute unfavorable effects on left and right ventricular function . to our knowledge , this is the first study to investigate the hazardous effects of mild co poisoning .
none of our patients died or experienced severe complications , such as the need for artificial ventilation .
these favorable outcomes possibly resulted from the mild exposure to co ; as demonstrated by the lack of cardiac enzyme or troponin elevations seen in moderate and severe co intoxication . during the early period
however , to determine the cardiac problems that may be induced in the long run by co poisoning , further long - term , randomized , and prospective studies with a greater number of patients are necessary . as
a measure of the combined systolic and diastolic function , conventional lv myocardial performance index ( lvmpi ) frequently comes into use .
it has been reported to be a reliable parameter for the evaluation of the performances of the right and left ventricles .
the mpi , as an index of global myocardial performance , can be obtained in an easy and reliable manner ; is independent of heart rate and blood pressure .
high levels of it have been reported to be associated with adverse events like myocardial infarction . in our study , mpir did not change significantly after mild co intoxication but were significantly higher after co poisoning than 1 week after poisoning . the major cause of death from co poisoning is myocardial injury and dysfunction . left ventricular systolic dysfunction was determined in patients with moderate co poisoning in several studies .
although significant systolic dysfunction was observed with severe co poisoning , we observed no significant difference regarding the contractile function of the left ventricle immediately and 1 week after co poisoning .
co binds to cytochrome - c oxidase of the electron transport chain in vitro , resulting in asphyxiation at the cellular level .
oxygen radical formation and subsequent lipid peroxidation have also been implicated as mechanisms for cell death .
cohb levels as low as 5% can cause a considerable decrease in the blood 's capacity to carry oxygen .
however , clinical studies in healthy humans suggest that modest levels of co have little effect on exercise performance , cardiac output , heart rate , blood pressure , or minute ventilation .
increased sympathetic activation and consequent hemodynamic effects of co may have implications for understanding the relationship between atmospheric co pollution and fatality rates in patients with acute myocardial infarction .
blood pressure , heart rate , and rate - pressure products were similar in the patient and control groups [ table 2 ] . as
tissue doppler imaging is more sensitive than conventional doppler methods in the assessment of lv function and is independent of filling pressure , we have combined the two techniques in our study , and found significant relaxation abnormalities related with co poisoning .
echocardiographic evaluation of right ventricular function is difficult because of the geometry of the ventricle and its position beneath the sternum .
it has been reported that the mpi is a useful index for evaluating rv function . as our study group consisted of patients with mild co intoxication ,
our results confirm a relaxation abnormality , despite preserved ventricular contractile function at relatively low levels of co intoxication .
the possible clinical results of co poisoning may be underestimated by the relatively small sample size of the study .
our study includes data from an earlier period . in order to determine the cardiac problems that may be induced in the long run by co poisoning , further long - term , randomized , and prospective studies with a greater number of patients are necessary .
it is believed that lv filling pressure , left ventricular disorder is reflected by the ratio of peak diastolic early velocity ( e ) of lv inflow to peak diastolic longitudinal velocity ( e ) of the mitral annulus ( e / e ) .
e / value would improve scientific value of our paper , however , we have not measured e / values due to the fact that it was not present in our initial working plan .
the possible clinical results of co poisoning may be underestimated by the relatively small sample size of the study .
our study includes data from an earlier period . in order to determine the cardiac problems that may be induced in the long run by co poisoning , further long - term , randomized , and prospective studies with a greater number of patients are necessary .
it is believed that lv filling pressure , left ventricular disorder is reflected by the ratio of peak diastolic early velocity ( e ) of lv inflow to peak diastolic longitudinal velocity ( e ) of the mitral annulus ( e / e ) .
e / value would improve scientific value of our paper , however , we have not measured e / values due to the fact that it was not present in our initial working plan .
we conclude that co intoxication leads to right and left ventricular relaxation abnormalities before the development of contractile dysfunction .
further studies with large number of subjects , investigating the possible chronic effects of mild co poisoning on left and right ventricular function will aid in obtaining more clinically relevant results .
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### Summary:
: rationale : carbon monoxide ( co ) poisoning is associated with direct cardiovascular toxicity . in mild co poisoning in which cardiovascular life support is not required ,
the effects of co on left and right ventricular functions are unknown in patients without cardiac failure.objectives:echocardiography was used to determine whether or not mild co poisoning impairs ventricular function .
twenty otherwise healthy patients with co poisoning and 20 age- and gender - matched controls were studied .
echocardiographic examinations were performed at the time of admission and 1 week after poisoning.results:the impairment observed in the left and right ventricular diastolic function at the time of admission was greater than the impairment 1 week after poisoning .
mild co poisoning did not have a significant effect on systolic function .
carboxyhemoglobin levels were positively correlated with left ventricular diastolic dysfunction , whereas the levels were not correlated with right ventricular diastolic function.conclusions:in co intoxication , the development of left and right ventricular diastolic dysfunction precedes systolic abnormality .
patients with mild co poisoning do not manifest cardiovascular symptoms ; however , it should be borne in mind that most of these patients have myocardial involvement .
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: harmful algal blooms ( habs ) are global phenomena throughout the world 's oceans that have led to increasing concerns in terms of human health , environmental preservation and economic challenges .
these concerns stem from the increasing frequency and geographic distribution of a number of toxin - producing algal species that cause habs in locations widespread around the globe .
the associated marine biotoxins produced by certain hab species become a major concern to consumers and fishery industries when filter - feeding shellfish , such as mussels , oysters , clams and cockles , ingest toxic algae and accumulate their biotoxins to dangerously high levels . in the case of ciguatera fish poisoning ( cfp ) ,
the causative ciguatoxins of algal ( dinoflagellate ) origin are transferred and accumulated through multiple trophic levels ranging from small herbivores to larger predatory fish species that are generally the most toxic due to biomagnification of ciguatoxins .
bacterially produced pufferfish poisoning ( pfp ) toxin has been detected in a number of pufferfish species as well as various marine invertebrates ( e.g. gastropods , crabs and octopus ) and is considered to reflect the acquisition of both toxigenic bacteria and exogenous pfp toxin via trophic interactions .
taking into consideration the health hazards posed by marine biotoxins , the european commission has developed regulatory limits for each toxin .
however , fearing that current regulations do not sufficiently protect human health , the european food safety authority ( efsa ) has made recommendations to change the current european union ( eu ) regulations to impose stricter limits on marine biotoxins ( table 2 ) .
these limits were developed based on the criteria that , if consuming a large portion ( 400 g ) of shellfish , one would not exceed the acute reference dose ( arfd ) for the associated toxin .
for example , consumption of a 400 g portion of shellfish contaminated with the eu limit of 160 g of okadaic acid ( oa ) equivalent / kg of shellfish would lead to a dietary exposure approximately three times higher than the arfd . *
value equals us food and drug administration ( fda ) action limit the economic implications of habs and marine biotoxins are associated with the closure of coastal fisheries , losses of valuable shellfish goods , job losses and a reduction in tourism and recreational activities .
one study from washington state , usa , estimated the annual losses from two counties due to coastal fishery closures were in the tens of millions of us dollars .
another study estimated the global economic impact of marine biotoxins was approximately us$ 4 billion per year .
habs have been linked with climate change and eutrophication ; therefore , as habs and , by extension , marine biotoxins are likely to occur more frequently and over a larger area due to these factors , it is imperative that sufficient monitoring programmes are in place to reduce the risk to consumer health and global economies . in this review , the monitoring of habs and their associated marine biotoxins will be discussed in the context of two applications : first , the methods currently used to monitor habs will be considered ( e.g. light microscopy ( lm ) ) and compared with emerging autonomous platforms that can monitor these algae in situ and that can , in certain cases , also detect and quantify levels of algal toxins in seawater ; secondly , methods for the detection of marine biotoxins in shellfish samples will be outlined , comparing the current regulatory - approved methods with emerging biosensors .
in 1995 , a human food poisoning event occurred in the netherlands following the consumption of blue mussels ( mytilus edulis ) originating from ireland .
a number of people became ill , displaying symptoms characteristic of diarrhetic shellfish poisoning ( dsp ) .
it was not for another two years that , in 1997 , using nuclear magnetic resonance ( nmr ) and mass spectrometry ( ms ) analysis , the causative toxin , a novel biotoxin designated azaspiracid ( aza ) was discovered . to date , over 20 aza analogues have been identified in plankton and shellfish ( reviewed in ) . until 2007 ,
the plankton species protoperidinium crassipes was deemed to be the primary producer of aza . however , in pure culture , p. crassipes could not produce the toxin .
, aza has been detected largely in europe , but also on the western coast of north america , both coasts of south america and in east asia .
monitoring of hab species is currently heavily reliant on the use of traditional methods , such as lm .
this technique is highly time - consuming and labour - intensive , and requires trained personnel .
accurate identification of certain species using lm is also very difficult , often requiring the use of electron microscopy for confirmation , and there is a demand for frequent sample acquisition .
other advanced methods of hab monitoring make use of satellite imaging to remotely sense ocean colour that serves as a proxy for in - water molecules , such as chlorophyll , which can be used to estimate levels of and changes in algal biomass . however , this method is limited by factors such as poor sensitivity at low cell concentrations , detection being restricted to the water surface , and interference from clouds and coloured dissolved organic matter ( cdom ) in the water .
additionally , hab detection methods such as lm and satellite imaging can not determine toxin levels associated with a given bloom population and thus the likelihood of adverse effects , such as the contamination of fishery resources .
molecular methods , namely quantitative polymerase chain reaction ( qpcr ) , hold great potential to address the specificity and sensitivity limitations associated with the above techniques .
such methods involve the amplification of specific genomic deoxyribonucleic acid ( dna ) sequences in the target species using gene - specific primers .
these primers incorporate fluorescent probes that can be quantified and correlated with the relative abundance of the target gene .
one such assay involves the amplification of genes associated with saxitoxin ( stx ) production in alexandrium species and could allow the side - by - side identification and enumeration of potentially toxic algal species .
note , however , that simply the presence of toxin genes does not necessarily translate into the production of toxin , only the potential to synthesize these metabolites under the appropriate environmental conditions .
such assays are amenable for point - of - need ( pon ) use , but currently require trained personnel to carry out the procedure .
however , one can envisage such systems being automated in the near future , thereby allowing the fully autonomous monitoring of toxigenic algal species in situ ( for further reading , see ) .
autonomous and in situ monitoring of algae and their associated marine biotoxins is a concept that is emerging rapidly .
such systems , which are now becoming commercially available , allow for real - time or near - real - time monitoring of algae and their toxins at the site of an ongoing bloom or early in the process of bloom initiation and the relaying of this information to the relevant authorities .
they can be deployed on stationary moorings or potentially on autonomous underwater vehicles ( auvs ) .
one example is the imaging flow cytobot ( ifcb ; mclane research laboratories , inc .
, east falmouth , ma , usa ) , which combines high - resolution video imagery with flow cytometry to allow the autonomous in situ classification of marine algae to species level .
another example is the environmental sample processor ( esp ) developed by the monterey bay aquarium research institute ( mbari ) and collaborators at the national oceanic and atmospheric administration ( noaa ) , which has been deployed in monterey bay , ca , usa , for the detection of both pseudo - nitzschia species and the neurotoxin domoic acid ( da ) produced by some of these organisms . the robotic esp system , also available from mclane research laboratories , inc .
, allows the autonomous sub - surface detection of the toxin and algae using enzyme - linked immunosorbent assay ( elisa ) and dna probe arrays , respectively .
other esps have been deployed in the gulf of maine to monitor levels of alexandrium species and paralytic shellfish poisoning ( psp ) toxin levels .
this project will determine the feasibility and the economic advantage of deploying remote , autonomous sensors for harmful algal species ( see the noaa website at http://oceanservice.noaa.gov/news/weeklynews/jun13/esp-robot.html and the nccos website at http://www.coastalscience.noaa.gov/projects/detail?key=137 ) .
these unmanned systems currently have the ability to autonomously provide spatial and temporal information on algal pigment distributions that can be useful for hab monitoring , but provide no data on the species or toxin present . in order to address this shortcoming
, scientists are currently developing a redesigned esp that will fit within the payload of an auv ( c. scholin , personal communication ) and thus enable measurements of algal and toxin concentrations on this mobile platform , which is something as yet unavailable to marine scientists and coastal managers .
this could allow an advanced understanding of hab occurrences , their frequency and their causes , and may potentially allow the enhanced prediction and protection of public health as well as economic interests in the future .
to date , the detection of marine biotoxins , as opposed to the hab toxin - producers , has focused mainly on detection in shellfish tissue more so than in seawater .
this is largely due to the regulation of toxin levels in seafood and the absence of regulation of toxins in seawater .
the most widely employed method for the screening of shellfish tissue was the mouse bioassay ( mba ) .
this method involves the intraperitoneal ( ip ) injection of suspect shellfish tissue extract into a mouse and the monitoring of symptoms over time until death . aside from the obvious ethical issues ,
it also does not provide information as to the exact toxins present in the sample .
for these reasons , as of 1 january 2015 , mba has been prohibited in the eu for use in detecting the presence of marine biotoxins in shellfish material .
the approved reference methods for the detection of marine biotoxins in shellfish samples are now established as high - performance liquid chromatography ( hplc ) ( for da , oa and stx ) and liquid chromatography http://www.coastalscience.noaa.gov/projects/detail?key 137 tandem mass spectrometry ( ms ) ( lc http://www.coastalscience.noaa.gov/projects/detail?key 137 ms / ms ) ( for brevetoxin ( btx ) and aza ) . however , although the hplc methods have greater sensitivity than mba at toxin concentrations reflecting the current regulatory levels , these sensitivities would need to be improved for certain methods should the regulatory limits be lowered .
this issue may be addressed through use of lc http://www.coastalscience.noaa.gov/projects/detail?key 137 ms / ms , as it possesses excellent sensitivity and is also amenable for high - throughput analysis .
ms / ms has not yet been validated in inter - laboratory studies for all toxin classes and both of these methods are labour - intensive and require highly trained personnel and expensive equipment .
thus , there is an open niche for an easy - to - use , rapid , inexpensive and accurate pon monitoring device for marine biotoxins in shellfish tissue .
an accepted and proven approach that fits these criteria is the use of biosensors , which have been discussed extensively in this volume and other review articles ( see ) .
assays conducted on such devices incorporate a biorecognition element coupled to a chemical / physical measurement system that allow the detection of a target analyte(s ) .
they also have excellent potential to serve as an in situ screening tool for marine biotoxins in shellfish samples and also in seawater .
many of these assays utilize the naturally high binding affinity of marine biotoxins to their cellular target , e.g. voltage - gated sodium channel receptors for psp , btx , ciguatoxin ( ctx ) and tetrodotoxin ( ttx ) , glutamate receptor for da or protein phosphatase for oa ( see table 1 and figure 1 ) .
receptor - based assays ( rbas ) , although currently restricted to the laboratory bench , have excellent sensitivity and working range for their respective toxins , provide an estimate of integrated toxic potency for a sample and have a very rapid turnaround time ( tat ) . however , rbas may have limited applicability for pon testing as their biorecognition elements have a limited stability at temperatures greater than 4c [ 2025 ] .
pp2a catalyses the conversion of p - nitrophenyl phosphate ( p - npp ) into p - nitrophenol ( p - np ) .
dsp group toxins , such as oa , block the binding site of the pp2a enzyme , preventing the catalysis of p - npp .
many biosensor assays for small haptenic molecules such as marine biotoxins use antibodies as their biorecognition elements , and are based on a competitive immunoassay format , utilizing the highly specific interaction between an antibody and its target antigen ( figure 2 ) .
plate - based elisa is amenable for high - throughput analysis and has excellent performance characteristics .
however , this assay is not truly rapid ( i.e. tat of less than 1 h ) and requires numerous reagent additions and wash steps , incubations , trained personnel and dedicated equipment for the measurement of results [ 2629 ] .
other systems for toxin detection use the same competitive format principle , but have improved read - out or incorporate high - density spotting in a microarray format . surface plasmon resonance ( spr ) biosensors allow automated and multiplexed analysis as well as the regeneration and reusability of assay surfaces .
luminex microsphere , liquid - based array assays , as used by fraga et al .
, use flow cytometry principles coupled with the competitive format to allow the high - sensitivity multiplexed detection of toxins . however , both of these systems generally require dedicated expensive equipment and trained personnel , limiting their use at the pon . in the case of spr ,
the potential for pon applications is starting to be addressed through the development of field - portable instrumentation .
the field - portable spirit device ( seattle sensor systems , inc . ) has been demonstrated for the detection of the amnesic shellfish poisoning ( asp ) toxin da , although extensive validation of this technology is lacking . the mbio waveguide - based system , in development at mbio diagnostics , inc .
, is a highly flexible detection device , [ 3639 ] , has a 15 min test time , is highly sensitive and allows multiplexed detection of asp , dsp and psp or additional toxins .
moreover , the mbio single - use waveguide cartridges along with a dedicated reader represent a very economical approach to testing for multiple toxins in a single sample and require minimal training of end - users .
direct label - free immunoassays are also beginning to emerge such as that developed by hayat et al . .
this sensor , which utilizes anti - oa monoclonal antibodies bound to an impedimetric electrochemical surface , was capable of high - sensitivity detection with a short tat . also , being relatively simple to perform and inexpensive to produce means that such an assay shows promise for pon testing .
enzyme - labelled anti - toxin antibodies are added to a microwell plate coated with toxins conjugated to a carrier protein .
( a ) in the absence of free toxin in solution , the antibodies are uninhibited and bind to the coated surface at a high concentration .
addition of a substrate ( e.g. 3,3,5,5-tetramethylbenzidine ( tmb ) in the case of horseradish peroxidase ( hrp)-labelled antibodies ) produces a coloured product of high intensity .
( b ) in the presence of free toxin in solution , the free toxin competes with the immobilized toxin - conjugate for binding to the antibodies .
many , if not all , of the above assays are likely to be laboratory - based alternatives to high - performance analytical methods such as hplc and lc
none of these assays , perhaps with the exceptions of the mbio system and direct electrochemical assay , are currently amenable to pon testing .
a final assay format , lateral flow immunoassay ( lfia ) , may present a suitable alternative for this .
these tests are cheap to manufacture , easy to use , rapid , have good performance characteristics and , with the incorporation of simple reader systems , are easy to interpret .
these benefits , coupled with excellent shelf life and temperature stability , infer that lfias have great potential to be used as dockside screening assays of recently landed shellfish for the presence of marine biotoxins .
however , due to the qualitative or semi - quantitative output of these assays , further confirmatory laboratory - based analysis would probably be required for regulatory clearance of a commercial product [ 4144 ] .
a potential problem with antibody - based toxin sensors is the issue of cross - reactivity ( cr ) between toxin analogues of the same group .
for example , the psp toxin group has more than 20 analogues that may differ by only a single side group , each with differing toxicities .
therefore , an assay incorporating an antibody that targets stx and shows strong cr for only a small number of stx analogues would probably underestimate the overall psp toxicity of a sample , depending on the sample 's toxin composition . a potential solution to this would be to incorporate a cocktail of different antibodies , each with a different cr profile for the psp toxins .
however , it would be highly challenging to characterize the cr of such a large number of antibodies for numerous targets .
chemical conversion of low into high cr analogues is also a potential means of addressing this issue .
these short oligo - dna or -rna molecules can bind to a wide range of targets with high affinity and specificity , including environmental pollutants ( the reader is directed to for a review ) . without the need for an animal host , they are relatively easy to generate to a range of targets
. their small size may also allow them to distinguish subtle differences between toxin analogues .
to date , aptamers have been developed against stx , oa and btx-2 [ 4648 ] .
aptamers represent an expanding area in the field of diagnostics and may have potential for marine biotoxin detection due their relatively high stability .
in many cases , there will be a need to pre - concentrate and extract the specific targeted toxin or its producer from marine or freshwater . in this case
, the use of the aforementioned biorecognition ligands in the form of a solid - phase extraction system may also be important prior to determination of actual toxin levels by biosensors .
habs and their associated marine biotoxins present a serious concern for global economies , consumer health and the environment . these toxins are associated with acute short - term symptoms as well as long - term risks such as cancer .
currently , international regulatory - approved detection methods for toxins require expensive equipment , trained personnel , long tat , and laborious sample acquisition and processing .
thus , there is a need for inexpensive , easy - to - use , rapid and sensitive tests that can take toxin monitoring out of the laboratory and into the field ( or water ) .
biosensors have the potential to address this need , in particular those with antibody- and aptamer - based recognition elements , as their excellent sensitivity , specificity and stability lend themselves extremely well to pon testing .
however , few automated systems are currently available to allow completely hands - off remote monitoring , which is highly relevant to in - sea monitoring of habs and toxins .
sample processing to concentrate algal target cells and their toxins is a significant challenge , yet a critical component for such automated systems in order to achieve appropriate limits of detection .
the area of microfluidics has proven very promising for allowing automated lab - on - a - disc devices to carry out immunoassays remotely and could have potential to address this need .
additionally , further work must go into developing higher specificity antibodies for various toxin analogues , as currently there is the possibility of underestimation of sample toxicity .
this review discussed two applications of toxin / algae monitoring : first , front - line sensors for in - sea detection may help to mitigate the harvesting of contaminated shellfish in areas prone to blooms ; secondly , sensors for the shipboard and dockside detection of toxins serve as a second line of defence and may help to avoid the processing of already harvested contaminated shellfish and prevent their consumption by consumers .
these sensors will hopefully help to mitigate some of the adverse effects of the growing problem of habs and marine biotoxins in the coming years , allowing the harvesting of safe food and reduction of global economic losses .
the six major marine intoxication syndromes each have their own unique mode of action and associated symptoms , which range from moderate to severe .
current monitoring programmes for habs and marine biotoxins are expensive , labour - intensive and have a relatively long turnaround time .
biosensors present a favourable alternative to the laboratory - based analytical methods currently used in monitoring as they boast excellent performance characteristics , ease - of - use , cost - effectiveness and short turnaround time .
a number of recently developed biosensors for marine biotoxins were discussed . in particular , immunoassay - based methods have great promise as their robustness and stability mean that they are flexible for analysis in complex matrices such as seawater and shellfish extract .
currently , the main drawback of immunoassays for toxins is their underestimation of sample toxicity due to the poor cross - reactivity of antibodies to certain toxin analogues .
this could be addressed in the future via the development of higher - specificity antibodies or aptamers for the various toxin analogues .
we acknowledge support from science foundation ireland [ grant number 10/ce / b1821 ] and the irish research council .
we also acknowledge support from the national science foundation [ grant numbers oce-0982032 and oce-314222 ] . this material is based upon work supported by the national science foundation [ grant numbers oce-1440299 and poce-1440198 ] ( eager collaborative ) .
we have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed .
disclaimer : this publication does not constitute an endorsement of any commercial product or intend to be an opinion beyond scientific or other results obtained by the national oceanic and atmospheric administration ( noaa ) . no reference shall be made to noaa , or this publication furnished by noaa , to any advertising or sales promotion which would indicate or imply that noaa recommends or endorses any proprietary product mentioned herein , or which has as its purpose an interest to cause the advertised product to be used or purchased because of this publication .
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### Summary:
: increasing occurrences of harmful algal blooms ( habs ) in the ocean are a major concern for countries around the globe , and with strong links between habs and climate change and eutrophication , the occurrences are only set to increase
. of particular concern with regard to habs is the presence of toxin - producing algae .
six major marine biotoxin groups are associated with habs .
ingestion of such toxins via contaminated shellfish , fish , or other potential vectors , can lead to intoxication syndromes with moderate to severe symptoms , including death in extreme cases .
there are also major economic implications associated with the diverse effects of marine biotoxins and habs .
thus , effective monitoring programmes are required to manage and mitigate their detrimental global effect
. however , currently legislated detection methods are labour - intensive , expensive and relatively slow .
the growing field of biosensor diagnostic devices is an exciting area that has the potential to produce robust , easy - to - use , cost - effective , rapid and accurate detection methods for marine biotoxins and habs .
this review discusses recently developed biosensor assays that target marine biotoxins and their microbial producers , both in harvested fish / shellfish samples and in the open ocean .
the effective deployment of such biosensor platforms could address the pressing need for improved monitoring of habs and marine biotoxins , and could help to reduce their global economic impact .
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: the purpose of this research was to better understand the outcomes of integration by asking what promotes the experience of continuity of care from the point of view of people with long - term neurological conditions .
[ 1 , 2 ] as a conceptual framework with which to consider people s experiences of using services within more and less integrated systems .
in - depth case studies were undertaken in six service systems across england with varying levels of social and health care integration .
the findings presented here come primarily from in - depth interviews with people with ltncs who used services in these systems .
the following service models promote continuity of care for people with ltncs : community interdisciplinary neuro - rehabilitation teams , day opportunity services , nurse specialists and other forms of care co - ordination .
not everyone who might benefit from these service models is currently able to do so .
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### Summary:
: purposethe purpose of this research was to better understand the outcomes of integration by asking what promotes the experience of continuity of care from the point of view of people with long - term neurological conditions.theorywe used the definitions of continuity of care developed by freeman et al . [ 1 , 2 ] as a conceptual framework with which to consider people s experiences of using services within more and less integrated systems.methodsin-depth case studies were undertaken in six service systems across england with varying levels of social and health care integration .
the findings presented here come primarily from in - depth interviews with people with ltncs who used services in these systems .
data were thematically analysed and triangulated with other case study information.results and conclusionthe following service models promote continuity of care for people with ltncs : community interdisciplinary neuro - rehabilitation teams , day opportunity services , nurse specialists and other forms of care co-ordination.discussionnot everyone who might benefit from these service models is currently able to do so .
how can we ensure equity of coverage and access ?
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<s> [INST] <<SYS>> You a helpful assistant capable of providing accurate and concise responses. You will assist me in generating Summary.<</SYS>> [/INST] <s> ### Text:
: marine and freshwater teleosts are constantly exposed to opposite osmotic gradients leading respectively to passive influx or efflux of water and ions . such gains and losses
are compensated through the coordinated control of osmoregulatory organs that mediate opposite fluxes within body fluids in order to maintain homeosmotic balance ( marshall and grosell , 2006 ) . amongst other mechanisms , water channels or aquaporins
recent studies have advanced this notion by revealing that teleosts harbor a large repertoire of water - selective aquaporins and water and solute ( glycerol , urea ) permeable aquaporins , also known as aquaglyceroporins ( cerd and finn , 2010 ; tingaud - sequeira et al . , 2010 ) .
an overview of the evolution and nomenclature of piscine aquaporins , including the recently renamed aquaporin-1 paralogs , as well as their permeability properties and expression profiles , is provided by cerd and finn ( 2010 ) and finn and cerd ( 2011 ) . in this mini - review ,
oviparous marine and catadromous teleosts release their gametes into the marine environment where external fertilization takes place .
considering that the gametes lack the adult organs that deal with ion and water balance , it seems likely that molecular adaptations should be present in the reproductive organs , gametes , and early embryos to cope with the external osmotic challenges .
we therefore discuss recent studies that highlight the mechanistic roles of aquaporins , and how such channels may be associated with the adaptation of teleosts to diverse life histories and habitats .
during spermatogenesis diploid spermatogonia associated with somatic sertoli cells enter meiosis to become primary and secondary spermatocytes , and eventually haploid spermatids , which elongate and differentiate into flagellated spermatozoa . in teleosts , this process is regulated by pituitary gonadotropins , via specific receptors in leydig and sertoli cells , through the synthesis and release of sex steroids ( androgens and progestins ) and growth factors , respectively ( schulz et al . , 2010 ) .
the final stage of spermatogenesis or spermiation principally involves the production of hydrated seminal fluid that facilitates the acquisition of motility and the passage of spermatozoa through the sperm ducts ( scott et al . , 2010 ) .
in mammals , different aquaporins are found in spermatozoa , as well as in testicular germ and somatic cells ( yeung , 2010 ) .
aquaporin-7 ( aqp7 ) is localized in late spermatids , both in the cytoplasm and later in the plasma membrane , whereas aqp8 shows a more variable distribution from restriction to certain spermatogenic cell types to all germ cells .
these three aquaporin isoforms are subsequently found in spermatozoa , as well as aqp3 , although they are differentially localized along the sperm tail ( yeung , 2010 ; chen et al . , 2011a ) .
although a role of aqp8 in volume regulation of murine spermatozoa has recently been suggested ( yeung et al . , 2009 ) ,
knockout mice models for aqp7 and -8 , have failed to show clear phenotypes during spermatogenesis or sperm viability ( yang et al . , 2005 ; sohara et al . , 2007 ) .
the function of aqp11 is also yet uncovered because aqp11 knockout mice die of renal failure before puberty ( morishita et al . , 2005 ) .
however , a recent study shows that aqp3-deficient sperm displays defects in volume regulation and excessive cell swelling upon physiological hypotonic stress in the female reproductive tract ( chen et al . , 2011a ) .
in teleosts , as suggested for mammals , aquaporins may be involved in the hydration of the seminal fluid as well as in sperm physiology . however , although mrnas of different aquaporin paralogs have been found in the teleost testis ( cerd and finn , 2010 ) , their specific cellular localization and the function of the protein products during spermatogenesis remain to be investigated .
( 2009 ) have investigated the role of aquaporins during the activation of spermatozoa motility in marine teleosts . in these species ,
the hyperosmotic challenge faced by the spermatozoa when discharged into seawater leads to a rapid water efflux .
this rapid efflux , which causes membrane hyperpolarization resulting in the activation of cell motility ( alavi and cosson , 2006 ; zilli et al . , 2008 ) , was suggested to be mediated by aquaporins ( cosson et al . , 2008 ) .
( 2009 ) showed that both the water - selective aqp1aa ( ralda et al . , 2008 ) and the aquaglyceroporin channel aqp10b ( formerly named glp ; santos et al . , 2004 ) are indeed expressed in the head and flagellum of gilthead sea bream ( sparus aurata ) spermatozoa .
further functional expression and sperm activation assays in the presence of mercury chloride , a non - selective inhibitor of aquaporin permeability , suggested that aqp1aa might mediate sperm activation ( zilli et al . , 2009 ) .
the model proposed by the authors suggests that the hyperosmotic stimulus upon release of spermatozoa into seawater induces the accumulation of aqp1aa in the plasma membrane to facilitate the rapid water efflux .
this results in the reduction of cell volume and concomitant rise of the intracellular ion concentration , which in turn activates the camp signaling - pathway leading to the downstream phosphorylation of the flagellar proteins and the initiation of sperm motility .
this model may be premature , however , since it is based on sperm activation assays in the presence of the aquaporin inhibitor hgcl2 and the reducing compound -mercaptoethanol ( which can not reverse the mercurial inhibition of aqp10b expressed in xenopus laevis oocytes ; santos et al .
in addition , a number of key questions remain to be addressed , such as the role of aqp10b - mediated water and/or solute transport in spermatozoa and of other aquaporins during germ cell differentiation , and the distribution and function of aquaporins in sertoli and leydig cells . whether the expression of aquaporins during teleost spermatogenesis is hormonally controlled still needs to be clarified . in mammals
, aqp8 is expressed in the sertoli cells of all testicular tubules , whereas aqp0 is only expressed within sertoli cells in tubules containing elongating spermatids just before being released into the lumen ( hermo et al . , 2004 ) .
these observations suggest that aqp0 might be hormonally regulated . however , whether aqp0 or -8 in sertoli cells are modulated by steroids , as it occurs for aqp1 and -9 in the epididymis ( oliveira et al . , 2005 ) or for aqp2 in the uterus ( jablonski et al . , 2003 ) , remains to be investigated . in teleosts
, the hydration of the seminal fluid during spermiation and acquisition of sperm motility seems to be regulated by progestins such as 17,20-dihydroxypregn-4-en-3-one ( 17,20p ) or 17,20,21-trihydroxypregn-4-en-3-one ( 20-s ; scott et al . , 2010 ) .
these steroids can potentially activate nuclear progestin receptors expressed in sertoli and leydig cells , spermatogonia and/or spermatocytes ( miura et al .
, 2006 ; chen et al . , 2010b , 2011b ; hanna et al . , 2010 ) .
in addition , progestins can directly stimulate spermatozoa hypermotility through membrane receptors coupled to adenylyl cyclase located in the plasma membrane ( tubbs et al . , 2011 ) .
therefore , it will be of interest to investigate if testicular and sperm aquaporins may be under 17,20p- or 20-s - mediated transcriptional and/or posttranslational regulation .
in mammalian oocytes , expression of mrnas encoding different aquaporins has been described ( e.g. , edashige et al . , 2000 ) , although so far detection of the corresponding polypeptides remained elusive , except for aqp3 in bovine oocytes ( jin et al . , 2011 ) .
in the granulosa and theca cells associated to the oocyte , however , several functional aquaporins such as aqp1 - 4 , -5 , and -9 are differentially localized ( skowronski et al . , 2009 ; thoroddsen et al . ,
2011 ) . as an adaptation to the hyperosmotic condition of seawater , the oocytes of oviparous marine teleosts hydrate during meiosis resumption ( oocyte maturation ) .
this mechanism provides a water reservoir in the embryo to compensate for the passive water efflux until osmoregulatory organs develop , and improves oxygen exchange and egg dispersal in the ocean ( fyhn et al . , 1999 ; finn and kristoffersen , 2007 ; cerd , 2009 ; finn and fyhn , 2010 ) .
early studies in the gilthead sea bream ( fabra et al . , 2005 , 2006 ) , and later in the japanese eel ( anguilla japonica ; kagawa et al . , 2009 , 2011 ) , identified the novel role of aqp1ab in this process .
this duplicated paralog facilitates the temporal water permeation and the pre - ovulatory swelling of the oocyte .
the mechanism is coregulated with yolk proteolysis and ion fluxes that generate the intracellular osmotic driving force for fluid transport , a feature well established in both old and modern teleost species ( cerd et al . , 2007 ;
further functional , genomic and phylogenetic analyses revealed that aqp1ab belongs to a teleost - specific subfamily of water - selective aquaporins , which evolved by tandem duplication of a common ancestor ( martinez et al .
interestingly , aqp1ab transcripts have also been found in the ovary of the freshwater teleost stinging catfish ( heteropneustes fossilis ) , in which oocytes moderately hydrate during meiotic maturation ( singh and joy , 2010 ) , although the role of aqp1ab in the oocyte of this species is yet unknown ( chaube et al . , 2011 ) .
the role of aqp1ab during oocyte hydration in marine teleosts is supported experimentally by the observation that the swelling of oocytes is blocked by aquaporin inhibitors such as mercury and tetraethylammonium ( fabra et al . , 2005 , 2006 ;
2009 ) . however , these compounds can also affect k channels and other ion transport proteins ( armstrong , 1990 ; jacoby et al . , 1999 ) , which may play a role for inorganic osmolyte accumulation in the oocyte ( cerd et al .
more conclusive data have been recently obtained in the atlantic halibut ( hippoglossus hippoglossus ) , a marine teleost that reproduces at low temperature and spawns one of the largest pelagic eggs known ( zapater et al . , 2011 ) .
in this study , atlantic halibut oocytes undergoing hydration were microinjected with an antiserum specific for halibut aqp1ab , resulting in a dose - dependant inhibition of oocyte hydration in the presence of yolk hydrolysis .
the immunological inhibition could be fully reversed by the artificial expression of halibut aqp1aa which is not recognized by the antibody .
therefore , these findings indicate that the decrease of oocyte hydration of atlantic halibut oocytes can be directly related to the loss of function of aqp1ab , providing for the first time functional evidence of the essential physiological role of this water channel .
recent studies in the gilthead sea bream have begun to dissect the molecular mechanisms involved in the physiological regulation of aqp1b in the oocyte .
preliminary data suggest that transcriptional activation of the aqp1ab promoter in primary growth oocytes may be dependent on sry - related high mobility group [ hmg]-box ( sox ) genes , as well as on the nuclear progestin receptor , which are highly expressed in oogonia ( zapater et al . , unpublished data ) .
this mechanism likely results in the accumulation of high levels of aqp1ab transcripts and aqp1ab peptides in primary growth oocytes .
subsequently , aqp1ab - containing vesicles are transported toward the oocyte cortex throughout the period of oocyte growth , and during meiotic maturation and hydration they are temporarily inserted into the oocyte plasma membrane ( fabra et al . , 2006 ) .
structural analyses have revealed that the cytoplasmic tail of aqp1ab , although highly divergent among teleosts , retains specific motifs that regulate vesicular trafficking , and therefore they may be involved in the control of aqp1ab translocation into the oocyte plasma membrane during hydration ( tingaud - sequeira et al . , 2008 ; chaube et al . ,
these processes appear to involve alternative mechanisms of phosphorylation and/or dephosphorylation of specific c - terminal residues , but the specific intracellular signaling pathways involved are yet unknown . these observations thus indicate that aqp1ab in the oocyte is tightly regulated at the transcriptional and post - translational level during oogenesis , oocyte growth , and meiotic maturation .
the studies carried out so far are revealing that the aqp1ab - mediated mechanism of oocyte hydration in marine teleosts is a conserved and highly regulated process , based on the interplay between osmolyte generation and the controlled synthesis and insertion of aqp1ab at the oocyte surface .
however , there are still many unresolved issues , such as the transductional pathways activated in the oocyte during hormone - induced meiotic maturation and hydration that coordinate osmolyte generation , aqp1ab intracellular trafficking and meiosis resumption . in this regard
, it will be of interest to investigate the role of g protein - coupled progestin receptors on the oocyte surface , as well as the classical nuclear progestin receptor , during the control of aqp1ab trafficking , as these receptors may be the physiological transducers of progestins to activate meiosis resumption ( thomas et al . , 2004 ) .
however , it is known that in the teleost ovary , in addition to aqp1ab , mrnas encoding many other aquaporin paralogs are found ( cerd and finn , 2010 ) , although the cellular sites of expression have not yet been defined .
whether the accumulation of these transcripts corresponds to maternal messengers stored in oocytes required for early development , or reflect the coordinated role of different aquaporins in ovarian fluid homeostasis , remains to be investigated .
very limited information is available on the localization and function of aquaporins during mammalian and teleost early embryonic development . in the mammalian morula ,
aqp3 , -8 , and -9 are detected in the cell cell contact domains of blastomeres , despite observations that these embryos show very low water and solute permeability ( barcroft et al .
, 2003 ; edashige et al . , 2007 ) , although this may differ among species ( jin et al . , 2011 ) . at the blastula stage ,
blastoderm cells express only aqp3 , whereas aqp3 and -8 are accumulated at the basolateral membranes of trophectodermal epithelial cells of blastocysts , which also express aqp9 at the apical membrane ( barcroft et al . , 2003 ) .
the change in the subcellular localization of these aquaporins coincides with the enhanced water permeability of blastula stage embryos , and consequently it was suggested that these channels may mediate transepithelial water and solute movements .
the function of these aquaporins could compensate each other because aqp3 knockout mice can develop to term ( ma et al . , 2000 ) .
moreover , solute permeability is not completely abolished in embryos in which aqp3 expression has been suppressed by injection of aqp3 double - stranded rna ( edashige et al . , 2007 ) .
during teleost embryonic development , changes in the expression and cellular localization of aquaporins have only been investigated in zebrafish ( danio rerio ) and common mummichog ( fundulus heteroclitus ; tingaud - sequeira et al .
, 2009 ; chen et al . , 2010a ) . in zebrafish , aqp1aa , -3a , -7 , and -10b
transcripts are detected at the 24 cell and morula stages ( figure 1a ) , suggesting that these aquaporins are maternally inherited , as reported for mummichog aqp1aa ( tingaud - sequeira et al .
interestingly , transcripts encoding zebrafish aqp3b and mummichog aqp3a are first noted at the onset of gastrulation , during which they are apparently accumulated in embryos ( tingaud - sequeira et al .
, 2009 ; figure 1a ) . later in development , aquaporin expression is generally enhanced where the expression of other paralogs such as aqp0a , -0b , -8aa , -10a , and -11b may be detected .
for example , aqp1aa and -8aa have been related to somitogenesis and vascular development ( sumanas et al . , 2005 ; tingaud - sequeira et al . , 2009 ;
, 2010a ) , aqp0a and -0b to normal lens development and transparency ( froger et al . ,
2010 ) , and aqp11b to tail differentiation ( ikeda et al . , 2011 ) .
standart rt - pcr analyses of aquaporin transcriptional expression in zebrafish embryos reveals that aqp3a , -7 , and -10b transcripts are detectable throughout development , whereas aqp3b and aqp10a expression is only detected during gastrulation and onward , and at the onset of organogenesis , respectively .
( b e ) whole - mount immulocalization of aqp3b in zebrafish blastula embryos ( left ) and 50% epiboly embryos ( right ) using specific antibodies ( chauvign et al . , 2011 ) .
( d e ) aqp3b is not detected in the blastula ( d ) , whereas it appears in migrating blastomeres [ ( e ) arrows ] during gastrulation .
ys , yolk sac ; b , blastomeres ; g , gastrula . bar , 500 m . in the early embryos of common mummichog ( tingaud - sequeira et al . , 2009 ) and zebrafish ( figures 1b e ) , immunolocalization experiments using specific antibodies have respectively revealed the presence of aqp3a and -3b in the blastoderm cells as well as in the enveloping layer ( evl ) . in the mummichog ,
further accumulation of the aqp3a protein is evident in the basolateral membrane of the evl epithelium as well as in the membrane of migrating blastomeres at the marginal region of the blastoderm ( tingaud - sequeira et al . ,
the localization of aqp3a in the evl of teleost embryos may indicate a role of this channel in water and solute transport during epiboly .
interestingly , the embryos of the common mummichog respond to environmental desiccation by accelerating development ( tingaud - sequeira et al . , 2009 ) . under these conditions
aqp3a expression in the evl is reduced , which could be a mechanism to reduce evaporative water loss through the evl , while membrane localization of aqp3a in migrating blastomeres remains unchanged ( tingaud - sequeira et al . , 2009 ) .
in recent years , water and solute transport mediated by mammalian aqp1 , -3 , or -4 has been proposed to be involved in cell migration and proliferation by driving water influx , thus facilitating lamellipodia extension and cell migration ( papadopoulos et al . , 2008 ; monzani et al . , 2009 ) .
a similar role for aqp3 has been proposed during neural tube closure in x. laevis embryos ( cornish et al . , 2009 ) .
in teleost embryos , the specific pattern of aqp3a expression in the plasma membrane of migrating blastomeres , and its persistence in mummichog embryos showing an accelerated rate of epiboly under desiccation conditions , also suggests the involvement of this aquaporin in cell migration during gastrulation .
preliminary experiments in common mummichog have shown delayed epiboly of embryos injected with an specific antibody against aqp3a , and thus these observations may support the role of this aquaporin during cell migration ( chauvign and cerd , unpublished data ) .
moreover , teleost embryos also express other aquaporins such as aqp1aa , -7 , and -10b during gastrulation ( tingaud - sequeira et al .
, 2009 ; figure 1a ) , and therefore their functional relationships need to be elucidated .
although available information remains scarce , increasing data indicate that aquaporins are involved in water homeostasis in reproductive organs and gametes of teleosts in addition to osmoregulatory mechanisms .
at least one paralog ( e.g. , aqp1ab ) , appears to be tightly regulated both at the gene and protein level during gametogenesis , underlining its importance for the production of gametes well adapted to the reproductive habitats .
however , more studies are necessary in teleosts , particularly those using genetic and molecular approaches , as well as specific aquaporin blockers , to elucidate aquaporin function during reproduction . an understanding of the involvement of aquaporins in fluid movement in the teleost gonads and gametes may also lead to improved cryopreservation protocols to assist breeding and species conservation programs .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
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### Summary:
: aquaporins are believed to be involved in homeosmotic mechanisms of marine teleosts .
increasing data suggest that these molecular water channels play critical roles associated with the adaptation of gametes and early embryos to the external spawning environment . in this mini - review , we discuss recent studies suggesting the function of aquaporin - mediated fluid homeostasis during spermatozoa activation and egg formation in teleosts . in addition , we address the potential role of water channels in osmosensing and cell migration during early embryonic development .
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