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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 anterior cruciate ligament ( acl ) is the most frequently disrupted ligament in the human knee ( johnson , 1982 ) .
measurements of the integrity of knee ligaments are used to diagnose injuries as well as to document the state of recovery .
ligament laxity measurement is clinically valuable to diagnosis injury and also to compare laxity before and after surgical procedure .
however , few studies have examined the reliability of clinical methods or instruments used to measure anterior - posterior laxity .
the lachman test is characterized as the most direct and definitive evaluation examination used to determine the status of acl ( benjaminse et al . , 2006 ;
anterior drawer test is also an accurate test for detecting acl tear to evaluate anterior displacement of tibial manually a sensitivity of acl tears ( calmbach and hutchens , 2003 ) .
the kt1000 ( medmetric corp . , san diego , ca , usa ) is a mechanical joint arthrometer allowing for stabilization of the femur with concurrent instrumented assessment of the lower leg ( daniel et al .
the aim of the study was to compare the accuracy of the lachman and anterior drawer tests to evaluate the knee examination with the kt1000 arthrometer after surgery in early follow - up period .
the patients included in the study who had minumum 6-month follow - up period and had the same surgery technique procedure .
there was no involvement of the posterior cruciate ligament injury as detemined by a negative posterior sag test that was administered prior to each operation .
fourty acl reconstructed knees were examined with the lachman and anterior drawer tests and kt1000 arthrometer with compariable intact knee of same patients .
one orthopaedic surgeon had 12-yr experience with evaluating knee stability and other had 9-yr experience .
the examinations were conducted with each examiner blind to the other s findings . after enrollment
the active drawer test performed to the patient with knee flexed at 90 , hip at 45 and foot stabilized on the firm examination table .
while the foot was stabilized on the examination table and the hamstrings were relax , frequent manual gentle antero - posterior forces were applied to the proximal tibia , and tibia anteroposterior displacement in flexed knee was measured and recorded by the nurse based on international knee documentation committee ( ikdc ) knee examination form .
the lachman test was performed with the patient lying supine on a firm examination table and knee flexed to 2030 degrees .
the examiner s upper hand stabilized the unsupported distal thigh , while the lower hand , and finders feeling to ensure that the hamstring were relaxed , pulled the tibia forward .
anterior translation of tibia was measured and noted by same nurse based on ikdc knee examination form . after the manual examination each patient was evaluated with the kt1000 arthrometer to record the milimiters of anterior translation at 6.8 , 9.1 , 13.6 kg and the maximum power of force .
the arthrometer detects motion between two sensor pads , one in contact with the femur and the other in contact with the tibial tubercule . with a force - sensing handle
the arthrometer emits an audible sound when 6.8 , 9.1 , 13.6 kg and maximum power force applied through the force handle .
two support platforms are necessary for the examination - a thigh support platform for positioning both knees of the patient in 2030 degrees of flexion and a foot support platform platform for maintaining both feet 15 degrees from midline with the hips in external rotation .
the examiners applied an anterior force by pulling slowly and smoothly on the force - sensing handle until four - consecutive audible tones indicated the each forces had been reached .
all examinations on one patient were performed by each of three examiners . for each patient
the uninvolved knee was evaluated first in order to establish a baseline by which the contralateral knee could be utilizied .
examiners paid attention to ensure the both knees were in the same degree of flexion during the physical examination procedure .
pass ( power analysis and sample size ) 2008 statistical software ( ncss , llc , kaysville , ut , usa ) program was used for statistical analysis .
data were analyzed by using descriptive statistical methods ( mean , standard deviation , median , frequency , ratio , minimum , maximum ) and for comparing quantitative data student t - test was used for three groups comparison of parameters with normal distribution , while mann
whitney u - test was used for three group comparisons of parameters without normal distribution .
the mean age of patients was 28.186.21 yr ( range , 1740 yr ) , and the mean follow - up was 23.099.08 months ( range , 942 months ) .
the mean kt1000 measurements of 40 operated knees state at 6.8 , 9.1 , 13.6 kg and maxium anterior displacement forces were 4.9 , 6.7 , 8.7 , and 11.9 mm , respectively .
the same values for the same acting forces of nonoperated knees were 4.2 , 5.9 , 7.8 , and 10.2 ( table 2 ) .
all seven patients had acl laxity with physical exams and also with the kt1000 arthrometer at 13.6-kg power .
spearman corelation test showed that there was a significant corelation between kt1000 arthrometer device at 13.6-kg power and lachman and anterior drawer tests ( p<0.1 and p<0.01 , respectively ) ( table 3 ) . in receiver
operating characteristic analysis at 13.6-kg power on kt1000 arthrometer certainly matches with pyhsical laxity examination tests ( p<0.1 ) ( table 4 , fig .
1 ) . thirty pound on kt1000 arthrometer was the only one power that had statistically significancy .
after acl rupture , most patients have detectable signs and symptoms of excess knee laxity and the joint becomes unstable .
anterior tibial translation in normal knees has very little different in right and left knees and in 95% of normal population ; this difference is less than 2 mm .
it is crucial to use the contralateral normal knee as control to compare the difference in laxity between normal and injured knees ( shelbourne , 2010 ) . in a clinical examination ,
the anterior displacement of the tibia on the femur is based on a subjective evaluation of acl disruption or anterior instability .
several manual tests are available to determine whether the acl has been injured and also to evaluate stability of acl at follow - up period . the classical test for acl deficiency , the lachman and anterior drawer tests are performed based on evaluation of the anterior instability ( solomon et al . , 2001 ) .
liu showed that the sensitivity of lachman and anterior drawer test was 95% and 61% , respectively .
lachman test sensitivity reaches up to 100% under anesthesia ( liu et al . , 1995 ) .
most commonly used devices available to assess ligament integrity are designed to assess the cruciate ligaments because they are accessible for testing and because they are important in maintaining knee stability .
the knee arthrometer kt1000 is a commercially feasible instrument designed to provide and objective measurement of anterior - posterior laxity ( bach et al . , 1990 ; daniel et al . , 1985 ; daniel and stone , 1990 ; wroble et al . ,
a study reported in 21 patients that kt1000 arthrometer can not be correlated with the clinical findings .
they supported doubt on the accuracy and usefulness of the kt1000 ( graham et al . , 1991 ) .
more recently , testing of knee ligament integrity with devices such as the kt1000 arthrometer has gained increasing popularity .
the kt1000 is a useful tool , as it is easy and fast to handle by an experienced examiner .
however , the importance of instrumental measurement should not be overrated even though reproducible results can be obtained . to compare the results of different studies the design has to be very similar .
it is important to know the accuracy of test used to establish a follow - up note in patients with knee stability .
so far , there is no study has considered to correlate the physical examination test with the insrumented examination at follow - up period of patients who had acl reconstruction surgery . in our study ,
therefore , the inexperienced examiner s interpretation could drop the sensitivity of these tests , regardless of which examiner findings could check with kt1000 instrumented examination . as for general practitioners who are less experienced in carying out these physical tests , they can certainly control their examination findings with the 30 pound power on kt1000 arthtrometer .
this suggests that the reserved and equivocal physical test findings can be coralated with the kt1000 arthrometer after acl surgery follow - up period . with kt1000 instrument measurements
are accurate in indicating anterior knee laxity , we tried to correlate the physical examinations of anterior - posterior laxity with kt1000 arthrometer device . taken into consideration ,
our results report that the accuracy of kt1000 arthrometer device at 13.6-kg power was statistically correlated to the lachman and anterior drawer tests . based on the follow - up performance in our study , correlation of physical examinations with
kt1000 arthrometer is a worthy evaluation technique that can be added to examination of acl reconstructed knee to control with inexperinced examiners findings .
we suggest that at 13.6-kg power on kt1000 arthrometer findings perfectly match the lachman and anterior drawer tests of knee .
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### Summary:
: ligament laxity measurement is clinically valuable to diagnose the injury and also to compare the laxity before and after surgical procedure .
the aim of the study was to compare the accuracy of the lachman and anterior drawer tests to evaluate the knee examination with the kt1000 arthrometer after the anterior cruciate ligament ( acl ) surgery in early follow - up period .
fourty acl reconstructed knees were examined with the lachman and anterior drawer tests , and kt1000 arthrometer with compariable intact knee of the same patients .
physical emanination findings were compared with the kt1000 arthrometer with each power . spearman correlation and receiver operating characteristic ( roc )
analysis were used for the evaluation of relations between parameters .
significance was evaluated in p<0.1 and p<0.05 .
the mean age was 28.186.21 yr , and the mean follow - up was 23.099.08 months .
the mean kt1000 measurements of 40 operated knees state at 6.8 , 9.1 , 13.6 kg and maxium anterior displacement forces were 4.9 , 6.7 , 8.7 , and 11.9 mm , respectively .
the same values for the same acting forces of intact knees were 4.2 , 5.9 , 7.8 , and 10.2 , respectively .
in spearman s correlation and roc analysis at 13.6-kg power on kt1000 arthrometer statistically matched with pyhsical examinations ( p<0.1 , p<0.01 ) . in our study ,
correlation of physical examinations with kt1000 arthrometer is a worthy evaluation technique that can be added to examination of acl reconstructed knee to control with inexperinced examiners findings .
we suggest that at 13.6-kg power with kt1000 arthrometer findings perfectly match the lachman and anterior drawer tests of the knee .
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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 lacrimal glands are unique structures possessing both epithelial and lymphoid tissue and may fall prey to an unusually wide range of pathologies including various neoplastic , infective , infiltrative , inflammatory and structural processes ranging from benign adenomas , adenocarcinomas , histiocytosis , benign dacrocysts and lymphomas to sarcoidosis.1 swelling and enlargement of one or both lacrimal glands remain the common denominator of most of these pathologies , suggesting size is an important factor in assessing the integrity of the lacrimal glands on most imaging studies .
a 40-year - old chinese lady presented with the history of vague headaches and blurring of vision bilaterally for three months .
magnetic resonance imaging ( mri ) of the brain was performed as part of routine work - up for headache .
no intracranial space - occupying lesions were detected ; however , the lacrimal glands appeared diffusely enlarged [ figure 1 ] .
a dedicated mri study of the orbits was recommended , with thin section , fat suppressed , gadolinium - enhanced axial and coronal t1-weighted sequences , which showed bilaterally symmetrical diffuse enlargement of the lacrimal glands [ figures 2a c ] .
a fine needle biopsy of the right lacrimal gland was performed , which showed multiple well - formed non - necrotizing granulomas in the gland parenchyma with scattered multinucleated giant cells and lymphocytes .
acid - fast bacilli or fungi were not identified and there was no evidence of malignancy .
other relevant laboratory investigations revealed an elevated angiotensin - converting enzyme level of 71 u / l .
axial t2-weighted image showing diffusely enlarged bilateral lacrimal glands thin - section ( 3 mm ) , fat - suppressed , gadolinium - enhanced axial ( a ) and coronal ( b , c ) t1-weighted sequences , showing bilaterally symmetrical diffusely enlarged lacrimal glands showing intense homogenous enhancement
the lacrimal gland is situated in the superotemporal aspect of the orbit , and is roughly the same size and shape as an almond , extraconal in position and extends deep into the orbital septum .
this gland is anatomically related to the orbit but embryologically and functionally it is more closely related to the salivary glands .
it is a unique structure possessing both epithelial and lymphoid tissue and as a consequence , it may be affected by an unusually wide range of pathologies including various neoplastic , infective , infiltrative , inflammatory and structural processes ranging from benign adenomas , adenocarcinomas , histiocytosis , benign dacrocysts and lymphomas to sarcoidosis.1 ophthalmic involvement in sarcoidosis is frequent , with anterior uveitis being the most common manifestation , in up to 85% of patients.2 isolated clinically evident lacrimal gland involvement , with absence of systemic signs of the disease is rare and is reported in about 1.74% in one study.3 these patients present with nonspecific neurologic signs such as headache,4 as was seen in our case . in the absence of systemic evidence of sarcoidosis , accurate diagnosis may be difficult .
the most common imaging finding is smooth , homogenous , diffuse and nearly symmetrical enlargement of the lacrimal glands bilaterally .
inflammation and infiltration are much more common causes of bilateral lacrimal gland swelling with sarcoidosis , lymphoma and leukemia being the prime differentials.5 diffusion - weighted imaging ( dwi ) can potentially help in differentiating lymphomatous infiltration from sarcoidosis , with restricted diffusion and low apparent diffusion coefficient ( adc ) values in the former.69 other unusual differential diagnoses also include kimura disease and primary lacrimal amyloidosis.1011 however , according to mafee et al.,12 bilateral diffuse enlargement of the lacrimal glands is highly suggestive of sarcoidosis . on imaging , normal lacrimal gland measures approximately 45 mm in thickness [ figure 3].13 in our case , both glands measured approximately 10 - 11 mm in maximum thickness .
izumi et al.,13 have shown that measuring the thickness of the lacrimal gland correlates well with measures of the areas of the lacrimal gland thus supporting the analogy that size does matter.14 thin - section ( 3 mm ) , fat - suppressed , gadolinium - enhanced axial t1-weighted image , showing normal appearing lacrimal gland in a control subject an objective measurement of the lacrimal gland is not required in the vast majority of cases and a visual assessment of gland size is sufficient .
dedicated orbital imaging with thin section , fat - suppressed , gadolinium - enhanced , axial and coronal sequences are fundamental to the optimal evaluation of lacrimal gland related pathologies.15
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### Summary:
: a 40-year - old woman presented with vague headaches and blurred vision .
contrast - enhanced magnetic resonance imaging of the brain revealed bilaterally symmetrical diffuse enlargement of the lacrimal glands .
a fine needle biopsy of the lacrimal gland was consistent with sarcoidosis .
although , isolated lacrimal gland involvement is rare , it may be the initial clinical presentation of sarcoidosis , as seen in this patient .
imaging plays a vital role in these unsuspected cases and careful evaluation of the lacrimal glands with dedicated thin section , fat suppressed , axial and coronal orbital imaging , may help identify a pathological cause and avoid a delay in 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:
: rett syndrome ( rtt ; omin # 312750 ) is a complex neurodevelopmental disorder characterized by the progressive loss of intellectual functioning and acquired speech , head growth deceleration , autistic features such as emotional withdrawal and diminished eye contact , motor stereotypies , early hypotonia followed by rigidity , epileptiform seizures , exaggerated responses to stress , and severe respiratory and autonomic ( cardiac and gastrointestinal ) dysfunction [ 13 ] .
rtt predominantly affects girls and , in most cases , it is consequent to loss - of - function mutations in the gene ( mecp2 ) encoding methyl - cpg - binding protein 2 .
the basic pathophysiology of rtt is considered as deficiency of the activities of the serotonin ( 5-th ) and the noradrenaline ( na ) neurons , which have roles in neuronal development in infancy from 4 months to 18 months of age .
hypofunction of the 5-ht and na neurons , which modulate the antigravity activities or postural tone , causes postural hypotonia and failure in locomotion ( crawling ) in infancy .
in addition to monoaminergic dysfunction , a study using receptor autoradiography demonstrated that rett syndrome is a genetic disorder of synapse development , especially synapses that use glutamate and gaba as neurotransmitters . to date , no successful medical treatments have been established ; current treatment includes symptomatic therapy , anticonvulsive therapy and physiotherapy .
brain - derived neurotrophic factor ( bdnf ) belongs to a family of proteins related to the nerve growth - factor family , widely expressed in the adult mammalian brain and responsible for neuron proliferation , survival and differentiation .
bdnf is also found in the blood , accumulating predominantly in platelets ; a rodent study showed that serum and cortical bdnf levels undergo similar changes during maturation .
like other neurotrophins , bdnf utilizes a dual receptor system to modulate diverse and sometimes opposing biological actions that consists of a specific high - affinity receptor ( tyrosine kinase receptor ) and a common low - affinity receptor ( p75 neurotrophin receptor ) . in 2006 , chang et al
. demonstrated that bdnf levels in the whole - brain lysate in mecp2 knockout ( ko ) mice are decreased to about 70% of the wild - type levels .
it was hypothesized that mecp2 deficiency decreases neuronal activity , thereby indirectly causing a decrease in bdnf protein levels . in their report , it was also demonstrated that deletion of bdnf in mecp2 mutants caused an earlier onset / accelerated disease progression , whereas bdnf overexpression in the mecp2 mutant brain led to a later onset / slower disease progression , suggesting that rtt pathogenesis may be partially mediated through bdnf ; therefore , manipulation of bdnf expression / signaling in brain could be therapeutic for this disease .
this notion is supported by the recent report that synaptic dysfunction in the brainstem nucleus tractus solitarius ( the principal site for integration of primary visceral afferent inputs to central autonomic pathways ) of mecp2 mutants could be rescued by application of exogenous bdnf . in another study ,
bdnf overexpression in embryonic day-18 hippocampal neurons prevents dendritic atrophy caused by mecp2 mutations . in a clinical study
, it was found that a bdnf functional genetic polymorphism may affect rett severity . on the basis of the above findings , agents such as lithium , antidepressants , and glatiramer acetate that could increase central bdnf levels may have potential for the treatment of rtt . in animal studies
it was demonstrated that desipramine , a tricyclic antidepressant , can improve breathing and survival in a rtt mouse model .
recently , it has been suggested that early intervention with antidepressants or psychostimulants could increase the mecp2 expression in females with rtt and normalize bdnf deficiency to improved rett syndrome . for a more direct intervention ,
here i propose that peripheral bdnf administration , either by intranasal delivery or intravenous injection , could be a possible approach for the treatment of rett syndrome .
like other secreted proteins , bdnf arises as a precursor , pro - bdnf , which is proteolytically cleaved to yield the mature protein .
mature bdnf is a 14 kda protein that may have poor blood - brain barrier penetrability .
however , earlier animal studies demonstrated that peripheral bdnf by intravenous injection can cross the blood - brain barrier [ 2325 ] . in a recent report
, schmidt et al demonstrated that peripherally administered bdnf ( by a subcutaneously implanted osmotic mini - pump ) produces antidepressant - like cellular responses in the mouse brain as well as antidepressant - like behaviors .
in addition , hippocampal neurogenesis was increased and bdnf levels were elevated in the hippocampus of adult mice after chronic , peripheral bdnf administration .
these findings suggest that peripheral bdnf has behavioral and cellular effects that are similar to antidepressants .
regarding intranasal delivery of bdnf , a recent animal study by alcal - barraza et al demonstrated that intranasal delivery of [ ( 125)i]-radiolabeled bdnf resulted in increased bdnf concentrations within 25 min in brain parenchyma .
in addition , not only did bdnf reach the brain , it also activates the prosurvival pi3kinase / akt pathway .
for the potential use of peripheral bdnf administration in the treatment of rtt , several points are suggested : first , the potential therapeutic effect of peripheral bdnf administration in rtt subjects could be evaluated in rtt animal models such as mecp2 ko mice , which may provide a new strategy for the treatment of this devastating disease .
it should be noted that mecp2 ko mice are a useful model to understand the physiological role of the protein in rett disease , but usually rett patients are not fully deleted but have a truncated mecp2 protein , thus data from peripheral administration of bdnf in mecp2 ko mice would certainly not be exhaustive .
second , although bdnf plays important roles in neuronal development , function and survival , it should be cautioned that too much bdnf is harmful and has been implicated in the pathogenesis of epilepsy , mania , anxiety and enhanced tumor cell survival .
thus , there is an obvious need for studies assessing the optimal dose of bdnf for rett disease patients .
third , mannitol , an osmotic diuretic agent , can be used to open the blood - brain barrier by temporarily shrinking the tightly coupled endothelial cells that make up the barrier .
a recent study in rats demonstrated that it can facilitate the entry of neurotrophic factors , such as bdnf , from the periphery into the adult stroke brain ; thus , combination use of mannitol may increase brain bdnf levels and improve the therapeutic effect of intravenous injection of bdnf in the treatment of rett syndrome . however , it should be cautioned that mannitol may induce some adverse effects , including severe allergic reactions , blurred vision , chest pain , chills or fever , confusion , headache , muscle cramps , and weakness .
fourth , the basic pathophysiology of rtt is considered as deficiency of the activities of the 5-th and the na neurons , which have roles in neuronal development in infancy from 4 months to 18 months of age .
sleep studies in children with rtt also suggested that the behavior in early infancy is due to the hypofunction of these monoaminergic systems in the brain stem .
these cause poor response to environmental stimulation , poor formation of circadian rhythm , and more sleeping during daytime , which also induces autistic tendency .
the axons of the 5-ht neurons involving the development of the central neurons system are pruned early , probably by absence of mecp2 .
restriction of atonia in rapid eye movement ( rem ) stage from the fourth month of age induces synaptogenesis of the brain and enables integrative function of the brain .
bdnf plays key roles in neuronal development and differentiation ( ie , promoting dendritogenesis and synaptogenesis ) .
this suggests early intervention with bdnf may improve the hypofunction of these monoaminergic systems in rett patients . finally , rtt is a neurodevelopment disorder and bdnf plays a critical role in neuron proliferation and differentiation .
testing bdnf administration in animal models at different ages and with different durations could be informative .
an early intervention with bdnf may be required to decrease the detrimental consequences of this disorder .
animal studies demonstrated that peripheral administration of bdnf , either by intravenous injection or intranasal delivery , could increase bdnf levels in the brain .
the hypothesis of peripheral treatment with bdnf in rett patients is rather far from clinical application .
before that can occur , many studies must be conducted in more than one animal model .
potential adverse effects of a peripheral treatment with a growth factor should also be seriously considered , as well as the feasibility ( and economic burden ) of bdnf treatment .
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### Summary:
: summaryrett syndrome ( rtt ) is a postnatal , severe , disabling neurodevelopmental disorder occurring almost exclusively in females and is the second most common cause for genetic mental retardation in girls . in the majority of cases
it is caused by mutations in gene ( mecp2 ) encoding methyl - cpg - binding protein 2 .
brain - derived neurotrophic factor ( bdnf ) is a neurotrophic factor playing a major role in neuronal survival , neurogenesis and plasticity .
animal studies suggested that abnormalities in bdnf homeostasis may contribute to the pathogenesis in mecp2 null mice , and bdnf administration in the mecp2 mutant brain led to later onset / slower disease progression , suggesting that increased bdnf in the brain could be therapeutic for this disease .
mature bdnf is a 14 kda protein that may have poor blood - brain barrier penetrability .
however , recent animal studies demonstrated that peripheral administration of bdnf , either by intravenous injection or intranasal delivery , could increase bdnf levels in the brain .
thus it is proposed that peripheral administration of bdnf in the early stage could have therapeutic potential for rtt subjects .
furthermore , the combination use of mannitol may temporarily open the blood - brain barrier and facilitate the entry of bdnf into brain . the potential therapeutic effect of peripheral bdnf administration
could be tested in rtt animal models such as mecp2 ko mice , which may provide a new intervention for this devastating 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:
: metformin is a biguanide antihyperglycemic agent commonly used as a glucose - lowering agent for the treatment of type - ii diabetes mellitus and is considered safe .
the potentially life - threatening complication of metformin overdose is metabolic acidosis described as metformin - associated lactic acidosis ( mala ) .
early recognition , correction of metabolic acidosis , intensive support of the cardiovascular system , and maintenance of body temperature and drug removal , mainly by extracorporeal therapy , are the essential aspects of management as metformin is dialyzable .
patients who are treated with high - volume continuous venovenous hemodiafiltration ( cvvhdf ) have a better outcome . as per the american association of poison centre ( 2004 ) , only few patients ( 0.05% ) needed extracorporeal treatment for poisoning .
extracorporeal treatment , particularly charcoal - based , may be lifesaving in patients with clinical evidence of severe toxicity such as lactic acidosis , shock , and hypoglycemia in patients who are not responding to supportive management .
a 49-year - old female , known case of type - ii diabetes mellitus ( on insulin ) , portal hypertension , and rheumatic heart disease , was admitted with an alleged history of consumption of 100 tablets of metformin ( 850 mg each , total dose 85 g ) around 2 h prior to presentation .
she presented with nausea , vomiting , and shortness of breath . on admission , she was conscious , heart rate was 88/min , blood pressure was 80/40 mmhg , respiratory rate was 28/min , and was afebrile .
her arterial blood gas revealed severe metabolic acidosis with hyperlactatemia ( ph 7.17 with lactate of 13.5 mmol / l ) .
she was continued on vasopressors and started on 50% dextrose and 7.5% sodium bicarbonate infusions .
she developed repeated episodes of hypoglycemia despite 50% dextrose infusion , and hence , glucagon bolus 2 mg followed by 12 mg / h infusion to target blood sugar level > 100 mg% was initiated .
hyperlactatemia gradually worsened with increasing levels ( 13.5 , 15 , 22 , 24 , and 27 mmol / l ) over 8 h [ chart 1 ] . in view of refractory hypoglycemia and refractory metabolic acidosis ,
charcoal - based sorbent hemoperfusion was started as rescue therapy [ figure 1 ] and high - volume cvvhdf was continued .
serial arterial blood gas extracorporeal therapy with continuous venovenous hemodiafiltration and charcoal - based sorbent hemoperfusion the patient 's condition started improving with increase in mean arterial blood pressure and decreasing lactate [ chart 1 ] around 6 h after starting charcoal - based sorbent hemoperfusion .
another session of charcoal - based sorbent hemoperfusion was given after 12 h. hypoglycemia and lactate levels gradually improved over the next 24 h. vasopressors , 50% dextrose , glucagon , and sodium bicarbonate were progressively weaned off in the next 48 h and stopped on day 3 .
cvvhdf without charcoal hemoperfusion was continued for the next 72 h and stopped after that as shock resolved , and acid base status became normal [ chart 1 ] .
the patient was extubated on day 4 and discharged on day 6 in stable condition with psychological consultation and counseling .
metformin is an antihyperglycemic agent of biguanide class used for the treatment of type - ii diabetes mellitus .
metformin has a low bioavailability and takes a long time ( around 6 h ) to get completely absorbed from gastrointestinal tract .
there are case reports of fatal intoxication with metformin with varying dosage , i.e. , 60 g , 76.5 g , and 100 g. in our case , the patient had consumed 85 g. metformin decreases blood glucose in diabetic patients , causes weight loss , improves lipid profile , and also causes a reduction in blood pressure .
mala is a life - threatening complication of metformin , which occurs either in cases of therapeutic dose or overdose or with concomitant risk factors , i.e. , renal failure , liver and cardiovascular diseases , infection and alcoholics , and has a high mortality rate .
metformin intoxication is known to cause acute renal failure , which aggravates toxicity . with lactic acidosis ,
patients usually present with tachypnea , lethargy , hypotension , tachycardia , and shock , if not treated in time , death is unavoidable .
the estimated rate of mala from previous studies is believed to range somehow between 4 and 9 cases per 100,000 patient - years .
the pathogenesis of mala is complex and not completely understood . in our case also , the patient presented with nausea , vomiting , hypotension , and severe lactic acidosis .
management of metformin toxicity is supportive and includes gastrointestinal decontamination , correction of acid base abnormalities , hypoglycemia , and hemodialysis .
success of hemodialysis depends on characteristics of the toxin , i.e. , lipid solubility , molecular weight , volume of distribution , protein binding , and technique used for hemodialysis .
metformin has a low volume of distribution , molecular weight of 166 da , and has almost negligible plasma protein binding , hence hemodialysis is an effective modality for removal of metformin . in this patient , gastric lavage ,
activated charcoal , and other supportive care were given , and cvvhdf was initiated in view of shock and persistent lactic acidosis . in spite of cvvhdf ,
the patient had persistent shock , hyperlactatemia , and hypoglycemia and hence , charcoal - based sorbent hemoperfusion was incorporated along with cvvhdf . till date , there is no report of using combination therapy with hemodiafiltration and hemoperfusion in metformin toxicity in the literature searched . despite their efficacy , the use of hemoperfusion cartridges has declined over the past 20 years , due to limitations of their indications and shelf life . to be removed by hemoperfusion
, the toxic substance must have binding affinity to the sorbent in the cartridge and a low volume of distribution .
we used this modality as metformin meets all the characteristics required for efficient removal by charcoal sorbent .
we continued cvvhd along with charcoal hemoperfusion because hemoperfusion lacks the efficacy of correcting acid base , fluid , and electrolyte abnormalities .
the patient 's condition started improving around 6 h after starting charcoal - based sorbent hemoperfusion .
we also gave another session of charcoal - based sorbent hemoperfusion with cvvhdf after 12 h. shock , hyperlactatemia , and hypoglycemia gradually improved and the patient weaned from the ventilator and extubated on day 4 .
metformin seems to cause more hypoglycemia than reported in literature and may be an important sign of severe toxicity .
although lactic acidosis associated with severe metformin toxicity can result in high morbidity and mortality , most of them may not require aggressive treatment including hemodialysis .
acute metformin overdose is potentially life - threatening condition , and patients may have rapid clinical deterioration and death , if not treated in a timely manner .
patients with metformin toxicity and mala should be treated aggressively with supportive measures and hemodialysis .
given the high mortality rate , patients who have refractory hyperlactatemia , refractory shock , and refractory hypoglycemia even with best supportive care and hemodialysis should be subjected to cvvhdf with charcoal - based sorbent hemoperfusion .
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### Summary:
: we present a case of a 49-year - old female with an alleged history of ingestion of approximately 100 tablets of metformin ( 850 mg each ) .
investigations revealed severe lactic acidosis with lactate levels of 13.5 mmol / l and ph of 7.17 .
this indicates severe toxicity and is associated with a high mortality .
charcoal - based sorbent hemoperfusion was done as a desperate effort , as patient continued to deteriorate despite supportive care and high - volume continuous venovenous hemodiafiltration .
the patient survived despite metformin - associated lactic acidosis related to severe metformin toxicity .
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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 objective of the surgical treatment of patients with chronic otitis media is to eliminate pathological changes , facilitate the drainage and ventilation of the post - operative cavity , and reconstruct the sound - conducting system in the tympanic cavity .
emphasis has recently been focused on the restoration of anatomy ( i.e. , reconstruction of the posterior - superior wall of the external auditory canal to protect the ear from water ) [ 13 ] .
the aim of ossiculoplasty is to reconstruct the sound - conducting system in the ear to the best possible degree after the elimination of pathological lesions from the middle ear .
the ossicular chain is reconstructed with the use of the patient s own properly modelled ossicles and synthetic prostheses .
the patient s own tissues are an acknowledged material for use in otosurgery [ 46 ] .
the use of artificial prostheses depends on the experience of the medical centre and the accessibility of this material .
it must be borne in mind that the artificial prosthesis can not come into direct contact with the tympanic membrane graft after the ossicular chain reconstruction , as it may lead to the perforation of the membrane . to prevent this
, a strip of cartilage is placed between the prosthesis and the material used to reconstruct the tympanic membrane .
depending on the degree of damage to the ossicular chain , total ossicular replacement prostheses ( torp ) or partial ossicular replacement prostheses ( porp ) are used . in the latter case
the prosthesis is placed between the head of the stapes and the tympanic membrane , provided that the tympanic membrane is protected with a strip of cartilage . for the past decade
the jagiellonian university s otolaryngological teaching hospital in cracow has been carrying out international research work as part of the otology audit group project .
the project has involved research into best practices in tympanoplasty . to achieve the best possible reconstruction of the sound - conducting system in the middle ear , innovative methods and materials
one such innovation is the application of the ventilation tube , the use of which is a standard practice in the treatment of secretory otitis media ( typically in our department we use a ventilation tube of 0.9 mm in inner diameter , made by mikolow , poland ) ( figure 1 ) .
typically attached to the tympanic membrane , the tube facilitates proper ventilation and drainage of the middle ear cavity and , in consequence , creates favorable conditions for the auditory tube to resume its normal function .
the material used to produce ventilation tubes has been approved for use in the middle ear surgery and has undergone the standard testing procedures for prostheses made without the use of biomaterials ; ventilation tubes have since long been used as typical otosurgical materials worldwide . as a non - standard application , the ventilation tube can be used for the reconstruction of the ossicular chain , especially when the normally mobile stapes has been preserved and the malleus and the incus have not .
many years of experience have shown that the surface of the ventilation tube is highly resistant to the formation of biofilm and the subsequent rejection of the tube by the body .
given its shape and size , the ventilation tube is naturally predisposed to be stably fixed onto the head of the stapes .
the above procedure permits the reconstruction of the ossicular chain , consisting of 2 vibrating elements , namely the stapes and the ventilation tube fixed onto it as a porp ( figure 2 ) .
the subsequent procedure the reconstruction of the tympanic membrane and the securement of the membrane with a strip of cartilage placed between it and the ventilation tube does not differ from comparable treatments in which a porp is used .
isolated cases of a similar use of the ventilation tube have been described in the literature .
the adverse effects of using a material of non - biological origin in ossiculoplasty are the same as for other types of porps and torps .
all the experiments reported in this manuscript were conducted in accordance with the recommendations of iasp and the nih guide for the care and use of laboratory animals and were reviewed and accepted by the local bioethics committee .
the objective of the study was to assess the degree of hearing improvement following tympanoplasty , including in patients for whom a ventilation tube was used as a porp .
a prospective analysis was carried out that included patients operated on due to middle ear conditions between 2009 and 2012 .
the patients operated on for the first time due to chronic otitis media were selected for the analysis .
the assessment of hearing improvement after the surgery was based on tonal audiometry carried out after 6 and 12 months following tympanoplasty and compared with the results of the test carried out immediately before the surgery .
hearing improvement was assessed on the basis of changes to the average air - bone gap ( abg ) as the arithmetic mean for the frequencies of speech : 500 hz , 1000 hz , and 2000 hz .
a group of 387 patients underwent otosurgery in the analyzed time span ; 134 patients were operated on due to otosclerosis , in 241 cases the surgery was required due to chronic otitis media , and in the remaining cases surgical treatment of the middle ear was necessary because of a tumor , damage , or inborn defect of the ear . there were 147 patients who underwent otosurgery due to chronic otitis media for the first time . in these patients ,
the perforation of the tympanic membrane was observed along with the abnormalities of the middle ear mucous ( figure 3 ) .
damage to the ossicular chain was observed during the course of surgical treatment in 78 patients . in the majority of cases
further analysis was concerned with the patients who had a vibrating element in the form of a modelled anvil or a ventilation tube attached to the preserved and normally mobile stapes . since the lesions of the middle ear mucous in the patients with reconstruction based on their modelled anvil were diverse , 2 basic groups were defined : patients with cholesteatoma and patients with granulation tissue .
the obtained results were compared with the results observed in the patients who underwent reconstruction with the use of a ventilation tube placed on the stapes in the course of simple chronic otitis media .
to prevent perforation of the tympanic membrane , a strip of cartilage was routinely added between the ventilation tube and the tympanic membrane ( table 1 ) .
the effectiveness of treatment was measured in terms of the closure of the air - bone gap ( abg ) as referred to the applied method of reconstruction of the ossicular chain .
the average value of abg after 12 months was smaller than the average value of abg at the beginning of treatment and statistically equal to the average value of abg after 6 months , while the average value of abg after 6 months was significantly smaller than the average value of abg at the beginning of treatment . in accordance with the philosophy behind ossiculoplasty , the elimination of cholesteatoma lesions and the successive type 2 tympanoplasty achieved satisfactory results in the form of hearing improvement . in group 2
significant changes ( the closure of the average value of abg ) were not observed over time .
the group consisted of patients with damaged ossicular chain and granulation within the middle ear .
although the performed reconstruction was similar to that in the patients with cholesteatoma ( group 1 ) , significant hearing improvement was not observed . the use of a ventilation tube ( group 3 ) to reconstruct the continuity of the ossicular chain resulted in a statistically significant change of the average value of abg ( p=0.046 ) as early as after 6 months following otosurgery , proving it justifiable to use this material as a porp in selected cases .
the comparison of the results obtained after 6 and 12 months following otosurgery did not reveal significant discrepancies , showing that the improved hearing effect was maintained during the successive checks ( table 2 ) .
another stage of the analysis consisted in dividing the results of otosurgical procedures into satisfactory and unsatisfactory depending on the average value of abg ( as the average for 500 hz , 1000 hz , and 2000 hz ) .
table 3 shows the otosurgery evaluation criteria according to which the particular procedures were classified into either of the above categories . the multi - way contingency tables were analyzed to determine whether the results obtained in the test groups changed with time .
when the results changed significantly , the percentage of patients in the satisfactory and unsatisfactory groups was presented after 0 , 6 , and 12 months from otosurgery into satisfactory and unsatisfactory groups on the basis of the inclusion criteria ( table 3 ) . a significant hearing improvement over time after otosurgery was observed in group 1 , where the number of satisfactory results rose from 58% before otosurgery to 92% at 12 months after surgical treatment . in this group ,
42% of the results were unsatisfactory prior to treatment and the percentage decreased to 8% after treatment ( table 4 ) . in group 2 , we found no significant hearing improvement in the closure of cochlear reserve during the 12-month observation following otosurgery .
the use of a ventilation tube as a porp ( group 3 ) resulted in a significant hearing improvement .
the percentage of patients in the group of satisfactory results defined according to the assumed criteria changed from 38% before treatment to 77% after a year - long observation of these patients ( table 5 ) .
in the cases of patients with cholesteatoma classified into group 1 , their own modelled ossicles were placed on the stapes after eliminating the pathological process . when performed at a relatively early stage ,
the treatment stopped the pathological process that damaged the ossicular chain and was followed by ossiculoplasty , resulting in significant hearing improvement in the patients with chronic cholesteatoma otitis media . according to data in the literature , confirmation that the suprastructure of the stapes is normal after the cholesteatoma lesions have been eliminated , and the subsequent reconstruction of the ossicular chain by placing the patient s own modelled ossicle on the head of the stapes , results in hearing improvement in nearly a half of the patients [ 26 ] . among the analyzed patients , the improvement was significantly greater in the group with cholesteatoma than in the cases where the ossicular chain was damaged to a comparable degree , but
the same conclusions were reported by other authors , especially in the context of the unfavorable effect of granulomatous lesions in the middle ear on hearing improvement .
after both 6 and 12 months , significant hearing improvement was also noted in the group of patients where the reconstruction was based on a ventilation tube placed on the head of the stapes .
this original method of restoring the continuity of the ossicular chain applied at the otolaryngological teaching hospital of the collegium medicum at the jagiellonian university of cracow turned out to be a good alternative for the patients whose own modelled ossicles can not be used due to the scope of damage done to the ossicular chain by the pathological process .
the use of this generally available and relatively inexpensive material as a porp is competitive with other solutions .
the abg closure obtained in this group is comparable to the results obtained by other authors using porp [ 1115 ] . the use of the ventilation tube as a porp is an innovative method of reconstructing the ossicular chain .
the significant discrepancies between the average values of abg for the particular groups are closely linked to the advancement of the pathological process in the middle ear and the possibility of the subsequent reconstruction of the sound - conducting apparatus . in the majority of cases
the degree of hearing impairment observed before treatment has a statistically significant link with the condition of the tympanic membrane and the ossicular chain .
judging from the degree of damage to the conductive apparatus in the middle ear , preliminary prognoses are made as to the improvement of hearing after the surgery [ 1620 ] .
the differences observed after 6 and 12 months reflect the impact of the reconstruction on the functional improvement of the middle ear .
these differences expose the limitations of tympanoplasty in terms of restoring normal functionality of the ossicular chain .
the obtained degree of abg closure verifies the earlier hearing improvement prognoses based on the advancement of the pathological process in the middle ear .
simple chronic otitis media is characterized by having relatively little damaging effect on the ossicles .
greater damage is observed in the cases of cholesteatoma or granulation tissue in the middle ear . as compared to the group of patients with cholesteatoma
, the patients with a predominance of granulomatous lesions did not have their hearing improved to a statistically significant degree after their ossicular chains were reconstructed using the same method .
this observation coincides with reports in the literature that hearing improvement in patients with simple chronic otitis media reaches 80% , while in the course of granulomatous lesions it is about 50% . in the cases of cholesteatoma ,
the hearing level is maintained or improved after the surgery in about 90% of the patients . the above information regarding chronic granulomatous otitis media point to the necessity of non - invasive treatment in the period preceding the surgery , which would be aimed at obtaining dry ear .
the elimination of otorrhea and an improvement of the condition of the mucous lining the ear have a significant effect on achieving better results of the surgical treatment [ 2125 ] .
the patient s own modelled ossicle is a good and acknowledged material in ossiculoplasty . a ventilation tube used as
a porp is an effective alternative in the reconstruction of the ossicular chain . in patients with cholesteatoma and minor damage to the ossicular chain
the occurrence of granulomatous lesions is an unfavorable factor in the prognosis of patients with chronic otitis media .
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### Summary:
: backgroundthe principal objective of ossiculoplasty is to reconstruct the sound - conducting system in the ear to the best possible degree after the elimination of pathological lesions from the middle ear .
the ossicular chain is reconstructed with the use of the patient s own properly modelled ossicles and synthetic prostheses .
the objective of the study was to assess the degree of hearing improvement after tympanoplasty in patients for whom a ventilation tube was used as a partial ossicular replacement prosthesis ( porp).material / methodbetween 2009 and 2012 , 387 patients underwent ear surgery at the otolaryngological teaching hospital of the collegium medicum at the jagiellonian university of cracow .
we focussed on the patients in whom a vibrating element in the form of a properly modelled anvil or a ventilation tube was attached to the preserved and normally mobile stapes.resultsa significant hearing improvement was observed in patients with type 2 tympanoplasty in the course of chronic cholesteatoma otitis media and in patients with simple chronic inflammatory process in whom a ventilation tube was used as a porp in the reconstruction .
granulation tissue was determined to be an unfavorable factor in the prognosis of hearing improvement following tympanoplasty.conclusionssignificant hearing improvement was observed after type 2 tympanoplasty in patients with cholesteatoma whose ossicular chain was not appreciably damaged .
a ventilation tube used as a porp is an effective alternative in the reconstruction of the ossicular chain .
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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:
: pruritus ani is an unpleasant cutaneous sensation , and its symptoms are characterized by varying degrees of itching around the anal orifice .
pruritus ani is a common proctological problem , and many physicians believe that it reflects hemorrhoidal disease .
the exact incidence worldwide is unknown , but men are affected more often than women by a ratio of 4:1 .
most patients are distributed in the 30 - 70 age group and it is particularly prevalent in the 40 - 60 age group [ 2 , 3 ] .
this article addresses the etiology of pruritus ani , its underlying disease , and current medical treatments for pruritus ani .
pruritus ani may have various causes , and it has been divided into two subtypes : idiopathic and secondary .
idiopathic pruritus ani accounts for 25 - 75% of pruritus ani cases depending on investigators , and it is diagnosed in cases in which no etiology can be found .
secondary pruritus ani is diagnosed when an underlying cause can be identified and treatment leads to an improvement in the pruritus ani .
there exists a long list of specific disease entities that may cause pruritus ani , and these are usually categorized into infectious and non - infectious causes .
the most prevalent anorectal diseases related with pruritus ani are hemorrhoids and anal fissures ; others are anal fistulas , abscesses , proctitis , rectal cancer , adenomatous polyps , etc .
skin disorders as etiologic factor are contact dermatitis , lichen planus , psoriasis , seborrheic dermatitis , vitiligo , squamous cell carcinomas , paget 's disease , etc .
infectious disease , such as infections due to bacteria and fungus , should not be overlooked .
fungal infections have been reported to account for up to 15% of the underlying causes of pruritus ani , and other infections , such as those due to viruses , parasites ( pinworms ) , etc .
, are also causes of pruritus ani . medications , such as tetracycline , colchcine , quinidine , local anesthetics , neomycin , etc . , and
systemic diseases , such as diabetes , lymphoma , obstructive jaundice , thyroid dysfunction , leukemia , chronic renal failure , and aplastic anemia , are considered as causative factors .
some studies have reported that pruritus ani was reduced within 2 weeks after avoiding specific foods , such as tomatoes , chocolate , citric fruits , spices , coffee ( including both caffeinated and decaffeinated ) , tea , cola , beer , milk and other dairy products [ 4 , 6 , 7 ] .
psychological factors , such as anxiety , agitation , and stress , may also cause pruritus ani .
others are fecal incontinence , excessive humidity , the use of soap , excess scrubbing of the anus , chronic diarrhea , and menopause ( table 1 ) .
it has been hypothesized that when sensory nerves in the perianal area are stimulated , skin irritation and subsequent pruritis is induced ; consequently , the skin is excessively scratched , which causes skin injury . fecal contamination due to abnormal transient internal sphincter relaxation
the main symptom of pruritus ani is the untolerable impulse to scratch the perianal area .
although that symptom can occur at any time , it is most common following a bowel movement , especially after liquid stools , and at bedtime , just before falling asleep
. some patients also experience intense itching during the night . as the area of involvement spreads and the intensity of itching increases
this leads to further skin damage , excoriation , and potentially a secondary skin infection .
gordon classified pruritus ani into three clinical stages according to the skin condition . in stage 0
the patient presents with lichenified skin , as well as coarse ridges of skin and often ulcerations secondary to scratching .
this history should include any change in bowel habit and details of any other previous or current dermatological or gastrointestinal problems .
clinicians should ask patients about the onset of symptoms and the relationship of the onset to diet , medication and anal hygiene practices .
pruritus ani can be caused by infestation with enterobius vermicularis , or pinworms , especially in children .
the worms emerge from the anal canal at night and early morning ; thus , pruritus is worst at those times .
sticky - tape tests should be performed for identifying the eggs or adult worms microscopically .
pruritus ani may develop due to gynecological causes in female patients ; thus , pruritus on the perineal region caused by vaginal discharge or urinary incontinence should be considered .
although rare , for postmenopausal women showing atrophic vaginitis findings , together with hot flushes due to hormonal changes , symptoms may be ameliorated by hormone replacement therapy . at the visual inspection , maceration , erythema , desquamation or lichenification of the skin
may be observed , and to assess the secondary causes of pruritus , which can be inferred from abnormalities of the sphincter and from the history of disease , digital rectal examination and anoscopic examination should be performed .
gayle et al . reported that the risk of harboring a neoplastic lesion was significantly related to the duration of symptoms and to an age greater than 50 years .
they concluded that pruritus ani was frequently a symptom attributable to other colonic and anorectal pathologies .
thus , the presence of prutitus ani of long duration , which is refractory to medical treatment , should alert the physician to the possibility of underlying colonic or anorectal neoplastic pathologies .
if pruritus ani that does not respond to two to three weeks of conservative treatment , efforts should be made to find underlying diseases that may have been easily overlooked .
this can be done by aggressively performing a biopsy on the area that is thought to be most appropriate for rendering a clinical diagnosis .
most patients with secondary pruritus ani are improved after correction of the causative agent . for patients who are thought be suffering from idiopathic pruritus ani
whose causative can not be found , life style modification should be suggested ( table 2 ) .
generally , the perianal skin should be maintained dry and clean and have weak acidity .
particularly , patients should be educated to clean the perianal area with water after defecation and to avoid severe rubbing .
the anus should be dried with a hair dryer or carefully tapped with cottons swabs .
when a bidet is used , it is better to use warm water and relatively low water pressure to avoid irritation of the anus . in regard to clothes , it is recommended to avoid underwear that can not absorb sweat well and to wear loose cotton underwear [ 7 , 9 ] .
the use of topical steroids , anti - histamine agents , and sedatives may be of help .
however , topical corticosteroids , especially if used for a long period , can cause atrophy , bacterial and fungal infections , allergic contact dermatitis , telangiectasia , purpura , and/or scar formation .
in addition , if constipation or defecation disorder is present , appropriate laxatives , as well as a high - fiber diet , may be of help .
psyllium agents are of help in reducing the injury to the anal canal and in maintaining better hygiene of the perianal area .
in addition , it is important to educate patients to avoid foods and drinks that exacerbate itching . as mentioned above , coffee , tea , cola , chocolate , and beer
are considered to be causes of pruritus . in regard to coffee , friend have stated that coffee is associated with the induction of pruritus ani and that one hour after coffee consumption , the resting anal pressure is decreased [ 4 , 11 ] .
however , generally , the direct association of coffee with the induction of pruritus is not clear , and more accurate studies are required .
generally , many cases of pruritus ani can be treated readily by improving dietary habits , correcting bowel habits , and avoiding certain mechanical or chemical irritations . for patients with persistent and severe pruritus that can not be treated by general conservative methods ,
in which skin discoloration in the perianal area is not severe , topical ointments , such as 1% hydrocortisone , can be applied [ 2 , 3 ] . however , once the symptoms have improved , steroid use should be discontinued , if possible , and replaced with other barrier creams , such as zinc oxide , and the side effects caused by the indiscriminate use of steroid cream should be explained sufficiently to the patient by the primary doctor . for severe pruritus ani cases with severe skin discoloration of the perianal area , a strong steroid must be used for a short time , but topical treatments that are longer than several weeks are not generally recommended . until now , a clear criterion for the duration of steroid use has not been established .
al - ghnaniem et al . reported that 1% hydrocortisone application for the treatment of pruritus ani resulted in a 68% improvement in symptoms compared to the placebo group .
although some investigators have stated that the local immune suppressor tacrolimus might be of help in preventing skin atrophy and anti - fungal effects , such data have not yet been reported .
lysy et al . reported that 0.006% topical capsaicin ointment was applied to 44 patients with incurable pruritus ani that was unresponsive to menthol treatments three times a day and that 31 patients showed an improvement of symptoms .
its pharmacological action is mainly depletion of substance p ( neuropeptide ) from sensory neurons .
capsaicin causes a mild perianal burning sensation , but a concentration of 0.006% capsaicin rather than 1% or 0.5% is effective in alleviating pruritus ani without the significant burning sensation associated with more concentrated preparations . in the future , the topical application of capsaicin may be of help in treating pruritus ani , if the side effects of the long - term use of steroids or cases unresponsive to other topical therapies are considered . since the intradermal injection of methylene blue for the treatment of refractory pruritus ani was introduced by rygick in 1968 , diverse treatments have been attempted .
the mechanism of methylene blue 's exerting therapeutic effects on pruritus ani has not been elucidated yet .
methylene blue may be directly toxic to the nerves supplying the perianal skin , thus suppressing the desire to scratch and disrupting the vicious itch - scratch - itch cycle . according to studies that have been reported until now ,
good outcomes have been reported in 64% to 100% of the patients treated with methylene blue .
recently , some investigators stated that intradermal injection of 0.5 - 1.0% methylene blue mixed with lidocaine and a steroid had good outcomes for the treatment of intractable pruritus ani [ 17 , 18 ] .
although there have been some reports on complications after tattooing , such as decreased perianal sensation , transient fecal incontinence and local inflammatory reactions in the injection area , it was well tolerated by the patients and resulted in no severe complications .
pruritus ani may manifest in response to various causes , particularly , dermal lesions , or diverse conditions of the anorectum .
hence , in outpatient clinics , attempts should aggressively be made to find its causes .
ultimately , it should be adjusted to the improvement of the symptoms and the consequent secondary skin discoloration . if the cause can not be determined despite such efforts , the pruritus ani should be considered as idiopathic and management of the condition should focus on reducing the source of irritation , changing of lifestyle , and improving perianal hygiene . in conclusion , for obtaining successful results from the treatment of pruritus ani , first of all , it is better to inform patients of the precise proceeding of the disease , the treatment strategies , and the possibility of recurrence , and the disease should be managed continuously .
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### Summary:
: pruritus ani is an unpleasant cutaneous sensation that induces the desire to scratch the skin around the anal orifice .
it may start insidiously and appears in 1% to 5% of the population .
it is classified as primary ( idiopathic ) pruritus ani when no cause can be found .
however , as 25% to 75% of cases have co - existing pathology , a detailed history and examination are necessary .
the goal of treatment is asymptomatic , intact , dry , clean perianal skin with reversal of morphological changes .
the management of pruritus ani is directed towards the underlying cause .
if the diagnosis is idiopathic pruritus ani , the patients can still be managed with great success by eliminating of irritants and scratching , by giving general advice regarding hygiene and lifestyle modification and by using active treatment measures .
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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:
: bovine tb , caused by the mycobacterium bovis , primarily affects cattle and other warm - blooded animals ( e.g. cattle , bison , deer and goats ) , and can be transmitted to humans as well .
wild animals , in most cases , become infected following contact with infected cattle or contaminated pastures through inhalation or ingestion of infectious organisms ( 1 , 2 ) .
this paper describes the first report of bovine tuberculosis in a european fallow deer ( dama dama dama ) in iran .
the female european fallow deer in the hoveize provincial zoo park ( in south - west iran ) was found emaciated and dead .
necropsy lesions , suppurative abscesses and diffuse severe granulomatous pneumonia in the lungs were observed .
in addition , the pharyngeal parotid and mesenteric lymph nodes ( enlarged to 25 cm in diameter ) contained pus and calcified materials ( figs . 1 , 2 , 3 ) . the other internal organs such as heart , liver , spleen , kidneys , intestine and rumen , reticulum and omasum appeared to be normal .
diffuse severe granulomatous pneumonia due to bovine tuberculosis in the lungs of a european fallow deer ( dama dama dama ) bovine tuberclosis suppurative abscess in european fallow deer ( dama dama dama ) lung bovine tuberclosis suppurative abscess in european fallow deer ( dama dama dama ) mesenteric lymph node the dental examination showed that the european fallow doe belonged to a species of dama dama dama and was three yr old .
the bacteriology tests and samples of lymph nodes were kept in a 10% formalin buffer , embedded in paraffin , sectioned at 5um , and stained with ziehl - neelsen and in turn revealed numerous acid - fast organisms resembling mycobacterium . besides , a pcr test was carried out on the fresh tissue samples prepared from the lungs and mesenteric lymph nodes homogenated , as well as for the dna extraction , using the nucleospin tissue kit ( macherey - nagel ) . the ultraclean forensic dna kit ( tuberculin department of vaccine and serum laboratories of the iran razi institute )
the primers were used to identify the m. bovis , which amplified a 123 bp fragment of insertion sequence is6110 ( 3 )
the detection of tb reservoirs in different varieties of domesticated and wild animals is very important , particularly in areas which have low incidence of the tb disease in domestic animals and where plenty of money is spent for test and eradication of tb .
this survey discusses the important implications of such findings for wildlife , especially livestock , as well as for human tb disease control , because deer are often conserved in public zoos and humans often come into contact with them .
such surveys can also expose the new reservoir of tb in iran or any other country that has or conserves deer .
tb in deer caused by m. bovis has been reported in countries where deer is kept as a domestic species grazing in common pastures ( 4 ) .
all deer and other animals kept in the hoveize zoo were tb tested , and the result was negative .
therefore , in this report , applying the strategy of control and eradication in iran reservoirs where bovine tb is present is considered .
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### Summary:
: at present , most of iran is free of bovine tuberculosis ( tb ) .
the strategy of control and eradication in iran involves a tuberculation test and slaughter of reactors , a procedure transformed the present - day prevalence of tb into a sporadic occurrence .
this paper describes the first report of bovine tuberculosis in a european fallow deer ( dama dama dama ) in iran .
the deer was emaciated and found dead in the hoveize provincial zoo park .
post - mortem examinations revealed multifocal granulomatous and suppurative abscesses in the lungs and mesenteric lymph nodes .
these post - mortem indicators led the authors to suspect tb , and the pcr test and bacteriology tests confirmed it as an infection by the mycobacterium bovis .
this survey discusses the important implications of such findings for wildlife , especially livestock , as well as for human tb disease control , because deer are often conserved in public zoos and humans often come into contact with them .
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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:
: sometimes , a meniscus may be found to be thickened and disc like and is called a discoid meniscus .
we report a case of an 18-year - old female , who presented to us with knee pain and was found to have a discoid medial meniscus with a tear .
discoid medial meniscus is a rare phenomenon which can present as a cause of knee pain .
the menisci are semilunar discs of fibrocartilaginous tissue which play critical roles in knee joint biomechanics .
menisci function to ( a ) distribute forces equally across the joint surface , ( b ) stabilize the contact between the femur and tibia , ( c ) aid in joint proprioception , and ( d ) aid in lubrication [ 2 , 3 ] .
a discoid meniscus is a thickened disk - like morphologic variant of a normal meniscus .
discoid meniscus is a relatively rare condition of the knee more frequently found in the lateral meniscus .
smillie reported that 467 patients had a discoid lateral meniscus and only 7 had a discoid medial meniscus in 10,000 meniscectomies .
we describe a case of discoid medial meniscus which was symptomatic due to a large intrasubstance horizontal tear .
an 18-year - old female patient presented to our outpatient department with pain in her left knee of 3 years duration .
there was no tenderness around the knee except for tenderness over the medial joint line .
we performed magnetic resonance imaging ( mri ) scan of the knee and expected it to show a medial meniscal tear .
initial reporting by the radiologist confirmed a medial meniscal tear without a mention of it being discoid .
however , because the body of the meniscus was seen in 4 consecutive sagittal sections of the mri scan ( fig . 2 and 3 ) , we suspected a discoid medial meniscus and got the scan reported again .
magnetic resonance imaging showing continuity between the anterior and posterior horns on 4 consecutive 5 mm sagittal cuts .
the anterior part of the discoid meniscus was attached along the anterior cruciate ligament ( acl ) ( fig .
we then trimmed the lateral edge of the meniscus lying toward the intercondylar region which revealed a large cleavage tear completely restricted to the interstitial part ( fig .
we resected the upper and lower flaps till a stable peripheral semilunar rim of meniscus was obtained ( fig .
postoperatively , the patient was started on a physiotherapy protocol to preserve range of motion and muscle strength .
2 weeks postoperatively , the patient attained full range of motion and was pain - free even on terminal flexion .
anterior horn of discoid medial meniscus ( # ) seen to be continuous with the anterior cruciate ligament ( * ) .
the lateral edge of discoid medial meniscus seen in the intercondylar region showing no evidence of tear .
the horizontal interstitial tear as seen after resecting the lateral edge in the intercondylar region .
discoid medial meniscus was reported for the first time by cave and staples in 1941 .
smillie implicated defective disappearance of the meniscal center during fetal development , with persistence of a fetal stage into adulthood . according to kaplan ,
discoid lateral meniscus is a pathologic entity developing under certain conditions and influenced by mechanical factors such as posterior segment hypermobility ; however , he had no explanation for discoid medial meniscus
. clinically , the most frequent symptoms in discoid medial meniscus are medial knee pain , iterative effusion , and locking in flexion none of which are specific .
pain and effusion are more probably due to the meniscal tear than to the discoid shape of the meniscus .
locking may be due to the discoid shape as such , with the thick central region passing forward of the medial condyle .
radiographs , in selected cases , may show a widened medial joint space with squaring of the femoral condyles or depression of the tibial plateau .
the mri is usually diagnostic , showing discoid medial meniscus with associated tears , and anomalies of attachment of the meniscal horns .
the diagnosis requires continuity between the anterior and posterior horns on three consecutive 5 mm sagittal slices .
recommend the systematic mri of the asymptomatic contralateral knee [ 12 , 13 ] ; they consider the incidence of bilateral cases to be underestimated . as
we performed mri of the opposite asymptomatic knee of our patient , but the medial meniscus of the opposite knee was not discoid .
these include depression of the tibial plateau , anomalous attachment of the anterior horn to the acl , meniscal cyst , pathologic medial patellar plica , and discoid lateral meniscus on the same knee [ 11 , 13 , 14 , 15 , 16 , 17 , 18 ] .
the most frequent anomalies are associated with anomalous insertion of the acl [ 15 , 17 , 18 ] .
kim et al . reported anterior transposition of the anterior horn of the medial discoid meniscus below the anterior edge of the tibia plateau .
patel believes that the discoid meniscus should be preserved if severe symptoms are not present .
partial meniscectomy , with excision of the central anomalous discoid meniscus and preservation of stable peripheral rim , is the preferred treatment .
the patients must always be counseled that they are always at a higher risk for meniscal injuries in the future due to the abnormal morphology of the meniscus and hence might require lifestyle and activity modification .
kim et al . have described a surgical technique of arthroscopic excision of the symptomatic discoid medial meniscus in one piece which leads to less formation of foreign bodies and is a time - saving technique .
discoid medial meniscus is a rare phenomenon which can present as a cause of knee pain .
the opposite knee must be screened to look for the presence of bilateral discoid medial menisci .
the patient must be advised to exercise precautions and activity modification to prevent future symptoms .
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### Summary:
: introduction : normal menisci of the knee are semilunar structures .
sometimes , a meniscus may be found to be thickened and disc like and is called a discoid meniscus .
such a discoid variant is usually found in the lateral meniscus .
its occurrence in the medial meniscus is extremely rare.case report : we report a case of an 18-year - old female , who presented to us with knee pain and was found to have a discoid medial meniscus with a tear .
we operated on her arthroscopically and performed meniscectomy and meniscoplasty .
postoperatively , the patient was free of her knee pain.conclusion:discoid medial meniscus is a rare phenomenon which can present as a cause of knee pain .
if discoid meniscus is symptomatic , the management includes arthroscopic meniscectomy and meniscoplasty .
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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:
: urothelial lesions have a pronounced ability for divergent differentiation . it is important for the pathologists to be aware of this potential for multidirectional differentiation as it has diagnostic , therapeutic and prognostic implications .
the cytology of one of the many faces of urothelial carcinomas , the micropapillary variant , is described in this study .
the purpose of this report is to underscore the importance of recognition of micropapillary variant of urothelial carcinoma , an aggressive tumor with deceptive morphology .
diagnosing this variant by cytology is important in distinguishing this lesion from the more indolent urothelial carcinoma .
no other lesions were seen in abdominopelvic region and the chest radiograph was within normal limits .
the routine urine analysis showed plenty of red blood cells and few pus cells per high - power field and traces of albumin .
microscopically , the highly cellular smears showed many clusters and some papillary fronds with central fibrovascular core .
the columnar cells had dense moderate cytoplasm and oval hyperchromatic nuclei [ figure 1 ] .
smears showing urothelial component ( h and e , 400 ) smears showing micropapillary component ( h and e , 400 ) the patient underwent transurethral resection of the tumor and the fragments were subjected to histopathological examination . the paraffin - embedded , h and e - stained sections showed a high - grade urothelial carcinoma infiltrating the muscularis mucosa , admixed with micropapillary component .
the extent of micropapillary component was moderate , accounting to 40% of the tumor specimen .
the micropapillary component consisted of small nests of tumor cells residing within the lacunae [ figure 3 ] .
section showing nests of tumor cells in lacunae ( h and e , 400 )
the spectrum of bladder carcinoma is quiet diverse , with urothelial carcinoma making up the vast majority of cases .
the recent world health organization classification has recognized 13 variant morphologies of bladder tumors , including those variants which have clinical significance like micropapillary , sarcomatoid , small cell and lymphoepithelioma - like carcinoma .
micropapillary urothelial carcinoma was first described in 1994 by amin et al . as an aggressive variant of urothelial carcinoma , with distinctive histological features reminiscent of ovarian papillary serous tumor .
this rare variant comprises 0.6 to 1% of urothelial carcinoma and shows definite male predominance ( male to female ratio is 5:1 ) , which is higher than in the conventional urothelial carcinoma ( 3 : 1 ) .
more than 95% of micropapillary urothelial carcinomas are muscle invasive compared with 45% of conventional urothelial carcinomas .
immunohistochemical profile ( ck 7 and ck 20 positive ) is similar to that of urothelial carcinoma . in addition , membranous staining of ca 125 has been reported at a higher frequency in micropapillary variant .
the tumors are stratified on the extent of micropapillary component into focal ( less than 10% ) , moderate ( 10 to 50% ) and extensive ( more than 50% ) . cases of extensive micropapillary component are associated with advanced stage of disease .
fine needle aspiration cytology shows the micropapillary component as tightly cohesive tumor clusters and morules .
histologically , it is characterized by the following five morphologic features : ( i ) a noninvasive filiform architecture and an invasive arrangement of small nests or balls of tumor cells ; ( ii ) psammoma bodies , a feature of papillary serous carcinoma of ovary are conspicuously absent ; ( iii ) the tumor cells are predominantly aggregated in lacunae ; ( iv ) it is associated with high nuclear grade and ( v ) more than half of the cases present with lymphovascular invasion .
identification of an admixed urothelial carcinoma or immunohistochemical support in the form of ck 7 , ck 20 and uroplakin iii positivity may be needed in doubtful cases .
the primary adenocarcinoma of bladder has greater variability in its acinar size and shape , in contrast to the typical uniform appearance of micropapillary component of urothelial carcinoma .
there are several important reasons for recognizing micropapillary variant of urothelial carcinoma , which are as follows :
( i)these tumors are high grade and high stage and are associated with vascular invasion.(ii)the micropapillary variant has a higher dna index than conventional carcinoma.(iii)presence of micropapillary component in metastatic sites forces the pathologist to consider the possibility of urothelial carcinoma.(iv)the high association of this variant with muscle - invasive disease .
presence of micropapillary component in metastatic sites forces the pathologist to consider the possibility of urothelial carcinoma . the high association of this variant with muscle - invasive disease .
the majority of these tumors ( 90% ) present with at least stage pt1 disease at the time of diagnosis and have a 5-year and 10- year survival rate of 54 and 27% , respectively .
the patients are at a high risk for treatment failure because of drug resistance to standard chemotherapeutic agents .
intravesical bacillus calmette - guerin therapy is ineffective in these patients , and radical cystectomy should be the treatment of choice .
the poor outcome underscores the need for an early and accurate diagnosis by cytological examination .
the accurate recognition of micropapillary variant of urothelial carcinoma is of paramount importance due to the diagnostic dilemma associated with it as well as prognostic and therapeutic implications , and fine needle aspiration cytology is a useful tool for an early diagnosis of this variant .
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### Summary:
: neoplastic urothelium has the capacity to demonstrate enormous plasticity . a variety of unusual morphological variants of urothelial carcinoma have been described .
micropapillary variant of urothelial carcinoma is a rare and recently described bladder tumor , associated with poor prognosis .
we present the cytological features of micropapillary urothelial carcinoma in a 65-year - old man with bladder mass .
the cytological features include tightly cohesive clusters of micropapillary component admixed with urothelial carcinoma .
histopathological sections showed small nests of tumor cells residing within the lacunae . establishing a diagnosis of micropapillary urothelial carcinoma indicates a high - grade and high - stage tumor with poor outcome , requiring an aggressive therapy .
it is thus important for the cytopathologist to recognise micropapillary variant of urothelial carcinoma , for early and better management of patients with bladder tumor .
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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 term cavernous sinus syndrome ( css ) is used to denote any disease process which affects the cs .
determination of exact etiology of css is often difficult due to the lack of amenability to tissue diagnosis .
thus , if the classification of css into different types can throw light on underlying etiology , it might help in further management .
css was first classified by jefferson into three types based on the extent of involvement of trigeminal nerve [ table 1 ] . since then
, this classification has been the gold standard and given in most textbooks of neurology . in 1996 , ishikawa emphasized the lack of clinico - anatomical correlation in jefferson 's classification and proposed a new classification of css [ table 1 ] .
subsequently , a japanese study found that majority of patients who remained unclassified by jefferson classification can be classified using ishikawa scheme .
furthermore , when classified according to ishikawa 's scheme , anterior cs lesions were often due to inflammatory etiologies , whereas middle and posterior cs lesions were due to malignancies , suggesting that this classification system may play a role in determining etiology of css .
however , etiological profile of css is likely to be different in developing countries ( e.g. , india ) where infections constitute a major chunk .
there is no data regarding the utility of these two classification schemes from developing world .
thus , we planned this study to compare utility of these two systems of classification in css .
jefferson 's and ishikawa classification of cavernous sinus lesions to compare the utility of jefferson versus ishikawa classification in the evaluation of css .
this prospective observational study was conducted from january 2014 to july 2015 , on 73 patients of css at a tertiary care hospital and university teaching center in northern india .
the study was approved by the institutional ethics committee and written informed consent was obtained from all the patients .
css was defined as involvement of 2 or more of the third , fourth , fifth ( v1 , v2 ) , or sixth cranial nerves , or involvement of only 1 of them in combination with a neuroimaging - confirmed lesion in the cs .
all the patients underwent investigations including detailed hemogram with erythrocyte sedimentation rate and c - reactive protein , biochemistry profile , serum electrolytes , testing for human immunodeficiency virus as well as hepatitis b and c viruses , gadolinium - enhanced magnetic resonance imaging brain on a 1.5 tesla magnetom with thin section cuts of the cs region . further etiological work - up including biopsies , antinuclear , and cytoplasmic anti - neutrophilic antibody testing , serum galactomannan , serum angiotensin converting enzyme levels , contrast - enhanced computed tomography scan of chest and abdomen and cerebrospinal fluid examination , was carried out wherever indicated .
all the patients were classified using jefferson and ishikawa schemes by two neurologists with experience in neuro - ophthalmology independently , and final decision was taken by consensus .
quantitative data were expressed in mean and or median . qualitative or categorical data were expressed in frequency or percentage .
chi - square or fisher 's exact test was applied to compare the discrete variables .
chi - square or fisher 's exact test was applied to compare the discrete variables .
the exact etiology of css was obtained in 63/73 ( 86.3% ) patients of css .
among the ten patients , in which , we could not establish exact etiology , six had probable fungal css ; two had probable diabetes - related ophthalmoplegia , and two remain unclassified
. clinical and demographic profile of patients with cavernous sinus syndrome all the patients were classified by ishikawa and jefferson schemes [ table 3 ] . the number of patients which could be classified using ishikawa classification ( n = 69 ; 95.5% ) was much higher than jefferson classification ( n = 34 ; 46.6% ) . using jefferson classification , css could be classified as anterior , middle , and posterior in 12 ( 16.4% ) , 16 ( 21.9% ) , and 6 ( 8.2% ) patients , respectively .
patients with middle css were significantly ( p = 0.045 ) more likely to have fungal css . as per ishikawa classification , 27 patients each ( 37% ) had anterior and posterior css [ figure 1 ] whereas 12 ( 16.4% ) had middle css and 3 ( 4.1% ) had whole css .
patients with anterior css were significantly more likely ( p = 0.005 ) to have vascular etiology .
overall , inflammatory causes accounted for maximum number of anterior css while tumors accounted for maximum cases of posterior css , although the difference was not statistically significant .
jefferson versus ishikawa classification in cavernous sinus syndrome meningioma in a 34-year - old female presenting with right lateral rectus palsy and numbness over mandibular division of trigeminal nerve .
extraocular movements in 9 cardinal positions of gaze ( a - i ) ( the black and white arrows indicate the direction of intended movement of eyeballs ) . note : restriction of right eye in lateral gaze ( two - dimensional ) suggestive of the right lateral rectus palsy ; contrast - enhanced magnetic resonance imaging of the brain ( 3j - k ) was suggestive of a meningioma ( 3j - coronal , 3k - axial ) ( black and white arrows ) .
as per jefferson classification , she would come under the unclassifiable category while as per the ishikawa classification ; she could be classified as a posterior cavernous sinus syndrome
the exact etiology of css was obtained in 63/73 ( 86.3% ) patients of css .
among the ten patients , in which , we could not establish exact etiology , six had probable fungal css ; two had probable diabetes - related ophthalmoplegia , and two remain unclassified
all the patients were classified by ishikawa and jefferson schemes [ table 3 ] . the number of patients which could be classified using ishikawa classification ( n = 69 ; 95.5% ) was much higher than jefferson classification ( n = 34 ; 46.6% ) . using jefferson classification , css could be classified as anterior , middle , and posterior in 12 ( 16.4% ) , 16 ( 21.9% ) , and 6 ( 8.2% ) patients , respectively .
patients with middle css were significantly ( p = 0.045 ) more likely to have fungal css . as per ishikawa classification , 27 patients each ( 37% ) had anterior and posterior css [ figure 1 ] whereas 12 ( 16.4% ) had middle css and 3 ( 4.1% ) had whole css .
patients with anterior css were significantly more likely ( p = 0.005 ) to have vascular etiology .
overall , inflammatory causes accounted for maximum number of anterior css while tumors accounted for maximum cases of posterior css , although the difference was not statistically significant .
jefferson versus ishikawa classification in cavernous sinus syndrome meningioma in a 34-year - old female presenting with right lateral rectus palsy and numbness over mandibular division of trigeminal nerve .
extraocular movements in 9 cardinal positions of gaze ( a - i ) ( the black and white arrows indicate the direction of intended movement of eyeballs ) .
note : restriction of right eye in lateral gaze ( two - dimensional ) suggestive of the right lateral rectus palsy ; contrast - enhanced magnetic resonance imaging of the brain ( 3j - k ) was suggestive of a meningioma ( 3j - coronal , 3k - axial ) ( black and white arrows ) .
as per jefferson classification , she would come under the unclassifiable category while as per the ishikawa classification ; she could be classified as a posterior cavernous sinus syndrome
ishikawa was the first author who studied cs structure by stereotaxically analyzing 30 m serial cs sections . based on his observations , ishikawa proposed his classification for cs lesions . in the current study , 35 ( 48.9% )
additional patients could be classified using ishikawa scheme similar to that reported by yoshihara et al .
jefferson classification is heavily biased toward trigeminal nerve and ignores other structures contained within cs such as optic nerve , oculosympathetic fibers , inferior division of the 3 cranial nerve and maxillary nerve either alone or in combination with mandibular nerve .
for instance optic nerve was involved in 17 ( 23.2% ) patients in this study . after leaving the internal carotid artery ,
although such lesions will remain unclassifiable as per jefferson scheme , these will be classified as posterior css in ishikawa scheme . in the current study , we had one patient secondary to carotid aneurysm .
similarly , while patients with isolated maxillary nerve involvement or both maxillary and mandibular nerve involvement would fall into posterior css in ishikawa classification , these will remain unclassified as per jefferon scheme .
, css could be classified as anterior , middle , and posterior in 12 ( 17.8% ) , 16 ( 21.9% ) , and 6 ( 8.2% ) patients , respectively , as per the jefferson classification and 27 ( 37% ) , 27 ( 37% ) , and 12 ( 16.4% ) as per ishikawa classification .
showed anterior cs involvement to be the most common ( 35% ) followed by posterior ( 22% ) and middle ( 10% ) as per ishikawa classification .
the difference between above series and ours is likely related to the different etiological profile of css in these series . using jefferson classification ,
middle css was significantly associated with the presence of fungal infections ( p = 0.045 ) . using ishikawa classification ,
overall , inflammatory causes were the most common cause for anterior css , while tumors accounted for maximum cases of posterior css , although the difference was not statistically significant .
anterior cs is likely to be affected by inflammatory pathologies more often due to its close proximity to ethmoid sinus ( most common site of paranasal sinusitis ) , while posterior cs is likely to be affected by tumors especially pituitary adenomas due to anatomical reasons .
our findings are similar to yoshihara et al . , who reported inflammation to dominate in anterior css and tumors to dominate in posterior css .
our study further emphasizes that many more patients with css can be classified using ishikawa scheme as compared to jefferson scheme .
however , when it comes to etiological profile of css , ishikawa classification did not score over jefferson scheme .
in fact , jefferson scheme gave a better idea to etiology as middle css in this scheme had a significantly higher chances of fungal css .
. that may be the main reason why some of our results did not reach statistically significance .
future studies with more patients may help to understand the utility of these two classification systems better .
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### Summary:
: introduction : ishikawa and jefferson are the two most commonly used systems used for the classification of cavernous sinus syndrome ( css ) . however , relative utilities of these two classification systems have not been evaluated in detail in developing countries . in this study , we compared relative utilities of these two classification schemes in the evaluation of css.objective:to compare the utility of jefferson and ishikawa classifications in the evaluation of css.patients and methods : a total of 73 consecutive patients of css were prospectively classified using either ishikawa or jefferson classification and relative utility of these two classification schemes in determining etiology of css was compared.results:while only 46.6% of patients could be classified using jefferson classification , 95.5% of patients could be classified using ishikawa scheme .
css was classified as anterior , middle , and posterior in 17.8% , 21.9% , and 8.2% of patients , respectively , as per the jefferson classification .
as per the ishikawa classification , 37% of patients each showed anterior and posterior css , 16.4% showed middle css , whereas 4.1% had whole css .
middle css was significantly associated with the presence of fungal infections ( p = 0.045 ) as per jefferson classifications , and anterior css was significantly associated with a vascular etiology ( p = 0.005 ) as per ishikawa classification .
overall , inflammatory causes were the most common cause for anterior css , while tumors accounted for maximum cases of posterior css.conclusion:although more number of patients could be classified using ishikawa classification , there was no advantage of ishikawa classification over jefferson with regard to determination of etiology of css .
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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:
: bhore ( 1946 ) , mudaliar ( 1961 ) , and srivastava committee ( 1975 ) for improvement of the health care system and has emphasized greater provision of traditional complementary and alternative medicine , , . the national health policy ( 1983 )
suggested phased integration of indigenous medicine with biomedicine . as a result of such concerted efforts , the department of indian system of medicine and homeopathy ( ism&h ) was established in 1995 .
successive review of national health policy in 2002 put still greater emphasis on indigenous health systems , and the department was renamed as ayush in 2005 with new administrative structures and improved functioning .
the same year , the national rural health mission ( nrhm ) came up with strategies for mainstreaming ayush for the rural health sector , , .
further , in 2014 the government of india carved out a full - fledged ministry to stress on various components of ayush medical education , quality control , drug standardization , research and development , and greater awareness of its potential , both within india and abroad . in compliance with the government of india guidelines and with technical and financial support from the government of india ,
the state of odisha implemented ayush in both primary health and community health centers ( phcs and chcs ) .
many strategies were adopted by the state government to improve delivery of ayush services in rural areas .
the state government also took steps to facilitate and improve the quality of laboratories , drug standardization procedures , research , and advocacy .
so far , it has successfully collocated 796 homeopathy and 680 ayurveda clinics in the phcs and chcs .
seventy - eight of these dispensaries are in balasore district and have been commissioned in 2005 with an initial grant of inr 4,978,000 for improvement of rural health , particularly maternal health .
the improved focus on ayush by the state government is especially important in the context of prevailing poor health indicators in the state which has prompted the planning commission to consider it as one of the empowered action group states .
one - quarter of the population of odisha consists of tribal community , who has historical inclination toward ayush system of medicine .
in addition , it is one among the eighteen high focus states for program implementation of the government 's nrhm , especially maternal health .
the state has a high maternal mortality ratio ( mmr ) that hinders the realization of millennium development goal of reducing mmr to 119 by the end of the 11th plan period ( 20072012 ) . following the central government guidelines ,
the odisha government has therefore made an attempt to provide an integrative treatment plan having plural medical choices for women .
homeopathy , ayurveda , and unani in the chcs , which are used as referral centers to the phcs .
later , every phc was equipped with at least one of the ayush systems of medicine .
the collocation of ayush unit was driven by medical plurality and revitalization of traditional therapies . in rural and tribal communities
, the women found an opportunity to come across ayush system in a government facility which is very similar to local health traditions ( lht ) and home remedies provided by local healers , hakims , and private practitioners .
unless emergency conditions arise , the tribal women were in the habit of using lht and home remedy rather than biomedicines .
this helps them to figure out ayush system of medicine perceiving less adverse effect with better accessibility .
existing health workers such as the accredited social health activists ( ashas ) , auxiliary nurses and midwifes ( anms ) , and anganwadi workers were thought to further improve the potential of ayush medicine .
some districts in the state of odisha such as balasore have done fairly well in the maternal health program .
unfortunately within these high performing districts , there are vulnerable tribal blocks which pose special challenges .
jaleswar block is one such area in balasore district of odisha with a very high concentration of poor tribal population .
the block is one among the 46 modified area development approach pockets of odisha where specialized development programs for tribal improvement are monitored by the ministry of tribal affairs .
the situation is also made difficult by the marked inaccessibility of this region due to its riverine geographical structure , and frequent floods interrupt the referral network to deliver optimal maternal care .
many of the health centers of jaleswar were declared as difficult by the national health systems resources centre for such reasons .
further , the tribal communities have marked dependence on ethnomedicine in comparison to modern biomedicine , making it difficult for the government to promote western methods of maternal care .
an analysis of hmis data for the year 2014 shows that only 46.4% of the pregnant women were registered in the first trimester among the total anc registrations . whereas , early registration for pregnancy not only reflects good health seeking behavior but also facilitates better birth preparedness and detection of obstetric complications .
one - fifth ( 21.4% ) of the registered women do not receive iron and folic acid tablets to combat pregnancy - related anemia . according to the health administrators of jaleswar ,
hmis data also showed home deliveries are prevalent in the block unattended by skilled birth attendants , which make the women vulnerable to various infections , leading to high mortality and morbidity .
nearly 70% of the women are discharged from the hospital within 48 h of delivery due to the lack of hospital beds and necessary amenities , whereas , normative guidelines prescribe 48 h hospitalization , post - delivery , for postnatal care .
. the main objective of the study was to assess the potential of collocating ayush to improve the maternal health program in the tribal dominated jaleswar block of the balasore district in odisha .
it also aimed to unearth the underlying challenges in mainstreaming ayush with a view to suggest recommendations for improving maternal health .
a review of policy documents and guidelines of both the central and the state government are made to assess the implementation of ayush in odisha at the vulnerable area .
in addition to secondary data , primary data were collected through interviews of tribal women and ayush doctors , district and block health administrators such as district program manager , block program manager , district data manager , and medical officer ( in - charge ) having specialized knowledge for implementation of ayush to know the operational problems in its implementation .
the initiative for strengthening ayush for improvement of maternal health program was on principle well intended given the fact that the state has adequate provision for education and training of ayush professionals at both undergraduate and postgraduate levels .
there is a facility for training of 180 and 160 undergraduate doctors in ayurveda and homeopathy , respectively , in an academic year .
further , training for 15 ayurveda and homeopathy doctors each at postgraduate level is available in ayush medical colleges of odisha .
many rural and inaccessible places of odisha are already served by ayush dispensaries owned by odisha government . currently , there are 624 ayurveda , 537 homeopathy , and 9 unani dispensaries in the state .
further , there are 4458 ayurveda and 3835 homeopathy doctors working in government and private organizations and on self - employment basis in the state .
the government appointed ayush doctors having a minimum of undergraduate degree which may be : bachelor of ayurvedic medicine and surgery , bachelor of homeopathic medicine and surgery , and bachelor of unani medicine and surgery as mandatory qualifications .
further , a quarter of them recruited under nrhm have a postgraduate degree in their respective specialization .
details of ayush infrastructure and manpower in odisha are provided in table 1
.
the number of ayush health centers in jaleswar are listed in table 2
.
the women requiring referral services in homeopathy mostly relied on the medical college hospital for further consultation . in case of ayurveda referrals ,
the patients are referred to nearest ayurveda hospital of odisha government , which is functioning directly under the aegis of department of ism&h . moreover ,
the logic of collocating ayurveda or homeopathy units in phcs and chcs under nrhm is derived from the existence of ayurveda or homeopathy hospitals under the department of ism&h in that particular locality .
if there was the existence of ayurveda hospital nearest to the phc , then a homeopathy unit was recommended for the phc and vice versa .
however , in actual , the referral network is not kept intact and most of the pregnant women have to take the help of biomedicines . according to ayush operational guidelines
, there should be ayush opd clinics at phc , ayush ipd at chc , and full - fledged ayush wing with specialty care at district head quarter hospital . despite the elaborate infrastructure outlined above ,
the contribution of ayush to maternal and child health ( mch ) programs , in odisha and in jaleswar block in particular , has been less than optimal .
field data highlighted some of the limitations arising due to preconceived biases against ayush vis - a - vis biomedicine .
this is well - illustrated in the skewed appointment of ayush physicians in different tiers of health delivery system .
presently , most are posted at the lowest administrative health tier at phcs and chcs .
while two allopathic doctors are employed at phc , only one ayush doctor remains in charge .
the number of allopathic doctor increases to four at chc level , but the corresponding number of appointed ayush doctors remains static at one only .
in other words , there is no increase in deployment of ayush manpower at higher referral levels . this is unfortunately given the fact that disease - specific interventions are charted out at a higher level , thereby compromising specialized ayush inputs to health delivery system .
in addition to the skewed deployment of ayush personnel , it was seen during field work that they were mostly engaged in iec activities related to key events such as pustikar diwas , mamata diwas , and village health and nutrition day .
these involve extensive traveling and supervisory skills which consume time and energy , leaving little scope for specialized ayush services at dispensary .
ayush doctors are supposed to supervise ongoing public health programs for a minimum of 1216 days per month . moreover , since these engagements are well supported by government incentive schemes , there is a little motivation to focus on specialized ayush activities related to diagnosis and cure .
ayush doctors also engage themselves in jobs which could otherwise be well - supervised by block extension educators and lady health workers .
very often woman in need of emergency care complains of not finding ayush doctors in their dispensaries due to latter 's preoccupation in off - site activities . an ayush doctor ( homeopathy specialization )
detailed how discontinuity adversely affects the performance:pregnant women are prescribed homeopathic medicines after proper case analysis .
but , due to field supervision , i am unable to monitor and follow - up patients ' treatment .
complementary doses , proper substitutes , and antidotes under conditions of homeopathic aggravations are especially difficult to administer .
this seriously impedes the progress of ayush services delivery which relies heavily on repeat visits and customized interventions .
there is also a dearth of pharmacists and other paramedic staffs which undoubtedly affects efficient delivery of ayush services . as a result
but , due to field supervision , i am unable to monitor and follow - up patients ' treatment .
complementary doses , proper substitutes , and antidotes under conditions of homeopathic aggravations are especially difficult to administer .
this seriously impedes the progress of ayush services delivery which relies heavily on repeat visits and customized interventions .
there is also a dearth of pharmacists and other paramedic staffs which undoubtedly affects efficient delivery of ayush services . as a result
contractual appointments have also seriously impacted the motivation levels of the ayush doctors , predisposing them to services , which fetch merely incentives rather than job satisfaction .
the planning commission had recommended provision of contractual recruitment , training , and involvement of human resources for program implementation plans .
these recommendations have been adopted by the government of odisha in the year 20082009 for ayush services . however , a piecemeal implementation of the recommendations has ensued with no financial provisions made in the state during the said period , with the result that the doctors interviewed were dissatisfied with the existing salary and delay in receiving the same .
this indirectly compelled them to involve themselves in incentive programs ( mentioned earlier ) and private practice , thereby , seriously impacting the government 's maternal health program . in jaleswar
, there are 11 ayush physicians appointed on contractual terms , most of them working for more than 6 years of service without any further scope for regularization of services . on the other hand ,
biomedical physicians working in phcs and chcs enjoy permanent status under the government of odisha as
if due to unavailability of biomedical physicians , the posts remain vacant ; contractual personnel are appointed till their replacement by permanent doctors by the government of odisha .
they are well - remunerated and entrusted with clinical activities at phc or chc unlike their ayush counterpart who are primarily engaged in public health activities .
it may be noted that initially nrhm worked in a mission mode during 20052012 with almost 75% funding from the government of india and 25% matching share from the government of odisha toward manpower costs .
the mission document proposes the state governments to arrange the expenses of necessary manpower and infrastructure after the said period .
, government of odisha adopted a policy to regularize staffs in various departments after rendering 6 years of contractual services . in health department
also , various categories of service staff such as pharmacists , staff nurses , and technicians ( working under ent , eye , ot , laboratory ) were regularized after 6 years of contractual services by creating new posts .
however , this policy was not adopted in the case of ayush doctors , showing the discriminative attitude of government toward ayush doctors .
updating knowledge and practice is a prerequisite for efficient functioning of any system of medicine . while continuing medical education ( cme ) conducted at district head quarters hospital , balasore , considerably help allopathic doctors , ayush doctors do not have such opportunities for knowledge sharing despite having played an important role in maternal health services since 2008 .
the interviews reveal an inter - district sharing of clinical knowledge , health information , and challenges could have paved the way for improvement in the field .
the ayush physicians interviewed in jaleswar block opines that despite more than 6 years of services under nrhm there is no cme program for the update of professional knowledge .
the need for upgradation and information sharing for critical case management has also been corroborated by a study of the planning commission for ayush doctors .
the ayush system is not supported by the standard treatment guidelines ( stgs ) for commonly occurring diseases during pregnancy .
for instance , ayush medical officers in jaleswar were found to adopt multiple treatment modalities for single disease condition , thereby violating some of the best practice procedures in ayush system .
many doctors complained of a lack of standard protocols for maternal health , particularly for tribal women .
an ayush doctor ( ayurveda specialization ) recounts:there was a case of a women with severe hypertension who came to the hospital when the allopathic unit was closed .
meanwhile , i consulted a senior ayush physician and on his suggestion modified my present line of treatment .
a scientifically well documented stg would be helpful for colleagues who do n't have guidance of such senior physicians .
there was a case of a women with severe hypertension who came to the hospital when the allopathic unit was closed .
meanwhile , i consulted a senior ayush physician and on his suggestion modified my present line of treatment .
this yielded good results and i continued this treatment plan for similar cases . a scientifically well documented stg would be helpful for colleagues who do n't have guidance of such senior physicians .
the overall association of ayush with public health ( rather than clinical ) interventions has seriously underplayed its specialized potential in maternal health . as an illustration ,
the role of homeopathy in the treatment of gynecological problems and pregnancy - related complications in maternal health has not been explored well in the ongoing mch program , despite the fact that available literature has good documentation of effective remedies to combat such problems .
pregnant women , who frequently suffer from ailments relating to urinary tract infection ( uti ) , insomnia , hypertension , thrush , and varicose vein , particularly respond well to homeopathy medicines , , .
however , during field work , the use of such therapeutic regimen was hardly evident . an ayush physician ( homeopathy specialization ) also testified the therapeutic efficacy of ayush drugs in promoting maternal health:when pregnant women visit dispensary regularly , this provides scope for follow - up and helps in ascertaining the prognosis at different stages of labor .
it is found that the progress of pregnancy is then quiet smooth and results in normal delivery compared to cases where no homeopathic medicine is taken .
however , lack of specialized ayush inputs to emergency maternal care compels them to use it as a preventive rather than a dedicated system of care . when pregnant women visit dispensary regularly , this provides scope for follow - up and helps in ascertaining the prognosis at different stages of labor .
it is found that the progress of pregnancy is then quiet smooth and results in normal delivery compared to cases where no homeopathic medicine is taken .
however , lack of specialized ayush inputs to emergency maternal care compels them to use it as a preventive rather than a dedicated system of care .
another ayush doctor ( ayurveda specialization ) spoke thus:pregnant women who regularly take ayush medicines are sometimes forced to take allopathic medicines and undergo surgical procedures because of emergency interventions .
but , after the emergency episode gets over , they revert to ayush medicines being overtly concerned about the side effects of allopathic medicines .
pregnant women who regularly take ayush medicines are sometimes forced to take allopathic medicines and undergo surgical procedures because of emergency interventions .
but , after the emergency episode gets over , they revert to ayush medicines being overtly concerned about the side effects of allopathic medicines .
many folk medicines in jaleswar which use local botanical resources have hardly been explored by ayush doctors for their potential in improving maternal health . during field work , it was found that the region is rich in many medicinal herbs and plants such as tulsi ( ocimum sanctum ) , guduchi ( tinospora cordifolia ) , dadima ( punica granatum ) , haritha manjari ( acalypha indica ) , matsyakshi ( alternanthera sessilis ) , chakramuni ( sauropus androgynus ) , nimba ( azadirachta indica ) , parnayavani ( coleus amboinicus ) , shigru ( moringa oleifera ) , agastya ( sesbania grandiflora ) , brahmi ( bacopa monnieri ) and kakamachi ( solanum nigrum ) all of which can play a significant role in maternal health . historically , tribal pregnant women have had less access to modern biomedicines and rely on local healers and traditional herbal remedies .
for example , peppermint leaf ( lamiaceae mentha ) is used for curing morning sickness , ginger roots ( zingiber officinale ) for nausea and vomiting and triphala ( emblica officinalis , terminalia bellirica , terminalia chebula ) for ailments of stomach and abdomen during pregnancy .
the ayush system in a government facility offers the rural tribal women a system of healing , which is very similar to lht and home remedies provided by local healers and hakims .
barring emergency conditions , tribal women have a greater dependence on traditional and home remedies .
therefore , an effective ayush health delivery system needs to align local resources through the greater affirmation of their medicinal worth .
more specifically , there is a need for training of community workers ashas to identify and administer local herbs and shrubs for common ailments of pregnant women .
moreover , since local healers play an important role in healing , their services could also be utilized for improving the integration of ayush medicines in the community .
ayush clinics in most of the health centers of jaleswar are located in a secluded corner of the hospital premises and in some places the signage for ayush services is even not prominently visible .
this spatial marginalization prevails against the operational guidelines for provision ( in phcs and chcs ) , of a separate physician consultation room and a distinct space for storing medicines .
however , in reality , only one cramped room is available at phc and chc of jaleswar .
this spatial marginalization has negative consequences for integration of ayush services to maternal health program .
it goes without saying that like other pharmaceutical products , ayush medicines also require proper storage conditions and monitoring of shelf life to prevent decay .
hence , cramped conditions affect the quality of medicines and speedy delivery of services to women .
it would be easier for the tribal women to adopt ayush system of medicine for various ailments if privacy , confidentiality , and accessibility could be ensured .
tribal rituals and beliefs on pregnancy are , in general , shrouded in secrecy and prevent openness and disclosure of problems .
hence , special precaution needs to be made to ensure private spaces for health inspection . by denying such spaces in phcs of jaleswar ,
the existing health delivery system subdues the medical choices of the tribal women and their family members .
there is also a poor logistic cycle to support the vibrant plan of integrating ayush in phcs and chcs .
an interview with an ayush doctor ( homeopathy specialization ) revealed that during the 1st year of his appointment to the dispensary , he could barely engage himself with diagnosis and treatment due to the lack of availability of medicines in the health center . during field work , many others complained of poor and insufficient medical stocks a grievance commonly shared by doctors in different parts of the country running the nrhm program .
ayush centers of jaleswar were also found to lack many essential facilities and medical equipment such as examination table , equipment for monitoring blood pressure , and for assessing sensory reflexes through knee hammer , and had to rely on resources of the allopathic dispensary for such basic clinical investigations .
ayush doctors in jaleswar complained of not being consulted in drug procurement plans , which drastically affected the prioritization of medicines according to the local needs . while the computerized system of odisha drug inventory management information system takes care of the procurement and supply of allopathic drugs and consumables for the community , ayush medicines
are unfortunately left out of its scope , thereby , bringing inefficiencies in the logistic cycle and creating bottlenecks in procurement and quality control .
in addition , the drug management policy is currently not supported by an expert committee , which could help to identify priority needs for replenishing essential ayush medicines according to local characteristics those at times fall outside the purview of a centralized drug list . although a digital monitoring system for drugs has been introduced , it only brings many errors and complications without bringing efficiency in procurement , maintenance , quality control , and preservation of ayush drugs .
strategies and policy prescriptions regarding an integrative framework of health delivery involving ayush system of medicine find an appropriate place in government documents , such as the framework for implementation of nrhm ( 20052012 ) , report of the working group on ayush ( by planning commission ) , and mainstreaming of ayush and revitalization of lht under nrhm , , .
however , 10 years down the line after the implementation of nrhm , the system faces many pitfalls , the chief burden of which is borne by the maternal health program .
the study in tribal dominated jaleswar block in odisha highlights the dissociated realty of ayush .
ironically , alternative and folk medicines have been an integral part of odisha 's medical history for centuries .
the ayush system , which shares and incorporates many common features with some of the local healing traditions , has a natural demand in the tribal community , generally known for its resistance to biomedicine .
moreover , the consideration of birthing as a natural phenomenon in women 's life , rather than a disease , subject to rigorous monitoring and hospitalization ( as in the biomedical paradigm ) , is still not a familiar phenomenon in the tribal culture .
the focus on collocation of ayush system in such a region is thus both theoretically and strategically sound primarily because of three reasons its affordability , accessibility , and its congruence with tribal health beliefs and customs .
unfortunately , jaleswar presents a dismal scenario characterized by structural biases on one hand and by poor management and orientation of the ayush doctors on the other hand .
poor job profile , disproportionate salary structure , and contractual appointments have also been unraveled by other studies despite security and salary factors being identified as motivating factors by ayush doctors working in phcs and chcs , , . in addition , their deployment for iec activities rather than specialized inputs for gynecological conditions , contribute to considerable subordination and deprofessionalization in the overall system of health delivery .
similar problems have also been identified in rajasthan and in other indian states such as andhra pradesh , uttar pradesh , bihar , and rajasthan , .
a multi - state indian study in three different states , kerala , meghalaya , and delhi , also reports a lack of infrastructure and coordination as the main obstacle for delivery of health services . a major impediment in ayush delivery is the inadequate logistic cycle of medicines , which creates difficulties in dispensing medicines to the pregnant women in jaleswar .
lack of effective monitoring of supply chain management for ayush drugs and consumables create problems in the follow - up of patients and specialized care .
such delays in supply and erratic replenishment of ayush medicines have also been observed in andhra pradesh .
in addition , studies from delhi show lack of a robust logistic mechanism with improper indentation , supply , and storage of medicines . given such glaring problems , the question may be raised whether collocating ayush does actually have a beneficial effect ?
a study in chandigarh reveals that mere collocation of ayush facilities creates a high degree of satisfaction among women .
the present study suggests that without a robust health delivery mechanism and effective guidelines for cross referrals , collocation may not be a fruitful strategy .
if ayush were to serve an important place in maternal health , it needs to be fully equipped to handle all emergencies , a feature not difficult with its available staff of postgraduate personnel who could provide specialty services had they been technically supported in the phcs and chcs . in other words , there is a need for greater strengthening of its own treatment and referral network rather than shifting critical gynecological cases to biomedical domain . it may be mentioned that there is a provision in the guidelines for referral of ayush patients to higher centers for specialized ayush care from phc to higher centers . according to ayush operational guidelines , there needs to be an ayush opd clinic at phcs , chcs and full - fledged ayush wing with specialty care at district head quarter hospital .
however , in reality , the referral network is not kept functional with the result that most pregnant women have to fall back on biomedicine . at the community level ,
some degree of reorientation of ayush doctors regarding the scope , strength , and limitations of integrative health care , improved management of critical cases , and appreciation of community characteristics are required .
improper coordination runs the risk of disastrous outcomes in the delivery of health care services in rural india , a feature noticed in different studies in other indian states as well , , .
integrative medicine in a tribal community needs greater effort toward identifying medicinal plants and orienting drugs according to familiar dietary and healing strategies of the community .
table 3 presents a few challenges and recommendations for improving ayush 's contribution to maternal health program in jaleswar .
recommendations along similar lines have , in fact , been submitted to the ministry of health and family welfare along with the suggestion that ayush physicians practice their respective specializations at local phcs rather than heading phcs in far - flung areas in order to ensure a greater familiarity with local community needs . according to normative guidelines , health workers such as ashas
, anms also need to be trained in dispensing ayush medicines , particularly ayurveda supplements for iron deficiency of pregnant women and homeopathy formulations for both health promotion , basic , and emergency care .
but , field observations suggest that few ayush medicines are available in asha kits and their supply and replenishment are seriously affected .
this has unfortunately given the evidence about high reliance on indigenous therapies among tribals for maternal health in other districts of odisha .
the santhals , bhujus , and bhumijas of jaleswar too have strong belief on folk and indigenous medicines and an integrative approach is likely to yield good outcomes for maternal health .
the study concludes that although there is a huge scope for integrating ayush in maternal health program under the ongoing nrhm , the full potential is yet to be exploited . in jaleswar ,
serious barriers exist in creating a dedicated ayush workforce and in training ancillary health workers to improve the acceptability of ayush in the community .
the study has also highlighted special provisions that need to be made for remote tribal - dominated regions such as jaleswar , which already have a rich history of lht and home remedy .
given the fact that these regions are economically underdeveloped , have distinct orientation toward natural healing systems , ayush on account of its holistic approach and proven cost effectiveness can be a viable option for improving maternal health .
however , to make the plan operationally vibrant , the existing glitches in medicine procurement , storage and supply need to be removed .
the spatial de - marginalization of ayush also needs considerable attention from the planners through architectural modification and not mere collocation of services as envisaged by the government .
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### Summary:
: mainstreaming of ayush and revitalization of local health traditions is one of the innovative components of the national rural health mission ( nrhm ) in the state of odisha , india . in this study
, an attempt was made to assess the potential of collocating ayush to improve maternal health services in tribal dominated jaleswar block of the balasore district .
in addition , the study aimed at unearthing the underlying challenges and constraints in mainstreaming ayush and linking it with the maternal health program.review of the policy documents and guidelines , both central and state government , was made to assess the implementation of ayush in odisha .
primary data were collected through interviews with ayush doctors , district and block level health administrators , and tribal women.the study revealed the inadequacy of basic amenities , infrastructure , drugs , and consumables in the health centers for integrating ayush in the delivery of maternal health services .
analysis of the job chart and work pattern of ayush doctors showed underutilization of their specialized knowledge to treat patients .
lack of continued medical education , standard operating procedures for treatment and spatial marginalization made suboptimal utilization of ayush services .
this is unfortunate given the fact that such regions are economically underdeveloped and already have a distinct orientation toward indigenous health systems .
ayush , on account of its holistic approach and proven cost - effectiveness , could be a viable option for improving maternal health in the region.the study concluded that although there is huge scope for integrating ayush in maternal health program under the ongoing nrhm , the full potential is yet to be exploited .
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: mice were obtained from jackson labs ( bar harbor , me ) and housed under specific pathogen - free conditions .
ethical approval was obtained from the animal welfare committee at the university of alberta , and all animal care was in accordance with the guidelines of the canadian council on animal care .
ep1013 was obtained from epicept corporation ( san diego , ca ) , and ctla4-ig was obtained from bioexpress ( west lebanon , nh ) .
mouse islets were isolated from balb / c ( h-2d ) and c3h ( h-2k ) donors using established methods ( 13 ) .
streptozotocin ( sigma - aldrich , canada , mississauga , on ) was used to induce diabetes in c57bl/6 ( b6 , h-2b ) recipients ( 250 mg / kg i.p . ) . before transplantation
, mouse islet preparations were incubated in medium containing caspase inhibitor ( ep1013 at 100 mol / l in dulbecco 's modified eagle 's medium with 10% fcs , invitrogen canada ) or vehicle for 2 h. transplant recipients were treated with either vehicle solution ( dmso in sterile saline ) or caspase inhibitor ( 3 mg / kg s.c .
ctla4-ig was administered on days 0 , 2 , 4 , and 6 post - transplant ( 0.25 mg i.p . )
animals were monitored three times per week , and two consecutive blood glucose values > 18 mmol / l was considered to be evidence of rejection .
euglycemic animals from each cohort were selected randomly , and the graft - bearing kidney was removed to establish that the islet graft was functional , as determined by a return to hyperglycemia postnephrectomy ( > 18 mmol / l ) .
cryostat sections ( 10 m ) of islet grafts were stained as previously described ( 15 ) .
rat anti - mouse cd4 ( clone gk1.5 ) , rat anti - mouse cd8 ( clone 53 - 6.7 ) , rat - anti - mouse foxp3 ( clone fjk-16s ) , and polyclonal guinea pig anti - insulin were used .
all slides were photographed at 100200 magnification , and the total number of fluorescein isothiocyanate ( fitc ) cells per section were quantified from n = 45 animals per treatment group ( minimum three sections per animal analyzed ) .
serum was harvested from treated animals and stored until the completion of the study for bulk analysis .
alloantibody levels were determined using the indirect cellular enzyme - linked immunosorbent assay ( elisa ) method described by fan et al .
animals were killed at 11 days post - transplant , and splenocytes were harvested and purified using lympholyte - m ( cedarlane ) .
donor - type balb / c splenocytes were harvested , purified , and irradiated ( 1,500 rad ) .
the 5 10 recipient splenocytes were incubated with 5 10 irradiated balb / c splenocytes in rpmi medium supplemented with 10% fcs ( invitrogen ) for 48 h ( elispot ) or 96 h ( mixed lymphocyte reaction [ mlr ] ) . after the incubation period ,
ifn- elispot plates were washed and processed according to the manufacturer 's protocols ( ebioscience ) .
after the culture period , cells were pulsed for an additional 18 h with 1 ci h thymidine / well and harvested , and thymidine incorporation was determined using a scintillation counter . for both experiments ,
also , for both mlr and elispot assays , wells containing splenocytes from each treatment group , as well as irradiated target cells , were analyzed as negative control samples to rule out any nonspecific proliferation or ifn production .
all statistical analyses in this study were carried out using sigmaplot 10 and sigmastat 3.5 ( systat , inc . ) , and results are expressed as mean sem .
mann - whitney rank - sum tests and anova with bonferroni post hoc analysis were used to analyze multiple groups .
mice were obtained from jackson labs ( bar harbor , me ) and housed under specific pathogen - free conditions .
ethical approval was obtained from the animal welfare committee at the university of alberta , and all animal care was in accordance with the guidelines of the canadian council on animal care .
ep1013 was obtained from epicept corporation ( san diego , ca ) , and ctla4-ig was obtained from bioexpress ( west lebanon , nh ) .
mouse islets were isolated from balb / c ( h-2d ) and c3h ( h-2k ) donors using established methods ( 13 ) .
streptozotocin ( sigma - aldrich , canada , mississauga , on ) was used to induce diabetes in c57bl/6 ( b6 , h-2b ) recipients ( 250 mg / kg i.p . ) . before transplantation
, mouse islet preparations were incubated in medium containing caspase inhibitor ( ep1013 at 100 mol / l in dulbecco 's modified eagle 's medium with 10% fcs , invitrogen canada ) or vehicle for 2 h. transplant recipients were treated with either vehicle solution ( dmso in sterile saline ) or caspase inhibitor ( 3 mg / kg s.c .
ctla4-ig was administered on days 0 , 2 , 4 , and 6 post - transplant ( 0.25 mg i.p . )
animals were monitored three times per week , and two consecutive blood glucose values > 18 mmol / l was considered to be evidence of rejection .
euglycemic animals from each cohort were selected randomly , and the graft - bearing kidney was removed to establish that the islet graft was functional , as determined by a return to hyperglycemia postnephrectomy ( > 18 mmol / l ) .
cryostat sections ( 10 m ) of islet grafts were stained as previously described ( 15 ) .
rat anti - mouse cd4 ( clone gk1.5 ) , rat anti - mouse cd8 ( clone 53 - 6.7 ) , rat - anti - mouse foxp3 ( clone fjk-16s ) , and polyclonal guinea pig anti - insulin were used .
all slides were photographed at 100200 magnification , and the total number of fluorescein isothiocyanate ( fitc ) cells per section were quantified from n = 45 animals per treatment group ( minimum three sections per animal analyzed ) .
serum was harvested from treated animals and stored until the completion of the study for bulk analysis .
alloantibody levels were determined using the indirect cellular enzyme - linked immunosorbent assay ( elisa ) method described by fan et al .
animals were killed at 11 days post - transplant , and splenocytes were harvested and purified using lympholyte - m ( cedarlane ) .
donor - type balb / c splenocytes were harvested , purified , and irradiated ( 1,500 rad ) .
the 5 10 recipient splenocytes were incubated with 5 10 irradiated balb / c splenocytes in rpmi medium supplemented with 10% fcs ( invitrogen ) for 48 h ( elispot ) or 96 h ( mixed lymphocyte reaction [ mlr ] ) .
after the incubation period , ifn- elispot plates were washed and processed according to the manufacturer 's protocols ( ebioscience ) .
after the culture period , cells were pulsed for an additional 18 h with 1 ci h thymidine / well and harvested , and thymidine incorporation was determined using a scintillation counter . for both experiments ,
also , for both mlr and elispot assays , wells containing splenocytes from each treatment group , as well as irradiated target cells , were analyzed as negative control samples to rule out any nonspecific proliferation or ifn production .
all statistical analyses in this study were carried out using sigmaplot 10 and sigmastat 3.5 ( systat , inc . ) , and results are expressed as mean sem .
mann - whitney rank - sum tests and anova with bonferroni post hoc analysis were used to analyze multiple groups .
initially , fully mhc - mismatched islet allografts were completed using chemically diabetic recipients , and treatment with either ep1013 ( days 010 ) , ctla4-ig ( days 0 , 2 , 4 , and 6 ) , combination of ep1013 and ctla4-ig , or vehicle ( days 010 ) was commenced . as shown in fig .
1a , treatment with ep1013 resulted in no prolongation of islet allograft survival ( mean survival time 18.2 days ) compared with vehicle - treated animals ( mean survival time 22.8 days , p = ns ) .
ctla4-ig monotherapy resulted in prolonged graft survival in 40% of the animals ( mean survival time 103.0 days ) , whereas the addition of ep1013 to ctla4-ig resulted in a significant increase in graft survival ( n = 16/18 with long - term survival resulting in mean survival time > 180 days post - transplant ; p < 0.01 vs. ctla4-ig by log - rank ) .
ep1013 therapy , when combined with costimulation blockade using ctla4-ig , results in long - term islet graft survival and operational tolerance .
a : islet allografts were completed across a complete mhc mismatch using balb / c ( h-2d ) donors and chemically diabetic b6 ( h-2b ) recipients .
caspase inhibitor therapy ( ep1013 ) did not prolong graft survival compared with vehicle - treated animals .
monotherapy with ctla4-ig prevented graft rejection in 40% of recipients , whereas combination of ep1013 and ctla4-ig resulted in graft survival of > 200 days in 89% of recipients ( p < 0.01 vs. ctla4-ig ) .
b : to test for donor - specific tolerance , graft - bearing kidneys were removed , and animals were re - transplanted with either donor - type ( balb / c ) or third - party ( c3h , h-2k ) islets without further treatment or with a second 10-day course of ep1013 . when using balb / c islets , donor - specific tolerance was demonstrated in 30% of the transplant recipients ( either ctl4-ig or ctla4-ig+ep1013 cohorts ) .
re - transplantation with third - party islets resulted in robust rejection in all recipients . to further understand the enhanced outcomes using ep1013+ctla4ig versus ctla4-ig alone , a series of experiments was carried out in animals with long - term graft function in each group . to test for tolerance ,
after 2 days of hyperglycemia , either same - donor ( balb / c , h2-d ) or third - party ( c3h ; h2-k ) islets were implanted with no additional therapeutic intervention ( fig .
re - transplantation with balb / c islets led to prolonged graft survival in 2030% of the recipients , regardless of the initial treatment group .
this demonstrates that true donor - specific tolerance was only achieved in a subgroup of the transplant recipients , despite the presence of indefinite graft survival after the initial transplant ( i.e. , operational tolerance ) .
implantation of c3h islets resulted in rejection in all recipients in both treatment groups , confirming that operational tolerance to the initial graft was achieved without compromising the recipient 's immunological function ( fig .
the lack of donor - specific tolerance in this model is the effect of the tissue injury , local inflammation , and graft cell death at the time of and after the second transplant , which could alter the recipient 's ability to maintain donor - specific tolerance . to minimize these effects ,
an additional cohort of animals with long - term islet graft survival were re - transplanted with balb / c islets and also treated with a 10-day course of ep1013 , using the same dosing as the initial treatment period .
1b , this intervention did not improve the rate of donor - specific tolerance in animals previously treated with ep1013+ctla4-ig . to explore the immune response to these grafts at this late time point post - transplant , immunofluorescence staining for insulin , cd4 , or cd8
2 , histological analysis of grafts harvested from tolerant animals previously treated with either ctla4-ig alone or ep1013+ctla4-ig demonstrated intact islets with very few intragraft cd4 or cd8 cells .
quantification of these cells per high - power field ( hpf ) revealed that there was no difference in immune infiltrate between treatment groups .
thus , while combination of ep1013 and ctla4-ig resulted in a dramatic increase in islet allograft survival over time , analysis at this late time point could not explain the difference in outcomes observed between animals treated with ep1013+ctla4-ig versus ctla4-ig alone .
allogeneic islet grafts harvested from tolerant animals > 150 days post - transplant exhibit minimal immune infiltrate and intact islets .
renal subcapsular islet grafts were harvested from animals surviving > 150 days after receiving ctla4-ig monotherapy or ctla4-ig / ep1013 combination therapy .
a : cryosections of islet grafts were co - stained for insulin ( tritc ; red ) and either cd4 ( fitc , green ; left panels ) or cd8 ( fitc ; right panels ) .
dapi nuclear stain ( blue ) was used to identify all cells present on the section .
representative slides from both treatment groups are shown at 200 magnification and demonstrate that the transplanted islets were largely intact with no invasive immune infiltrate and rare cd4 or cd8 lymphocytes .
b : quantification of cd4 and cd8 staining confirmed that cd4 and cd8 lymphocytes were infrequently observed within the sections , regardless of the initial treatment intervention . for these data ,
n = 10 sections from > 5 islet grafts per group were blinded and subsequently analyzed .
( a high - quality digital color representation of this fiugre is available in the online issue . ) to characterize the impact of ep1013 on the allogeneic immune response in this model , ex vivo analysis was conducted at an early time point post - transplant , 1 day after the final treatment ( day 11 post - transplant ) . as shown in fig .
3a , co - incubation with either donor type or third - party stimulators resulted in a robust proliferative response in splenocytes harvested from vehicle - treated animals , which was significantly higher than all other treatment groups ( p < 0.05 by anova ) .
splenocytes harvested from recipients treated with ctla4-ig or ep1013+ctla4-ig exhibited a markedly reduced proliferation , which was comparable to that observed in nave b6 animals .
interestingly , splenocytes harvested from animals treated with ep1013 monotherapy also displayed a markedly reduced proliferation compared with vehicle - treated animals ( p < 0.05 by anova ) .
ep1013 therapy inhibits early allogeneic t - cell responses , both as a monotherapy and in combination with ctla4-ig .
transplanted animals were sacrificed on day 11 post - transplant for ex vivo immune analysis using mlr and ifn- elispot assays to measure the allogeneic immune response . a : mlr assays revealed that splenocytes harvested from vehicle - treated ( control ) recipients reacted with a nearly twofold increase in proliferation to both donor and third - party stimulators as compared with nave animals ( p < 0.05 ) .
in contrast , splenocytes harvested with animals treated with ep1013 , ctla4-ig , or ep1013+ctla4-ig proliferated at rates that were comparable to nave animals , irrespective of the stimulator source ( p < 0.05 vs. control for all treatment groups ) .
b : ifn- elispot assays demonstrated that splenocytes from vehicle - treated control animals mounted a robust donor - specific allogeneic ifn- response , with a significant increase in number of spots compared with nave animals ( p < 0.05 by anova ) .
prior treatment with ep1013 , ctla4-ig , or ep1013+ctla4-ig markedly reduced the number of ifn-secreting alloreactive splenocytes , to levels comparable to those observed in nave animals ( p < 0.05 for each treatment group vs. control by anova ) . for these assays ,
n = 34 animals per treatment group were analyzed in triplicate in two separate experiments .
similar results were obtained using ifn- elispot to analyze allo - specific immune responses ( fig .
splenocytes harvested from vehicle - treated animals generated a large number of ifn spots when exposed to donor - type stimulators ( p < 0.05 vs. all other groups by anova ) , while co - incubation with third - party stimulators resulted in a response that was similar to nave b6 splenocytes .
splenocytes harvested from animals treated with ctla4-ig or ep1013+ctla4-ig generated few ifn+ spots when exposed to either donor - type or third - party stimulators , and no difference was observed when compared with the response generated using nave b6 splenocytes . of note , splenocytes harvested from animals treated with ep1013 monotherapy also displayed a marked reduction in ifn spots after exposure to donor - type stimulators , as compared with splenocytes harvested from vehicle - treated animals ( p < 0.001 by anova ) .
immunofluorescence staining of sections cut from the islet grafts harvested at this early time point was completed to characterize the relative contribution of different t - cell subsets to the allogeneic immune response in each treatment group ( fig .
sections were co - stained for insulin and cd4 , cd8 , or foxp3 , and the immunological markers were quantified per hpf .
representative tissue sections demonstrate that treatment with either ctla4-ig ( 155.0 15.5 cells / hpf , fig .
4j ) resulted in a 5070% decrease in cd4 t - cell infiltration compared with vehicle - treated controls ( 299.8 26.8 cd4 cells / hpf , fig .
similar results were observed when cd8 staining was quantified , with both ctla4-ig ( 134.5 11.9 cells / hpf , fig .
4k ) treatment groups exhibiting a nearly 50% decrease in cd8 t - cell infiltration compared with vehicle - treated animals ( 279.8 39.7 , fig .
no significant difference in either cd4 or cd8 infiltration was observed between animals treated with ep1013 ( 237.3 37.9 cd4 cells / hpf , fig .
histological analysis in the early post - transplant period demonstrates that ep1013 therapy promotes intragraft accumulation of foxp3 lymphocytes .
animals were sacrificed on day 11 post - transplant , and graft - bearing kidneys were harvested for immunfluorescent quantification of intragraft lymphocytic infiltrates .
insulin staining was used to identify transplanted islets ( tritc ; red ) , and the immune markers cd4 ( left column ) , cd8 ( middle column ) , and foxp3 ( right column ) were labeled with fitc ( green ) .
dapi counterstaining ( blue ) was used to identify all cells present within the sections , which are shown at 100 ( cd4 , cd8 ) or 200 ( foxp3 ) .
m : quantification of cd4 , cd8 , and foxp3 staining was conducted in sections from each treatment group .
a significant reduction in the number of cd4 cells / hpf was observed after treatment with ctla4-ig or ep1013+ctla4-ig compared with vehicle ( p < 0.01 vs. control for both groups ) .
similar results were observed for cd8 cells / hpf , with ctla4-ig or ep1013+ctla4-ig treatment cohorts exhibiting a significant decrease compared with vehicle - treated animals ( p < 0.01 vs. control for both groups ) .
quantification of foxp3 cells / hpf revealed that prior treatment with ep1013 , either alone or in combination with ctla4-ig , resulted in a significant increase in the frequency of intragraft regulatory t - cells ( p < 0.01 vs. control and vs. ctla4-ig alone by anova ) .
serial tissue sections from n = 34 animals per group were stained , blinded , and analyzed for this experiment .
( a high - quality digital color representation of this figure is available in the online issue . )
quantification of regulatory t - cell ( treg ) infiltration was carried out using the marker foxp3 ( 17 ) .
grafts harvested from vehicle - treated animals exhibited almost no intragraft foxp3 treg cells ( 5.7 1.7 cells / hpf , fig .
4c ) , which was similar to that observed in animals treated with ctla4-ig ( 12.3 3.9 cells / hpf , fig .
treatment with ep1013 , either alone ( 87.8 27.8 cells / hpf , fig .
4f ) or in combination with ctla4-ig ( 41.0 8.9 cells / hpf , fig .
4l ) , resulted in a 7- to 15-fold increase in the frequency of intragraft foxp3 treg cells ( p < 0.01 for each vs. control by anova ) .
development of alloantibodies and donor - specific sensitization is increasingly being recognized as an important prognostic factor in long - term allograft survival ( 18 ) . to understand the effect of caspase inhibitor therapy on the b - cell compartment during the allogeneic immune response ,
both igm and igg alloantibodies were measured prospectively post - transplant using a cellular elisa ( 16 ) .
treatment with ep1013 , ctla4-ig , or ep1013+ctla4-ig prevented the formation of either igm or igg alloantibodies over time , even after the discontinuation of treatment at day 10 ( p < 0.02 for all treatment groups versus control for igm , p < 0.05 vs. control for all treatment groups for igg , anova ) . of note ,
nave b6 serum demonstrated a consistent mean optical density of 0.30 0.09 for igm and a mean optical density of 0.19 0.07 for igg , which is statistically significant only when compared with control transplant mice at 2 and 4 weeks post - transplant .
thus , treatment with either ep1013 or ctla4-ig prevents allosensitization post - transplant in this model .
ep1013 therapy prevents both igm and igg alloantibody formation , both as a single agent and in combination with ctla4-ig .
sera were collected via tail vein bleeds prospectively and stored for bulk analysis at the completion of the study using a donor - specific cellular elisa to measure alloantibody production .
a : igm alloantibody formation was detected in vehicle - treated control animals ( ) , while treatment with ep1013 ( ) , ctla4-ig ( ) , or ep1013+ctla4-ig ( ) resulted in a significant reduction in igm alloantibody formation ( p < 0.02 for all treatment groups vs. control ) .
b : similar results were obtained when igg alloantibody levels were assessed , with vehicle - treated control animals becoming highly sensitized within 2 weeks post - transplantation ( ) .
igg allosensitization was prevented after treatment with ep1013 ( ) , ctla4-ig ( ) , or ep1013+ctla4-ig
a minimum of n = 5 serum samples from each treatment group were analyzed in duplicate for these assays .
initially , fully mhc - mismatched islet allografts were completed using chemically diabetic recipients , and treatment with either ep1013 ( days 010 ) , ctla4-ig ( days 0 , 2 , 4 , and 6 ) , combination of ep1013 and ctla4-ig , or vehicle ( days 010 ) was commenced . as shown in fig .
1a , treatment with ep1013 resulted in no prolongation of islet allograft survival ( mean survival time 18.2 days ) compared with vehicle - treated animals ( mean survival time 22.8 days , p = ns ) .
ctla4-ig monotherapy resulted in prolonged graft survival in 40% of the animals ( mean survival time 103.0 days ) , whereas the addition of ep1013 to ctla4-ig resulted in a significant increase in graft survival ( n = 16/18 with long - term survival resulting in mean survival time > 180 days post - transplant ; p < 0.01 vs. ctla4-ig by log - rank ) .
ep1013 therapy , when combined with costimulation blockade using ctla4-ig , results in long - term islet graft survival and operational tolerance .
a : islet allografts were completed across a complete mhc mismatch using balb / c ( h-2d ) donors and chemically diabetic b6 ( h-2b ) recipients .
caspase inhibitor therapy ( ep1013 ) did not prolong graft survival compared with vehicle - treated animals .
monotherapy with ctla4-ig prevented graft rejection in 40% of recipients , whereas combination of ep1013 and ctla4-ig resulted in graft survival of > 200 days in 89% of recipients ( p < 0.01 vs. ctla4-ig ) .
b : to test for donor - specific tolerance , graft - bearing kidneys were removed , and animals were re - transplanted with either donor - type ( balb / c ) or third - party ( c3h , h-2k ) islets without further treatment or with a second 10-day course of ep1013 . when using balb / c islets , donor - specific tolerance was demonstrated in 30% of the transplant recipients ( either ctl4-ig or ctla4-ig+ep1013 cohorts ) .
re - transplantation with third - party islets resulted in robust rejection in all recipients . to further understand the enhanced outcomes using ep1013+ctla4ig versus ctla4-ig alone , a series of experiments was carried out in animals with long - term graft function in each group . to test for tolerance ,
after 2 days of hyperglycemia , either same - donor ( balb / c , h2-d ) or third - party ( c3h ; h2-k ) islets were implanted with no additional therapeutic intervention ( fig .
re - transplantation with balb / c islets led to prolonged graft survival in 2030% of the recipients , regardless of the initial treatment group .
this demonstrates that true donor - specific tolerance was only achieved in a subgroup of the transplant recipients , despite the presence of indefinite graft survival after the initial transplant ( i.e. , operational tolerance ) .
implantation of c3h islets resulted in rejection in all recipients in both treatment groups , confirming that operational tolerance to the initial graft was achieved without compromising the recipient 's immunological function ( fig .
the lack of donor - specific tolerance in this model is the effect of the tissue injury , local inflammation , and graft cell death at the time of and after the second transplant , which could alter the recipient 's ability to maintain donor - specific tolerance . to minimize these effects ,
an additional cohort of animals with long - term islet graft survival were re - transplanted with balb / c islets and also treated with a 10-day course of ep1013 , using the same dosing as the initial treatment period .
1b , this intervention did not improve the rate of donor - specific tolerance in animals previously treated with ep1013+ctla4-ig . to explore the immune response to these grafts at this late time point post - transplant , immunofluorescence staining for insulin , cd4 , or cd8
2 , histological analysis of grafts harvested from tolerant animals previously treated with either ctla4-ig alone or ep1013+ctla4-ig demonstrated intact islets with very few intragraft cd4 or cd8 cells .
quantification of these cells per high - power field ( hpf ) revealed that there was no difference in immune infiltrate between treatment groups .
thus , while combination of ep1013 and ctla4-ig resulted in a dramatic increase in islet allograft survival over time , analysis at this late time point could not explain the difference in outcomes observed between animals treated with ep1013+ctla4-ig versus ctla4-ig alone .
allogeneic islet grafts harvested from tolerant animals > 150 days post - transplant exhibit minimal immune infiltrate and intact islets .
renal subcapsular islet grafts were harvested from animals surviving > 150 days after receiving ctla4-ig monotherapy or ctla4-ig / ep1013 combination therapy .
a : cryosections of islet grafts were co - stained for insulin ( tritc ; red ) and either cd4 ( fitc , green ; left panels ) or cd8 ( fitc ; right panels ) .
dapi nuclear stain ( blue ) was used to identify all cells present on the section .
representative slides from both treatment groups are shown at 200 magnification and demonstrate that the transplanted islets were largely intact with no invasive immune infiltrate and rare cd4 or cd8 lymphocytes .
b : quantification of cd4 and cd8 staining confirmed that cd4 and cd8 lymphocytes were infrequently observed within the sections , regardless of the initial treatment intervention . for these data ,
n = 10 sections from > 5 islet grafts per group were blinded and subsequently analyzed .
( a high - quality digital color representation of this fiugre is available in the online issue . )
to characterize the impact of ep1013 on the allogeneic immune response in this model , ex vivo analysis was conducted at an early time point post - transplant , 1 day after the final treatment ( day 11 post - transplant ) . as shown in fig .
3a , co - incubation with either donor type or third - party stimulators resulted in a robust proliferative response in splenocytes harvested from vehicle - treated animals , which was significantly higher than all other treatment groups ( p < 0.05 by anova ) .
splenocytes harvested from recipients treated with ctla4-ig or ep1013+ctla4-ig exhibited a markedly reduced proliferation , which was comparable to that observed in nave b6 animals .
interestingly , splenocytes harvested from animals treated with ep1013 monotherapy also displayed a markedly reduced proliferation compared with vehicle - treated animals ( p < 0.05 by anova ) .
ep1013 therapy inhibits early allogeneic t - cell responses , both as a monotherapy and in combination with ctla4-ig .
transplanted animals were sacrificed on day 11 post - transplant for ex vivo immune analysis using mlr and ifn- elispot assays to measure the allogeneic immune response . a : mlr assays revealed that splenocytes harvested from vehicle - treated ( control ) recipients reacted with a nearly twofold increase in proliferation to both donor and third - party stimulators as compared with nave animals ( p < 0.05 ) .
in contrast , splenocytes harvested with animals treated with ep1013 , ctla4-ig , or ep1013+ctla4-ig proliferated at rates that were comparable to nave animals , irrespective of the stimulator source ( p < 0.05 vs. control for all treatment groups ) .
b : ifn- elispot assays demonstrated that splenocytes from vehicle - treated control animals mounted a robust donor - specific allogeneic ifn- response , with a significant increase in number of spots compared with nave animals ( p < 0.05 by anova ) .
prior treatment with ep1013 , ctla4-ig , or ep1013+ctla4-ig markedly reduced the number of ifn-secreting alloreactive splenocytes , to levels comparable to those observed in nave animals ( p < 0.05 for each treatment group vs. control by anova ) . for these assays ,
n = 34 animals per treatment group were analyzed in triplicate in two separate experiments .
similar results were obtained using ifn- elispot to analyze allo - specific immune responses ( fig .
splenocytes harvested from vehicle - treated animals generated a large number of ifn spots when exposed to donor - type stimulators ( p < 0.05 vs. all other groups by anova ) , while co - incubation with third - party stimulators resulted in a response that was similar to nave b6 splenocytes .
splenocytes harvested from animals treated with ctla4-ig or ep1013+ctla4-ig generated few ifn+ spots when exposed to either donor - type or third - party stimulators , and no difference was observed when compared with the response generated using nave b6 splenocytes .
of note , splenocytes harvested from animals treated with ep1013 monotherapy also displayed a marked reduction in ifn spots after exposure to donor - type stimulators , as compared with splenocytes harvested from vehicle - treated animals ( p < 0.001 by anova ) .
immunofluorescence staining of sections cut from the islet grafts harvested at this early time point was completed to characterize the relative contribution of different t - cell subsets to the allogeneic immune response in each treatment group ( fig .
sections were co - stained for insulin and cd4 , cd8 , or foxp3 , and the immunological markers were quantified per hpf .
representative tissue sections demonstrate that treatment with either ctla4-ig ( 155.0 15.5 cells / hpf , fig .
4j ) resulted in a 5070% decrease in cd4 t - cell infiltration compared with vehicle - treated controls ( 299.8 26.8 cd4 cells / hpf , fig .
similar results were observed when cd8 staining was quantified , with both ctla4-ig ( 134.5 11.9 cells / hpf , fig .
4k ) treatment groups exhibiting a nearly 50% decrease in cd8 t - cell infiltration compared with vehicle - treated animals ( 279.8 39.7 , fig .
no significant difference in either cd4 or cd8 infiltration was observed between animals treated with ep1013 ( 237.3 37.9 cd4 cells / hpf , fig .
histological analysis in the early post - transplant period demonstrates that ep1013 therapy promotes intragraft accumulation of foxp3 lymphocytes .
animals were sacrificed on day 11 post - transplant , and graft - bearing kidneys were harvested for immunfluorescent quantification of intragraft lymphocytic infiltrates .
insulin staining was used to identify transplanted islets ( tritc ; red ) , and the immune markers cd4 ( left column ) , cd8 ( middle column ) , and foxp3 ( right column ) were labeled with fitc ( green ) .
dapi counterstaining ( blue ) was used to identify all cells present within the sections , which are shown at 100 ( cd4 , cd8 ) or 200 ( foxp3 ) .
m : quantification of cd4 , cd8 , and foxp3 staining was conducted in sections from each treatment group .
a significant reduction in the number of cd4 cells / hpf was observed after treatment with ctla4-ig or ep1013+ctla4-ig compared with vehicle ( p < 0.01 vs. control for both groups ) .
similar results were observed for cd8 cells / hpf , with ctla4-ig or ep1013+ctla4-ig treatment cohorts exhibiting a significant decrease compared with vehicle - treated animals ( p < 0.01 vs. control for both groups ) .
quantification of foxp3 cells / hpf revealed that prior treatment with ep1013 , either alone or in combination with ctla4-ig , resulted in a significant increase in the frequency of intragraft regulatory t - cells ( p < 0.01 vs. control and vs. ctla4-ig alone by anova ) .
serial tissue sections from n = 34 animals per group were stained , blinded , and analyzed for this experiment .
( a high - quality digital color representation of this figure is available in the online issue . ) quantification of regulatory t - cell ( treg ) infiltration was carried out using the marker foxp3 ( 17 ) .
grafts harvested from vehicle - treated animals exhibited almost no intragraft foxp3 treg cells ( 5.7 1.7 cells / hpf , fig .
4c ) , which was similar to that observed in animals treated with ctla4-ig ( 12.3 3.9 cells / hpf , fig .
in contrast , treatment with ep1013 , either alone ( 87.8 27.8 cells / hpf , fig .
4f ) or in combination with ctla4-ig ( 41.0 8.9 cells / hpf , fig .
4l ) , resulted in a 7- to 15-fold increase in the frequency of intragraft foxp3 treg cells ( p < 0.01 for each vs. control by anova ) .
development of alloantibodies and donor - specific sensitization is increasingly being recognized as an important prognostic factor in long - term allograft survival ( 18 ) . to understand the effect of caspase inhibitor therapy on the b - cell compartment during the allogeneic immune response , both igm and igg alloantibodies were measured prospectively post - transplant using a cellular elisa ( 16 ) .
treatment with ep1013 , ctla4-ig , or ep1013+ctla4-ig prevented the formation of either igm or igg alloantibodies over time , even after the discontinuation of treatment at day 10 ( p < 0.02 for all treatment groups versus control for igm , p < 0.05 vs. control for all treatment groups for igg , anova ) . of note ,
nave b6 serum demonstrated a consistent mean optical density of 0.30 0.09 for igm and a mean optical density of 0.19 0.07 for igg , which is statistically significant only when compared with control transplant mice at 2 and 4 weeks post - transplant .
thus , treatment with either ep1013 or ctla4-ig prevents allosensitization post - transplant in this model .
ep1013 therapy prevents both igm and igg alloantibody formation , both as a single agent and in combination with ctla4-ig .
sera were collected via tail vein bleeds prospectively and stored for bulk analysis at the completion of the study using a donor - specific cellular elisa to measure alloantibody production .
a : igm alloantibody formation was detected in vehicle - treated control animals ( ) , while treatment with ep1013 ( ) , ctla4-ig ( ) , or ep1013+ctla4-ig ( ) resulted in a significant reduction in igm alloantibody formation ( p < 0.02 for all treatment groups vs. control ) .
b : similar results were obtained when igg alloantibody levels were assessed , with vehicle - treated control animals becoming highly sensitized within 2 weeks post - transplantation ( ) .
igg allosensitization was prevented after treatment with ep1013 ( ) , ctla4-ig ( ) , or ep1013+ctla4-ig ( ) ( p < 0.05 for each treatment group vs. control ) . a minimum of n = 5 serum samples from each treatment group were analyzed in duplicate for these assays .
the present study demonstrates for the first time that combination of ep1013 , a selective pan - caspase inhibitor therapy with ctla4-ig , a selective immunomodulatory therapy , results in long - term islet allograft acceptance .
this approach had a global effect on the allogeneic immune response , as shown by experiments evaluating both t- and b - cell compartments .
ep1013+ctla4-ig reduced the frequency of intragraft cd4 and cd8 t - cells both in the short term ( fig .
2 ) , and it reduced the functional alloreactive t - cell response , both in production of ifn-secreting allo - specific lymphocytes and overall allo - stimulated t - cell proliferation ( fig .
, the immunomodulatory effects of combination of ep1013+ctl4-ig far exceeded the short treatment period post - transplant , without further requirements for immunosuppression .
taken together , these data indicate that prevention of donor tissue apoptosis using caspase inhibitor therapy during the engraftment period can dramatically lower the threshold for anti - rejection therapy , such that brief treatment with the costimulation blockade agent ctla4-ig results in robust indefinite islet allograft survival . in the setting of islet transplantation ,
a significant fraction of the transplanted islets fail to engraft , resulting in a large requirement for donor tissue and ultimately a flood of alloantigen during the post - transplant period .
our group has proven that caspase inhibitor therapy protects islets during the engraftment period and thus minimizes the total number of islets required to reverse diabetes ( 8,9 ) . from these previous experiments ,
it is clear that intragraft apoptosis is markedly reduced , demonstrating the anticipated cytoprotective effect of caspase inhibitor therapy on the graft .
however , data in the present study illustrate another potential beneficial effect of caspase inhibitor therapy
previous data in other experimental models have suggested that caspase inhibitors can alter the function of lymphocytes . in vitro studies
have shown that caspase inhibitors can have a negative regulatory effect on the immune system , given that caspases play a critical role in cell cycle regulation of lymphocyte populations ( 1921 ) .
studies using a pan caspase inhibitor ( zvad ) on human lymphocytes demonstrated that this agent potently suppressed lymphocyte proliferation ; recall antigen response ; the upregulation of mhc - ii , cd25 , and cd69 ; and il-2 production after stimulation ( 19 ) .
data in the present study clearly indicate that caspase inhibitor therapy strikingly increases the frequency of intragraft treg cells , while at the same time reducing the frequency of alloreactive ifn-secreting lymphocytes ( figs . 3 and 4 ) .
whether this effect is the result of enhanced proliferation or a lower threshold for activation selectively within these key populations is not clear and is on an ongoing area of research in our lab . despite clear differences in intragraft t - cell populations and alloreactive t - cell responses ex vivo ( figs . 3 and 4 ) ,
no functional difference in graft survival was observed using ep1013 monotherapy in the traditional allograft model ( fig .
it is likely that the multiple noxious stimuli surrounding the transplant procedure ( anesthesia , surgical manipulation , stress - induced cytokines , etc . )
provide too much nonspecific immune stimulation and thus limit the effectiveness of ep1013 monotherapy as an immunomodulatory agent .
thus , while the mechanism of caspase inhibitor mediated immunomodulation is complex , it is evident from data in this study that a brief post - transplant therapeutic period is of marked benefit in transplantation . with regard to tolerance ,
our data suggest that the combination of a potent cytoprotective agent ( ep1013 ) with a selective immunomodulator ( ctla4-ig ) promotes a state of immunological ignorance , where the immune system is in a state of passive tolerance to the graft , versus mounting an ongoing and reproducible state of active donor - specific tolerance
. it may be that early upregulation of regulatory t - cells promotes this type of operational tolerance , which could explain the observations in this study , especially given the almost complete absence of lymphocytes within the graft at late time points ( fig .
3b ) supports this theory , since ifn- production has been implicated as an important component of donor - specific tolerance induction ( 24 ) .
the present study was conducted using islet allograft transplantation , and our results indicate that this approach could be of particular benefit in the clinical setting .
brief treatment with caspase inhibitors can minimize the amount of donor tissue required to restore euglycemia by as much as 80% , thereby increasing the transplantability of high - quality clinical islet preparations of low yield by current standards ( < 300,000 islet equivalents ) ( 8,25 ) .
whereas true donor - specific tolerance was not universally achieved in our study , our data strongly suggest that this approach will reduce the intensity and/or duration of immunosuppression required , which would still represent a major advance in the field .
another important consideration is the lack of donor sensitization in this model , which has recently been identified as a potential cause of chronic graft failure in clinical islet transplantation ( 26,27 ) .
previous studies have shown that costimulation blockade can prevent allo - sensitization post - transplant ( 28 ) .
our data support these findings and demonstrate that combination therapy with ep1013 does not reduce the efficacy of ctla4-ig in this regard . while this study was limited to islet allograft transplantation , it is likely that the combined use of caspase inhibitors and costimulation blockade will be of benefit in all areas of solid organ transplantation .
as the demand for organs continues to outpace donation rates worldwide , it has increasingly become the trend to use organs procured from extended criteria donors or even after donation after cardiac death .
use of extended criteria donor and donation after cardiac death organs increases the rate of delayed graft function and reduces long - term graft survival rates ( 29 ) .
the inclusion of a caspase inhibitor in the preservation solution in a murine model of acute kidney injury dramatically reduced renal tubular apoptosis and brush border injury , two processes that have been linked to delayed graft function ( 30 ) .
similar results have been obtained in a cardiac allograft model , where early treatment with a caspase inhibitor reduced intimal proliferation and vessel occlusion , which are both important markers of chronic allograft vasculopathy ( 31 ) .
thus , it is likely that the cytoprotective benefits of caspase inhibitor therapy combined with selective nontoxic immunosuppression using costimulation blockade will broadly improve both graft function and long - term survival in many areas of organ transplantation . in summary ,
data in this study indicate that caspase inhibitors represent the first single agent therapy that has the potential to benefit the graft directly , while also regulating the allogeneic immune response .
caspase inhibitors have been used clinically in liver transplantation and so far have proven to be safe and effective in improving graft function post - transplant ( 3234 ) .
it is likely that inclusion of caspase inhibitors in clinical transplantation protocols will be of greatest benefit in situations where considerable stress to the donor organ is generated , particularly after the process of brain death , prolonged ischemic time , or use of extended criteria donors .
it is also likely that this approach will reduce the amount and intensity of anti - rejection therapy , accelerating accommodation and drug minimization . if this could be achieved , or if the stable immunological tolerance enhanced by caspase inhibitor co - treatment could be translated to the clinic , transplantation would be potentially safer and therefore more available to a broader spectrum of patients .
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### Summary:
: objectivecostimulation blockade has emerged as a selective nontoxic maintenance therapy in transplantation . however , these drugs must be combined with other immunomodulatory agents to ensure long - term graft survival.research design and methodsrecent work has demonstrated that caspase inhibitor therapy ( ep1013 ) prevents engraftment phase islet loss and markedly reduces the islet mass required to reverse diabetes .
the danger
hypothesis suggests that reduction in graft apoptosis should reduce the threshold for immunosuppression and increase the possibility for tolerance induction .
thus , the impact of combination of ep1013 treatment with costimulation blockade ( ctla4-ig ) was investigated in this study.resultsislet allografts were completed in fully major histocompatibility complex ( mhc)-mismatched mice ( balb / c to b6 ) . when animals received vehicle or ep1013 , there was no difference in graft survival .
ctla4-ig resulted in prolonged graft survival in 40% of the animals , whereas ep1013+clta4-ig resulted in a significant increase in graft survival ( 91% > 180 days ; p = 0.01 ) .
ex vivo analysis revealed that animals receiving ep1013 or ep1013+ctla4-ig had a reduced frequency of alloreactive interferon ( ifn)-secreting t - cells and an increased frequency of intragraft foxp3 + treg cells .
alloantibody assays indicated that treatment with ep1013 or ctla4-ig prevented allosensitization.conclusionsthis study suggests that addition of caspase inhibitor therapy to costimulation blockade will improve clinical transplantation by minimizing immune stimulation and thus reduce the requirement for long - term immunosuppressive therapy .
the approach also prevents allosensitization , which may be an important component of chronic graft loss in clinical transplantation .
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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 present the case of a 69-year - old female patient with giant aortic aneurysm who underwent previously multiple cardiac surgeries or interventions .
ross procedure was performed in 2006 due to aortic valve regurgitation and aneurysm of the ascending aorta . in 2010
the patient was re - admitted for pulmonary valve insufficiency and a transcatheter pulmonary valve was implanted .
recently , the patient presented with an aortic arch aneurysm , maximum diameter 78 mm , which was treated by a hybrid approach , implanting a frozen elephant trunk and a covered stent graft .
the current case report demonstrates a suitable hybrid option for an extremely demanding procedure by multiple previous cardiac procedures .
aneurysms of the entire thoracic aorta are severe diseases due to high risk of dissection , rupture , and death .
necessary surgery can be extensive and challenging , especially if the patient underwent previously multiple cardiac surgeries .
a 69-year - old female patient presented with a newly found aneurysm of the thoracic aorta , maximum 78 mm diameter , in the zone of the aortic arch ( figure 1a ) .
the patient underwent ross procedure and replacement of the ascending aorta in 2006 . in 2010 pulmonary valve replacement was performed due to pulmonary insufficiency . in 2015
the patient was re - admitted with the above findings and , after clarifying therapeutic options , a hybrid approach was planned to replace the aortic arch and the descending aorta .
hypothermic cardiopulmonary bypass was implemented by cannulation of the right axillary artery and the femoral vein to open the chest because the aneurysm was directly behind the sternum . after exposing the aneurysm , circulatory arrest with cerebral perfusion
in the course of the procedure , due to heavy adhesions of the lung to the heart , the aneurysm and the chest wall had to be loosened .
the aortic arch was excised and a thoraflex hybrid ( vascutek , hamburg , germany ) prosthesis was inserted distal of the left subclavian artery .
after reconnection of the detached arteries , circulation was re - induced after 89 minutes .
due to respiratory failure , extracorporeal membrane oxygenation was necessary to support lung function for the following 5 days .
at 12 days after the operation , a valiant thoracic stent graft ( medtronic , berlin , germany ) was implanted interventionally in the descending aorta ( figure 1b ) .
the postoperative course was complicated , including temporary renal failure ( requiring dialysis ) , pneumonia , long - term ventilation ( including tracheotomy ) , peripheral embolization due to heparin - induced thrombocytopenia , and critical - illness polyneuropathy / myopathy .
however , due to optimal interdisciplinary teamwork , the patient was discharged to a rehabilitation facility on the 40 postoperative day and went home 2 months later completely recovered .
the replacement of the aortic is an extensive operation with operative mortality between 2.5% and 10% and stroke rates between 5.0% and 11.8% .
secondary procedures are usually more complex due to aging and adhesions involving the whole operative area .
the established method is either the 1-stage treatment using the clamshell incision , or the 2-stage treatment by a secondary lateral thoracotomy .
the combined open surgical and endovascular approach for the treatment of aortic arch aneurysms has emerged as a safe treatment with good midterm results .
this so - called frozen elephant trunk technique reduces surgical trauma , as well as reducing the duration of cardiopulmonary bypass , circulatory arrest , and the whole procedure .
additionally , a survival advantage of this hybrid technique compared to the surgical method has already been shown . in the presented case
, the 2-stage hybrid procedure was performed despite the high - risk profile of the patient , leading to a satisfactory operative result .
alternative treatment options like the 1-stage and 2-stage approach cause a higher operative risk and would , in retrospect , not have been an option in this patient due to the heavy adhesions of the aneurysm and the complete operative situs .
nonetheless , this case demonstrates that the postoperative course can still be complicated and demanding .
in conclusion , hybrid surgery can be an appropriate option to reduce surgical trauma in high - risk patients with aortic aneurysms and multiple previous cardiac procedures .
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### Summary:
: backgroundwe present the case of a 69-year - old female patient with giant aortic aneurysm who underwent previously multiple cardiac surgeries or interventions.case reportross procedure was performed in 2006 due to aortic valve regurgitation and aneurysm of the ascending aorta . in 2010
the patient was re - admitted for pulmonary valve insufficiency and a transcatheter pulmonary valve was implanted .
recently , the patient presented with an aortic arch aneurysm , maximum diameter 78 mm , which was treated by a hybrid approach , implanting a frozen elephant trunk and a covered stent graft.conclusionsthe current case report demonstrates a suitable hybrid option for an extremely demanding procedure by multiple previous cardiac procedures .
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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:
: lymphangioma circumscriptum ( lc ) is a relatively rare , benign , congenital disorder of the lymphatic channels with a nonspecific etiology
. surgical excision , cryotherapy , electrocoagulation and laser treatments for this pathology have all been reported , but surgical excision remains the mainstay of treatment . while initially effective in general , surgery is invasive and recurrence has been reported .
however , no previous reports have described lc treated with long - pulsed nd : yag lasers , or successful treatment using different lasers for similar lesions .
we selected different types of lasers for the treatment : co2 lasers with their confirmed effectiveness and nd : yag lasers .
a 16-year - old japanese girl presented with a 9-year history of vesicles on both sides of the vulva ( fig .
these lesions had developed at around 7 years of age and no treatment had been administered .
the medical history of the patient showed no other dermatologic or systemic abnormalities , and no family history of similar lesions was evident .
histopathologic examination revealed multiple thin - walled , dilated lymphatic spaces that contained lymphocytes and erythrocytes in the papillary dermis ( fig .
we decided to use different kinds of lasers for the right and left lesions . once a month , we treated the right - side vulval lesion with a co2 laser ( sharplan 30c , lumenis , yokneam , israel ) and the left - side lesion with a long - pulsed nd : yag laser from the xeo multi - platform device ( cutera , brisbane , calif .
the co2 laser was set to a wavelength of 10,600 nm at 4 w with a 1-mm spot size .
visually confirming cauterization of lymphatic channels on the surface , we treated the lesions little by little every month , as treatment of a wide area in a single session may lead to ulceration .
the long - pulsed nd : yag laser was set to a wavelength of 1064 nm with a fluence of 80100 j / cm at 20 or 30 ms and a 7-mm spot size .
energy and pulse length were adjusted to achieve only partial coagulation . after the fourth session ,
the region on the right vulva treated with the co2 laser was greatly improved , with no lesions visible to the naked eye .
the region on the left vulva was greatly improved after only 3 treatments using the nd : yag laser .
the patient preferred the results from the nd : yag laser as lymphatic fluid discharge was temporarily increased ( for 1 week ) after each co2 laser irradiation , but stopped after nd : yag laser irradiation .
however , the second session of irradiation with the nd : yag laser resulted in the development of a 4-mm linear scar after 1 week , which appeared as a slight textural change that disappeared within 3 months .
after completion of the laser treatment ( 4 sessions ) , the patient no longer needed to use incontinence diapers and her quality of life improved considerably .
no recurrence has been detected yet , 2 years after the last treatment , although follow - up is continuing ( fig .
lc is a relatively rare , benign , congenital disorder of the lymphatic channels with a nonspecific etiology .
these vesicles may sometimes become filled with blood , resulting in a frog spawn appearance . surgical excision ,
cryotherapy , electrocoagulation and laser treatments have all been reported as treatment modalities for lc .
surgical excision is initially effective in general , but it is invasive and recurrence has been reported .
cryotherapy appears rather ineffective , with low remission and high recurrence rates . in terms of laser treatments ,
obtained favorable results using a 900-nm diode laser and a co2 laser , respectively , in 2006 .
we therefore chose different types of lasers for treatment : co2 lasers , with their confirmed effectiveness , and nd : yag lasers , which were expected to achieve efficacy at least equivalent to that of the co2 lasers .
the 10,600-nm wavelength of the co2 laser is highly absorbed by water and evaporates skin tissue .
co2 lasers are effective for treating lesions that can be visually located to minimize the resultant scar , although excessive use can result in ulceration . in comparison ,
the long - pulsed nd : yag laser is moderately absorbed by hemoglobin , melanin and water , and has been used to treat deep or thick dermal lesions such as hemorrhagic malformations of the skin , although visual confirmation of applicable lesions is impossible and there is a risk of de - pigmentation and scarring due to over - irradiation .
although both lasers have specific advantages and disadvantages , we considered long - pulsed nd : yag lasers as more effective than either co2 lasers or dye lasers for targeting deep lymphatic channels to prevent recurrence . as no previous reports have described lc treated with long - pulsed nd : yag lasers , we decided to use and compare both co2 and nd : yag lasers .
no previous reports have described successful treatment using different kinds of lasers for similar lesions , particularly nd : yag lasers for the treatment of lc . as we expected , nd : yag lasers allowed safe and effective treatment . laser settings and treatment endpoints
however , we believe that employing different kinds of lasers was useful in this case . one year has passed since the final treatment , and the patient has experienced no recurrence . unlike the many cases of recurrence that have been reported after surgical excision , both long - pulsed nd :
yag lasers and co2 lasers appear effective for the treatment of lc and are less invasive than surgery .
a long - pulsed nd : yag laser from xeo multi - platform devices was borrowed from cutera inc .
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### Summary:
: a 16-year - old girl presented with a 9-year history of vesicles on the vulva .
she had initially taken a wait - and - see approach , but required treatment because of bleeding .
histological examination of a biopsied vesicle revealed dilated lymph channels in the upper dermis , suggesting lymphangioma circumscriptum ( lc ) .
the challenge for this pathology has been to find a conservative treatment with low morbidity and better results than those reported for surgical excision , which has been the mainstay of therapy . in this case , lc of the vulva was successfully treated using a 10,600-nm co2 laser and long - pulsed nd : yag laser .
use of the 10,600-nm co2 laser and long - pulsed nd : yag laser appeared effective for treating lc .
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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:
: is remarkably growing in recent years , as there is an increased demand of many clinical specialties for biomaterials able not only to substitute the lost or destroyed tissues but also to provide an environment that could induce its own regeneration .
extended research has started to emerge in the field of dental tissue regeneration based on the use of stem cells in combination with various scaffolds and relevant growth and differentiation factors which make the classical tissue engineering triad . in literature
, various types of biomaterial scaffolds have been developed as ecm analogs capable of supporting cell attachment , proliferation , and differentiation and , ultimately , forming new engineered tissues or organs [ 2 , 3 ] .
although a wide range of biomaterials have been proposed for this purpose ( ceramics , natural or synthetic polymers , etc . ) , to date , glass , glass - ceramic , and ceramic scaffolds present important advantages compared to polymeric scaffolds , such as porous structure and chemical texture that promotes mesenchymal cells differentiation and mineralization of the extracellular matrix , lack of toxic byproducts , and the formation of dentinal tubule - like structures [ 47 ] .
furthermore , ceramic scaffolds can be used as carriers of growth factors and angiogenetic agents , drugs , and cell differentiation products [ 8 , 9 ] . calcium - phosphate ( -tcp ) or hydroxyapatite ( ha ) scaffolds are the most investigated compositions for dental tissues regeneration due to their chemical resemblance to the mineral component of natural dentin in mammals . however , other ceramic compositions may be more beneficial in triggering dental tissue formation , although research in this area is limited .
mg - doped phosphate glasses and ceramics have been shown to enhance the bioactivity of the scaffolds related to osteogenesis .
however , to date , the effect of mg ions on dentin regeneration is largely unknown , although the use of mg - containing ceramic scaffolds for dentin regeneration seems a reasonable concept due to the increased amount of mg contained in dentin .
based on the fact that magnesium plays a fundamental role in cellular processes [ 12 , 13 ] and skeletal metabolism [ 14 , 15 ] , mg - containing glass - ceramics with high porosity , suitable degradability , and bioactivity have been only recently proposed for dental tissue regeneration .
huang et al . compared akermanite ( ca2mg(si2o7 ) ) and -tricalcium phosphate ( -tcp ) in their ability to induce differentiation of human mesenchymal stem cells ( mscs ) , showing that the release of si and mg significantly facilitated stem cell proliferation and differentiation .
furthermore , qu et al . reported that the sustained release of mg ions from magnesium - containing nanostructured hybrid scaffolds significantly enhanced the proliferation , differentiation , and biomineralization of human dpscs in vitro .
new studies over the introduction of various metallic ions when synthesizing bioactive glasses report that when used in small amounts , they could be beneficiary , since by tailoring the composition and ionic dissolution process of bioactive glasses , the stimulation of specific cell behavior may be achieved . the addition of cu ions has been proposed to show beneficial effects on angiogenesis and to induce an increase in differentiation of mscs whereas the addition of zn ion shows anti - inflammatory effects and stimulates bone formation in vitro by activating protein synthesis in osteoblasts [ 8 , 9 ] .
recently biomaterials with antibacterial properties have been suggested in dental tissues engineering for the creation of a bacteria - free environment while healing and regenerating the defect area .
this is particularly important for regenerating dental tissues which are prone to bacterial invasion from the oral cavity .
the synthesis of three - dimensional porous scaffolds with interconnected porous structure , able to function as temporary 3d templates for cell attachment , proliferation , and differentiation when in contact under controlled environment and capable of releasing ions with antimicrobial or cariostatic properties , could constitute a suitable inductive carrier that could enhance dentin regeneration and induce the optimal formation of new dentin matrix .
although the last few years mg , zn , and cu ions have shown promising results as additives or dopants to bioceramic scaffolds , the effect of their simultaneous presence in quaternary systems of sio2-cao - mgo - cuo or sio2-cao - mgo - zno has not been investigated , to the best of the authors ' knowledge .
consequently , the aim of this work was to synthesize mg - based glass - ceramic scaffolds with incorporated zn / cu ions and to investigate their physical , mechanical , and biological properties .
polyurethane ( pu ) foam was used as a sacrificial template in order to produce 3d porous scaffolds .
the foam was cut into pieces of 10 10 5 mm and used for the fabrication of the bioactive scaffolds through the foam replica technique as described by chen et al . while it was immersed in sol - gel .
briefly , teos was added in the mixture of ultrapure h2o and hno3 ( 2 n ) and stirred for approximately 30 min until partial hydrolysis of teos occurred .
calcium nitrate tetrahydrate ( ca(no3)24h2o ) , magnesium nitrate hexahydrate ( mg(no3)26h2o ) , and zinc nitrate hexahydrate ( zn(no3)26h2o ) or cupric nitrate hemipentahydrate ( cu(no3)22.5h2o ) were added to the mixture allowing 50 min for the hydrolysis reaction to complete at 60c .
after the immersion of the foam in the sol - gel and mechanical stirring for 5 min , the samples ( green bodies ) were retrieved from the sol - gel and squeezed in order to remove the excess of sol from the pores and then left to dry out for at least 12 h. the thickness of the bioactive glass on the green bodies was adjusted by pouring droplets of sol - gel .
the excess was removed after centrifuging the green bodies . in order to understand the structural changes upon heating of the bioactive glasses , as well as their mass loss percentage ,
the thermogravimetric ( tg ) and differential scanning calorimetry ( dsc ) curves were received with heating rate of 10c / min from room temperature to 1400c , under nitrogen atmosphere . according to tg - dsc results ,
the synthesized bioactive scaffolds were sintered at 890c ( zn - based ) and 866c ( cu - based ) with 2 h annealing .
fourier transform infrared spectroscopy ( ftir ) and x - ray diffraction analysis ( xrd ) were used in order to examine thoroughly the scaffold 's crystal structure . for ftir measurements
a perkin - elmer spectrometer spectrum 1000 in mir region was used to determine the chemical composition of the fabricated scaffolds .
representative scaffolds from both groups were ground into powder and pellets with powder to kbr ratio of 1 : 100 were fabricated under pressure ( 7 tons ) . for the xrd analysis a philips ( pw1710 ) diffractometer with ni - filtered cuka wave radiation was used .
archimedes method was used for the determination of the scaffold porosity , p , as indicated by the equation(1)p = vporesvbulk , where vbulk was calculated by the mass and dimensions of the scaffolds .
the morphology and microstructure of the scaffolds was monitored by the use of scanning electron microscopy with associated energy dispersive spectroscopic analysis ( sem - eds ) .
the mechanical properties of the synthesized scaffolds were tested by an instron 3344 loading apparatus in compression at a crosshead speed of 0.5 mm / min .
ten prismatic samples ( five from each group ) with dimensions 8 8 4 mm were tested .
the compressive load was applied until 1 mm ( 12.5% ) compressive strain was achieved in the 8 mm dimension ( height ) .
further loading applied during pilot experiments resulted in off - axis loading and thus the received stress values were not considered as valid .
the highest stress values included in the 1 mm stress - strain curve were recorded and mean values with standard deviations were determined .
degradation test was performed according to the iso 10993 - 14 : 2009 ( extreme and simulation solution tests ) .
mass calculation was performed with an electronic balance ( kern abs ) with an accuracy of 0.0001 mg and the specific mass of each scaffold was recorded as the difference between the mass of the container with and without the scaffold . for the simulation solution test
each container was filled with 100 ml of freshly prepared tris - hcl buffer , with ph 7.4 0.1 at 37 1c , while for the extreme solution test each container was filled with 10 ml of the buffered citric acid solution , with ph 3.0 0.2 at 37 1c .
then , all containers were placed in a controlled - temperature environment at 37 0.5c , for 120 h. the containers were agitated at 2 hz with circular movement .
after 120 h the containers with scaffolds were allowed to cool at room temperature .
then , filter paper and scaffold 's remnants were dried in an oven overnight at 100 2c .
the difference between the mass of the filter paper with and without the remnants was the actual mass of the nondegraded scaffold .
finally , the difference between the initial recorded mass of the scaffolds and the mass of the nondegraded scaffold remnants was recorded as the mass of the degraded scaffold .
the % weight loss was determined with the following equation : ( 2)weight loss % = wowtwo100 .
the scaffolds were placed in sterilized reagent bottles and submerged in sbf solution with mass to solution ratio adjusted at 1.5 mg / ml .
then they were placed in an incubator ( incucell 55 ) at 37c under renewal conditions for various times after immersion ( 6 h , 24 h , and then after every 48 h ) .
finally the specimens were removed from the sbf at each time point ( after 10 and 21 days of immersion ) , washed with distilled water , and dried at room temperature .
dpsc cultures were established from third molars of young healthy donors aged 1618 years and extensively characterized for several stem cell markers , as previously published by our group .
the collection of the samples was performed according to the guidelines of the institutional review board and the parents of all donors signed an informed consent form . for the establishment of cell cultures the enzymatic dissociation method was used .
briefly , teeth were disinfected and cut around the cementum - enamel junction to expose the pulp chamber .
the tissue was minced into small segments and digested in a solution of 3 mg / ml collagenase type i and 4 mg / ml dispase ii ( invitrogen , karlsruhe , germany ) for 1 h at 37c .
single cell suspensions were obtained by passing the cells through a 70 m cell strainer ( bd biosciences , heidelberg , germany ) .
cells were expanded with -mem ( minimum essential media ) culture medium ( invitrogen ) , supplemented with 15% fbs ( eu - tested , invitrogen ) , 100 mm l - ascorbic acid phosphate ( sigma - aldrich , taufkirchen , germany ) , 100 units / ml penicillin , 100 mg / ml streptomycin , and 0.25 mg / ml amphotericin b ( all from invitrogen ) ( complete culture medium ( ccm ) ) , and incubated at 37c in 5% co2 .
cultured dpscs in passage numbers from 3 to 6 were used for all experiments . to analyze cell viability / proliferation
scaffolds were first preimmersed into ccm for 30 min at 37c and 5% co2 atmosphere in an incubator in order to adjust ph and create a more biomimetic microenvironment before cell seeding . afterwards
, the medium was removed and dpscs were spotted at low volume ( 100 l ) into the scaffolds at 5 10 cells / scaffold in 48 well - plates and allowed to attach first for 45 min before being fully covered with 500 l ccm .
cell viability / proliferation was evaluated after 1 , 3 , 7 , and 14 days ( d ) by the mtt assay ( n = 4 ) .
medium change was performed every 3 days during the entire experimental period . at the end of each time point 50 l of mtt ( 5 mg / ml in pbs )
was added in each well and scaffolds / cell constructs were incubated for 3 h at 37c and 5% co2 . after this period ,
the medium containing the mtt solution was discarded , the scaffold / cell constructs were washed with pbs , and the insoluble formazan was dissolved with dmso overnight at 37c . the absorbance was measured against blank ( dmso ) at a wavelength of 545 nm and a reference filter of 630 nm by a microplate reader ( epock , biotek , biotek instruments , inc , vermont , usa ) . as controls , scaffolds ( cua2 and zna2 ) without cells were incubated under the same conditions and the optical density values were subtracted from values obtained by the corresponding scaffold / cell constructs . finally , od values were normalized to those of control dpscs cultures beginning with the same cell number ( 5 10 cells / well ) and the final results were expressed as % percentage of control . in order to evaluate cell attachment and morphology of dpscs seeded into the biomimetic scaffolds , samples of scaffold / cell constructs
after 3 , 7 , and 14 d , the scaffold / cell constructs were washed twice with pbs and fixed with 3% glutaraldehyde ( in 0.1 m sodium cacodylate , ph 7.4 , containing 0.1 m sucrose ) .
the specimens were subsequently dehydrated in a series of increasing concentrations of ethanol and hexamethyldisilazane .
for sem analysis they were carbon - coated and observed with a jeol ( japan ) electronic microscope at 20 kv .
thermal analysis of bioactive glasses can efficiently determine mass variations and thermal content changes as a function of temperature .
therefore , it is critically essential to determine these variations and changes for every material , which is going to receive heat treatment , in order to be able to predict its behavior at high temperatures .
as already mentioned , zna2 scaffolds were sintered at 890c and cua2 scaffolds at 866c , with 2 h annealing .
those temperatures were extracted from dsc curves ( figure 1 , red lines ) for each bioactive glass and represent exothermic peaks ( tc ) .
the temperature at these peaks corresponds to the crystallization of the samples , while additional exothermic peaks are observed at higher temperatures ( 1060c for cua2 and 1180c for zna2 ) .
endothermic peaks assigned to the melting point ( tm ) of each sample are observed at 1257c for the cua2 and 1290c for the zna2 glasses . in this study ,
sintering temperatures were chosen at the first exothermic peak of each glass , in order to produce scaffolds with improved mechanical properties , as the crystallization of a glass provides a mechanically enhanced system without necessarily impairing the bioactive response of the glass - ceramic .
the tg curves ( figure 1 , blue lines ) of both samples indicate that the mass variations were insignificant , being under 8% for both of them .
mass loss for both bioactive glasses takes place under 600c and is caused because of the h2o , co , and co2 release from the samples , which were entrapped inside during the synthesis process .
bioactive scaffolds in order to be applied for the development of calcified tissue should be able to favor cell penetration , vascularization , and nutrient and metabolic waste transportation [ 26 , 27 ] . to achieve such a goal scaffolds should exhibit interconnected porous structure with pore sizes between 300 and 500 m [ 18 , 28 ] .
the porous structure and morphology of the bioactive glass - ceramic scaffolds are shown in figure 2 .
the zna2 and cua2 scaffolds presented a mean porosity of 84% and 74% , respectively .
a primary goal of dental tissue regeneration is the development of suitable scaffolding materials that could support dental stem cells attachment and proliferation .
scaffolds of similar porosity and interconnectivity as those of the scaffolds fabricated in this study have been shown to support the attachment and proliferation of human dental pulp stem cells [ 18 , 28 ] .
ftir spectra of both zna2 and cua2 glass - ceramic scaffolds present the characteristic peaks of silicate glasses shown by a broad peak at 9001200 cm and the peak at ~470 cm .
in addition , the spectra of the zna2 reveal the presence of a strong peak at 796 cm indicating the existence of bridging oxygen , which are connected with the inability of a glass - ceramic material to exhibit bioactive behavior [ 30 , 31 ] .
this peak though present is not so intense in the spectra of the cua2 scaffolds . for cua2 scaffolds , the ftir peaks at 646 cm
, 690 cm , 902 cm , and 946 cm were attributed to wollastonite ( casio3 ) .
xrd patterns ( figure 4 ) revealed that zna2 scaffolds consist mainly of an amorphous phase . on the other hand ,
xrd patterns of cua2 glass - ceramic scaffolds indicate the existence of wollastonite ( approximate percentage 40%wt ) , while 10%wt of calcium copper silicate ( cacusi4o10 ) was also detected .
the mechanical strength of both zna2 and cua2 scaffolds under uniaxial compression stress was proven , as expected , rather low but in the range of values attained for ceramic scaffolds noncoated with gelatin or other polymeric materials [ 33 , 34 ] .
more specific , zna2 glass - ceramic scaffolds presented a mean compressive strength at 0.10 ( 0.06 ) mpa and cua2 glass - ceramic scaffolds a mean compressive strength of 0.02 ( 0.007 ) mpa . as it is shown from the typical stress - strain curves presented in figure 4 , a continuous section with peaks after isolating linear elastic regions and valleys , corresponding to the brittle crushing of the struts , was the dominant mode of fracture , as has been observed for brittle ceramic porous scaffolds [ 34 , 35 ] .
further improvements of the mechanical properties of the scaffolds are necessary for the maintenance of their structural integrity so as to allow time for the new calcified tissue to grow .
the capability of improving the mechanical properties of ceramic scaffolds has been demonstrated in several composite polymer - ceramic formulations [ 3639 ] .
it is highly possible that coating these scaffolds with gelatin or alginate hydrogel could significantly improve their mechanical behavior and this is a subject of future research .
results of degradation tests are presented in figure 5 . a mean degradation rate of 3.5% ( zna2)-3.7% ( cua2 ) was recorded for the simulation test in tris buffer solution after 120 h immersion , while extreme test in citric acid solution revealed slightly higher degradation rate for the same time period ( 5% for zna2 , 7% for cua2 ) .
the recorded degradation values were higher for the extreme test in comparison to the simulation test for both ceramic scaffolds ( zna2 and cua2 ) .
moreover , ceramic scaffolds of zna2 presented lower degradation values in extreme degradation test , in comparison with cua2 , while the two ceramic scaffolds presented almost equal degradation values in simulation degradation test . the higher degradation rate of the cua2 compared to the zna2 scaffolds can be explained by the presence of wollastonite in the cua2 scaffolds , as it has been found that the increase of wollastonite percentage rapidly increases the mass loss of composite poly(3-hydroxybutyrate - co-3-hydroxyvalerate ) ( phbv)/wollastonite scaffolds .
this increased weight loss may be attributed to the dissolution of wollastonite when immersed in aqueous solution , the release of alkaline ions , and the subsequent destruction of the three - dimensional structure of the scaffolds .
the release of alkaline ions of bioactive glasses is one of the basic mechanisms of apatite formation , as it leads to the formation of a high surface area of hydrated silica and finally to the crystallization of apatite through precipitation of p and ca from the surrounding environment
. the increased degradation rate may be the reason for the bioactive behavior of cua2 despite its lower porosity , while the lower degradation of zna2 that can be assigned to the presence of nonbridging oxygen as found with ftir explains its inability for in vitro apatite formation .
degradation of scaffolds is necessary during calcified tissue formation , as scaffolds are networks that assist initial cell attachment and proliferation but have to degrade simultaneously with the new tissue formation .
similar degradation rate values with those of the present study have been recorded for bioceramic scaffolds in literature [ 42 , 43 ] , although usually degradation rate of bioceramics is evaluated by measuring mass loss after immersion in solutions like sbf or pbs due to their resemblance with physiological body fluids . in this study degradation of ceramic scaffolds
was evaluated according to iso 10993 - 14 : 2009 which is more appropriate for testing materials in contact with fluids of different ph .
the simulation test is a mild , common test used to evaluate the degradation rate of most ceramic materials under physiological ph and temperature similar to physiological body fluids , while the extreme test is related to the more aggressive environment to which a material can be exposed to in the oral cavity due to low ph .
slight differences in scaffold 's porosity or structure through the fabrication process could explain such variation [ 42 , 45 ] .
greater degradation values were reported in literature , only for significantly longer immersion period ( 1428 days ) [ 43 , 46 ] .
lower degradation values were recorded after 3 days of immersion in tris buffer for wollastonite / tricalcium phosphate macroporous scaffolds , with significantly lower porosity ( 50% ) .
the degradation rate of ca - p bioceramics is influenced by several parameters such as the sintering process , microstructure , crystallinity , and porosity .
the porosity plays a dominant role in the degradation of bioceramics as it is related to high specific surface area .
however the results of this study indicate that other mechanisms rather than porosity may be more crucial in determining the degradation of the scaffolds , such as composition and crystalline structure .
ftir spectra of zna2 glass - ceramic scaffolds could not reveal any differentiation in their chemical composition even after 21 days of immersion in sbf solution , as shown in figure 6(a ) .
this result may be attributed to the presence of bridging oxygen as shown by the strong peak at 796 cm , as already mentioned . on the contrary ,
cua2 bioactive scaffolds presented bioactive behavior according to ftir spectra ( figure 6(b ) ) .
more specific , ftir spectra , after 10 days of immersion , revealed the formation of a weak double peak at 587 cm and 603 cm , which is attributed to the vibration of the p - o bond of the phosphate group .
the high amount of wollastonite crystallized on the initial material could explain the delayed formation of apatite on the surface of cua2 glass - ceramic scaffolds .
after 21 days of soaking in sbf solution , a stronger double peak at 587 cm and 603 cm was formed .
additionally , at the same immersion time , the broad peak at 9001200 cm shifted towards ~1100 cm and became less wide .
therefore , after 21 days of soaking in sbf there is a strong indication of the formation of apatite on the surface of the glass - ceramic scaffolds of the cua2 group .
these findings are in accordance with xrd patterns ( figure 7 ) for both groups of glass - ceramic scaffolds .
namely , zna2 samples did not show any compositional differentiation after 10 days of immersion in sbf solution , whereas cua2 patterns revealed a peak corresponding to apatite after 10 days of soaking .
the effect of zinc incorporation on the structure of various bioactive glasses has resulted in different results concerning bioactivity depending on the microstructure and physicochemical properties of zn - doped glasses .
although the acellular formation of calcium phosphate layer on the surface of bioactive silicate glasses doped with zn have been shown to occur after soaking in biological fluids [ 49 , 50 ] , other studies have shown that zn content reduces the overall leaching activity of the glass inhibiting the formation of the hca layer on its surface .
reported a delayed formation of hca which was related to the slower degradation profile of the zn - doped bioactive glasses , in accordance with the results of this study . on the other hand ,
cu - doped 45s5 bg scaffolds exhibit high apatite forming ability , as proven by the rapid formation of a carbonated ha layer on their surface ( 3 days in sbf ) .
hoppe et al . reported that cu addition ( up to 2.5wt% cuo ) had no effect on the reactivity of the undoped bg , as measured through immersion in sbf .
fabricated sol - gel mg - based scaffolds with the foam replica technique and reported apatite formation on scaffolds sintered at 1350c after 9 days in sbf .
as the authors in the current study used the same starting glass formulation , the incorporation of copper resulted in a slight delay of apatite formation , taking into consideration the lower crystallization temperature of the scaffolds .
dpscs were able to attach and proliferate in both biomimetic scaffolds ( figures 8 and 9 ) .
however , both mtt assay and sem analysis revealed a much better biological behavior of zna2 compared to the cua2 scaffolds .
zna2 supported a statistically significant higher viability of dpscs compared to the cua2 scaffolds at all time points tested ( p < 0.01 ) .
zna2 scaffolds showed an increase of cell viability / proliferation up to day 7 and decrease afterwards , which can be explained by the initiation of differentiation of dpscs inside the biomimetic microenvironment , which is usually accompanied by a cease in proliferation , as already shown in preliminary experiments with real - time pcr analysis and western blotting ( data under preparation ) . on the contrary cua2 scaffolds showed much lower od values compared to the zna2 scaffolds , with viability / proliferation increasing until day 3 and significantly decreasing afterwards .
whether this inferior biological behavior of cua2 scaffolds is due to a very high release of cytotoxic concentrations of cu or any other elements needs further investigation .
the results of the mtt assay were also in accordance with the results obtained by the sem analysis .
cells grown inside the zna2 scaffolds were more densely seeded , with an atractoid , spindle - shaped morphology , indicative of proper attachment and high viability of cells within the scaffold .
cells grown inside the cua2 scaffolds , on the other hand , were fewer and with a rather rounded morphology , indicative of poor attachment and potential cytotoxicity .
zn - doped sol - gel derived glasses based on 58s have shown higher cellular viabilities than similar cu - doped glasses , in a recent study by bejarano et al . , although both were cytotoxic compared to undoped control 58s .
the enhanced cell behavior recorded in the present study is probably attributed to a more stabilized zn - derived glass structure that restricted mass glass dissolution and ion release that could exert cytotoxic behavior .
preliminary , unpublished data of the authors suggest that zna2 scaffolds combined with dpscs and growth / morphogenetic factors such as dentin matrix protein , dmp-1 , and bone morphogenetic protein , bmp-2 , promote odontogenic differentiation and dentin - like tissue formation .
bioactive ceramic scaffolds , with adequate porosity , over 74% , and pore interconnectivity were produced by the foam replica technique .
cu - doped mg - based scaffolds revealed apatite forming ability after 10 days immersion in sbf , while zn - doped mg - based scaffolds failed to develop apatite formation even after 21 days in sbf .
differences in structure are responsible for the different degradation profile , mechanical behavior , and bioactivity of the synthesized scaffolds . despite failure to develop apatite zna2 scaffolds were proved very efficient to provide controlled degradation rate and a biomimetic environment for the long - term attachment and growth of dpscs ( up to 14 days ) , which makes them very promising for further research on their potential to induce odontogenic differentiation of dpscs and calcified dental tissue production for targeted dentin regeneration .
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### Summary:
: glass - ceramic scaffolds containing mg have shown recently the potential to enhance the proliferation , differentiation , and biomineralization of stem cells in vitro , property that makes them promising candidates for dental tissue regeneration .
an additional property of a scaffold aimed at dental tissue regeneration is to protect the regeneration process against oral bacteria penetration . in this respect ,
novel bioactive scaffolds containing mg2 + and cu2 + or zn2 + , ions known for their antimicrobial properties , were synthesized by the foam replica technique and tested regarding their bioactive response in sbf , mechanical properties , degradation , and porosity .
finally their ability to support the attachment and long - term proliferation of dental pulp stem cells ( dpscs ) was also evaluated .
the results showed that conversely to their bioactive response in sbf solution , zn - doped scaffolds proved to respond adequately regarding their mechanical strength and to be efficient regarding their biological response , in comparison to cu - doped scaffolds , which makes them promising candidates for targeted dental stem cell odontogenic differentiation and calcified dental tissue engineering .
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: the incidence of duodenal injuries is 11.226% due to blunt trauma.[14 ] on an average , one to four other abdominal organ injuries are associated with duodenal trauma , which makes an isolated injury a rarity .
the anatomical location of the duodenum makes diagnosis and treatment of isolated duodenal injury a difficult task . due to its rarity and subtle clinical features ,
we describe two patients with isolated blunt duodenal injuries and highlight some problems and principles in the management of duodenal injury .
he was initially managed in two private hospitals where he underwent a laparotomy and duodenorrhaphy for traumatic duodenal perforation 30 hours after injury .
on the 6 postoperative day ( pod ) , he was referred to our hospital with high - grade fever , altered mental status , abdominal distension and bilious discharge from the laparotomy wound .
after adequate resuscitation and stabilization , the patient was taken up for re - laparotomy .
the peritoneal cavity was filled with bilious fluid and there was crepitus along the paraduodenal and paracolic area .
the previous repair was seen intact on the anterior wall of the second part of the duodenum . on mobilization ( kocherization ) of the duodenum , another perforation of size 1.5 cm
the perforation was repaired in two layers and a triple tube decompression , i.e. tube gastrostomy , reverse tube duodenostomy and a feeding jejunostomy , was performed [ figure 1 ] .
an abdominal drain was placed in the paraduodenal area and a polypropylene mesh laparostomy was done
. graphical representation of the triple tube decompression technique ( case 1 ) ( a = tube gastrostomy , b = retrograde tube duodenostomy , c = feeding jejunostomy , p1 = site of the perforation on the anterior wall of the duodenum , p2 = site of the perforation on the posterior wall of the duodenum ) a contrast study on pod 15 showed normal passage of contrast into the jejunum , with no leak from the injury site .
though he had one episode of fever , he was finally discharged on pod 88 in a stable condition .
he attended the emergency department in a stable condition , and after primary assessment , the attending physician discharged him .
the patient returned to the emergency department with abdominal pain and vomiting 24 hours after discharge .
on examination , he was conscious , afebrile , with pulse rate 110/min and a blood pressure of 90/60 mm hg .
u / l ) ; total leukocyte count was 11,000/mm ( reference range 400011,000/mm ) .
contrast - enhanced computed tomography scan of abdomen with intravenous and oral contrast media revealed free gas in the retroperitoneum , extravasation of contrast and free fluid in the abdomen .
there was bile staining and crepitus in the paraduodenal area and nearly 200 ml of dirty fluid in the right paracolic gutter .
there was a perforation in the second part of the duodenum involving more than 50% of the circumference [ figure 2 ] .
a tube gastrostomy , reverse tube duodenostomy through the proximal jejunum , and a feeding jejunostomy and polypropylene mesh laparostomy were performed .
photograph showing the traumatic perforation on second part of duodenum ( a ) , gall bladder ( b ) .
please note the extensive bilious staining and pus flakes all around in the retroperitoneum we performed a polypropylene mesh laparostomy in both the patients , since a safe definitive closure of the abdominal wall was not feasible due to tension and a primary closure could have resulted in the development of an abdominal compartment syndrome .
instead , a transparent low - cost plastic sheath ( unprinted side of a sterile urine collection bag ) was placed between the abdominal wall and the exposed viscera
. an appropriate size of a plain polypropylene mesh was then sutured to the linea alba to cover the abdominal contents without tension .
after 48 hours , the plastic sheath was gradually removed through the caudal end of the laparostomy .
as the abdominal distension decreased , the polypropylene mesh was divided in the midline and gradually trimmed over several days .
each time the mesh was trimmed , the cut edges of the mesh were re - sutured with 1 - 0 polypropylene suture to maintain the continuity of the mesh .
he was initially managed in two private hospitals where he underwent a laparotomy and duodenorrhaphy for traumatic duodenal perforation 30 hours after injury .
on the 6 postoperative day ( pod ) , he was referred to our hospital with high - grade fever , altered mental status , abdominal distension and bilious discharge from the laparotomy wound .
after adequate resuscitation and stabilization , the patient was taken up for re - laparotomy .
the peritoneal cavity was filled with bilious fluid and there was crepitus along the paraduodenal and paracolic area .
the previous repair was seen intact on the anterior wall of the second part of the duodenum . on mobilization ( kocherization ) of the duodenum , another perforation of size 1.5 cm
the perforation was repaired in two layers and a triple tube decompression , i.e. tube gastrostomy , reverse tube duodenostomy and a feeding jejunostomy , was performed [ figure 1 ] .
an abdominal drain was placed in the paraduodenal area and a polypropylene mesh laparostomy was done
. graphical representation of the triple tube decompression technique ( case 1 ) ( a = tube gastrostomy , b = retrograde tube duodenostomy , c = feeding jejunostomy , p1 = site of the perforation on the anterior wall of the duodenum , p2 = site of the perforation on the posterior wall of the duodenum ) a contrast study on pod 15 showed normal passage of contrast into the jejunum , with no leak from the injury site .
though he had one episode of fever , he was finally discharged on pod 88 in a stable condition .
he attended the emergency department in a stable condition , and after primary assessment , the attending physician discharged him .
the patient returned to the emergency department with abdominal pain and vomiting 24 hours after discharge . on examination , he was conscious , afebrile , with pulse rate 110/min and a blood pressure of 90/60 mm hg .
u / l ( reference range 95 u / l ) ; total leukocyte count was 11,000/mm ( reference range 400011,000/mm ) .
contrast - enhanced computed tomography scan of abdomen with intravenous and oral contrast media revealed free gas in the retroperitoneum , extravasation of contrast and free fluid in the abdomen .
there was bile staining and crepitus in the paraduodenal area and nearly 200 ml of dirty fluid in the right paracolic gutter .
there was a perforation in the second part of the duodenum involving more than 50% of the circumference [ figure 2 ] .
a tube gastrostomy , reverse tube duodenostomy through the proximal jejunum , and a feeding jejunostomy and polypropylene mesh laparostomy were performed .
photograph showing the traumatic perforation on second part of duodenum ( a ) , gall bladder ( b ) .
we performed a polypropylene mesh laparostomy in both the patients , since a safe definitive closure of the abdominal wall was not feasible due to tension and a primary closure could have resulted in the development of an abdominal compartment syndrome . instead , a transparent low - cost plastic sheath ( unprinted side of a sterile urine collection bag ) was placed between the abdominal wall and the exposed viscera .
an appropriate size of a plain polypropylene mesh was then sutured to the linea alba to cover the abdominal contents without tension .
after 48 hours , the plastic sheath was gradually removed through the caudal end of the laparostomy .
as the abdominal distension decreased , the polypropylene mesh was divided in the midline and gradually trimmed over several days .
each time the mesh was trimmed , the cut edges of the mesh were re - sutured with 1 - 0 polypropylene suture to maintain the continuity of the mesh .
here , we have described two patients with duodenal perforation following blunt abdominal trauma . in both the patients , the diagnosis was delayed . in the first patient ,
diagnosis of blunt duodenal injury is often delayed unless a very high index of suspicion is kept during initial assessment and tertiary survey after resuscitation and stabilization of patients .
the mechanism of injury ( acceleration and deceleration impact ) , upper abdominal tenderness with tachycardia , raised temperature and vomiting should warrant further evaluation .
contrast - enhanced computed tomographic scan of the abdomen with oral and intravenous contrast media is highly sensitive to detect small amounts of retroperitoneal air , paraduodenal hematoma or extravasated contrast from the duodenum .
occasionally , contrast - enhanced computed tomographic scan may also be negative when performed early or may suggest subtle findings like small amount of unexplained fluid or unusual bowel morphology due to paraduodenal hematoma.[57 ] there are several options to deal with duodenal injury , which range from simple repair like primary closure ( duodenorrhaphy ) to more complex procedures like resection and anastomosis , duodenal diverticulation , pyloric exclusion , pancreaticoduodenectomy .
however , no single method of repair completely eliminates the possibility of a duodenal fistula .
most of the duodenal injuries are adequately managed with primary closure ( duodenorrhaphy ) in one or two layers or by resection and anastomosis .
this was evident in both of our cases . in both the patients , damage control surgery in the form of polypropylene mesh laparostomy after duodenorrhaphy , tube gastrostomy , reverse tube duodenostomy and a feeding jejunostomy was performed .
salvage procedures like quick damage control with delayed definitive surgery , foley catheter duodenostomy , duodenal decompression by quadruple tube technique are sparingly reported .
both of our patients were effectively managed by simple repair and duodenal decompression by triple tube technique .
simple repair followed by duodenal decompression with triple tube technique was originally described by stone and fabian .
this triple tube technique comprises a tube gastrostomy for decompressing the stomach , a reverse tube duodenostomy for duodenal decompression and an antegrade tube jejunostomy for enteral feeding [ figure 1 ] . for reverse tube duodenostomy
, the tube is passed through the proximal jejunum and guided into the second part of duodenum .
this triple tube technique is rapid , needs only basic surgical experience , and provides a portal for early enteral feeding obviating the need for intravenous hyperalimentation .
thus , it is a cost - effective option with least morbidity for managing these severely injured sick patients . in our first case ,
the injury on the posterior wall of the duodenum was missed at the time of the first laparotomy .
the obvious perforation on the anterior wall probably prevented the operating surgeon from proper mobilization ( kocherization ) of the duodenum .
in the second patient , the index of suspicion for severe internal injury was low in view of absence of clinical signs , hence the patient was discharged . mobilization of the duodenum is known to reveal significant injury even in the absence of apparent signs of trauma on it .
recently , zeli et al . reported a case of complete transection of the duodenum at two places , one just beyond the pylorus and the other between the second and third part of duodenum .
this report , as well as our first case , highlights the possibility of duodenal injury occurring at multiple sites .
we strongly suggest that in all major blunt trauma cases , even in the presence of obvious perforation on the duodenum , the duodenum should always be mobilized and evaluated for additional injury .
another option to manage such patients could have been a controlled duodenal fistula following peritoneal lavage .
however , we preferred triple tube decompression as the feeding jejunostomy associated with the procedure helps in early enteral feeding , thereby avoiding the need for more expensive total parenteral nutrition ( tpn ) with its attendant complications .
it also facilitates drainage of infectious material , permits visual control of the underlying viscera , facilitates wound care , simplifies repeated exploration if required , and hastens healing by secondary intention .
isolated duodenal injury following blunt abdominal trauma is rare ; therefore , most general surgeons have a low index of suspicion and may not be experienced in handling such problems .
these two cases highlight the difficulties that can be encountered during diagnosis and management of blunt abdominal trauma with isolated duodenal injury .
the diagnosis depends on a high index of suspicion not only during the initial clinical evaluation but also during trauma related laparotomies . when diagnosed late , especially when the patient 's general condition is severely compromised , simple duodenorrhaphy with duodenal decompression by triple tube technique may be a good selection because the procedure is simple , rapid , and provides a portal for early enteral feeding
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### Summary:
: duodenal perforation following blunt abdominal trauma is an extremely rare and often overlooked injury leading to increased mortality and morbidity .
we report two cases of isolated duodenal injury following blunt abdominal trauma and highlight the challenges associated with their management . in both
these patients , the diagnosis of the duodenal injuries was delayed , leading to prolonged hospital stay .
the first patient had two perforations , one on the anterior and the other on the posterior wall of the duodenum , of which the posterior perforation was missed at initial laparotomy . in the other patient ,
the duodenal injury was missed during the initial assessment in the emergency department .
he returned to the emergency department 24 hours after discharge with abdominal pain and vomiting . during trauma
related laparotomy , complete kocherization ( mobilization ) of the duodenum must be mandatory , even in the presence of obvious injury on its anterior wall .
we emphasize on keeping the management protocol simple by a triple tube decompression , i.e. duodenorrhaphy ( simple closure ) , tube gastrostomy , reverse tube duodenostomy and a feeding jejunostomy .
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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:
: many orthodontists believe that because dental arch length decreases and lower anterior crowding increases throughout life , the only way to maintain ideal alignment after orthodontic treatment is some form of permanent retention.1 - 6 fixed bonded retainers can serve in - mouth for decades.7 there have been a few long - term studies of the long - term effects of bonded retainers on teeth.7,8 dahl and zachrisson8 found no signs of dental caries or white spots after 3 - 6 years .
recently , booth et al.7 evaluated 60 patients who had permanent retainers in place for more than 20 years and concluded that orthodontists might recommend permanent retention to maintain the alignment of lower incisors . in 1983 , zachrisson9 introduced flexible spiral wire retainers ( fswrs ) .
the flexibility of the wire reduces the concentration of stress within the bonding composite , thus minimizing the probability of subsequent failure.10 bearn11 stated in a review that there is a trend toward the use of multistranded wires in the construction of bonded lingual retainers .
the diameter of these wires varies between 0.015 inch and 0.032 inch and thinner wires are preferred for fswrs .
however , there has been no consensus regarding the most clinically effective diameter of multistranded wire.12 the mode of failure for lingual retainers has been studied by several authors.8,13 - 16 artun and urbye13 found that the most common mode of failure was loosening between the wire and composite . dahl and zachrisson8 evaluated the failure rates of fswrs that were made with different wires and reported lower failure rates for five - stranded wires than for other wire types .
they found that three - stranded wires came loose from the composite at a similar rate to failure by fracture .
bearn et al.14 reported that the most common fracture mode was in the wire - composite interface , while lumsden et al.15 found that more fractures occur at the adhesive pad than at the wire - adhesive interface .
lumsden et al.15 indicated that early fractures were the result of adhesive bond failures , and wire breakages were seen primarily in older retainers .
lie sam foek et al.16 reported that the majority of the failures they observed occurred in the first 6 months after placement .
the most common causes of these failures were debonding ( 37.5% ) , fracture plus debonding ( 1.4% ) , and fracture ( 0.7% ) .
because bonded lingual retainers are intended to serve for long periods of time in the mouth , attempts should be made to increase the success rate of these devices .
loosening of the wire in bonded lingual retainers may result from cracks within the composite that arise from deformation of the interdental wire.12 wire choice may therefore be important for maximizing the success of lingual retainers . in this study , we tested three different wires used for lingual retainer fabrication in order to determine if they differ in ( 1 ) detachment force , ( 2 ) amount of deformation , ( 3 ) fracture mode , or ( 4 ) wire pull - out force .
ninety - four human lower incisor teeth were obtained from patients who were undergoing dental treatment .
soft tissue remnants were removed with a scaler and teeth were stored in thymol solution .
teeth were used within 1 month of extraction . the study design was adopted from cooke and sherriff.12 pairs of teeth were matched to form a contact area that mimics the intraoral situation . chemically cured acrylic resin was placed into plastic molds and the roots of the teeth were embedded in the acrylic .
the roots were mounted so that the long axes of the teeth were perpendicular to the base of the molds . in total , 47 blocks were constructed .
the lingual aspects of the teeth were polished with fluoride - free pumice , etched for 30 seconds with 37% ortho - phosphoric acid ( transbond xt etching gel system ; 3 m unitek , monrovia , ca , usa ) , rinsed with water for 30 seconds using a three - in - one syringe , and dried for 20 seconds using an oil - free air source .
primer ( transbond xt ) was applied and left uncured , in accordance with the manufacturer 's instructions . to provide best fit of the wire over the tooth ,
the blocks of teeth were divided into 3 groups and a different type of wire was bonded to the teeth in each group .
the wires used in each group were : group i : 0.0215-inch five - stranded wire ( pentaone ; masel orthodontics , carlsbad , ca , usa).group ii : 0.016 0.022-inch eight - stranded rectangular wire ( bond - a - braid ; reliance orthodontic products , itasca , il , usa).group iii : 0.0195-inch dead - soft coaxial wire ( respond ; ormco corp . , orange , ca , usa ) .
group i : 0.0215-inch five - stranded wire ( pentaone ; masel orthodontics , carlsbad , ca , usa ) .
group ii : 0.016 0.022-inch eight - stranded rectangular wire ( bond - a - braid ; reliance orthodontic products , itasca , il , usa ) .
group iii : 0.0195-inch dead - soft coaxial wire ( respond ; ormco corp . , orange , ca , usa ) .
a 10 mm length of test wire was cut and the midpoint of the wire was marked with a pencil .
great care was taken to place the wire parallel to the base of the mold and below the point of contact between the teeth in the mold .
we used a commercially available adhesive set in order to standardize the amount of adhesive applied to each tooth ( mini - mold ; ortho - care ltd . ,
the composite was applied with wire bonder tips ( dome shaped ) and cured for 10 seconds with a light emitting diode curing unit ( eliparfreelight-2 ; 3 m espe , st .
the wire bonder tips have grooves that allow for placement of the wire in the middle of the composite bulk .
the tip of the light curing unit was placed as close as possible to the surface of the tooth .
the teeth were stored in distilled water at room temperature for 24 hours before testing .
embedded specimens were secured in a jig attached to the base plate of an instron testing machine ( instron corp . , norwood , ma , usa ) .
a chisel - edge plunger was mounted in the movable crosshead of the testing machine and positioned so that the leading edge was aimed at the marked midpoint of the wire ( figure 1 ) .
the chisel - edge was carefully placed so that it would not contact any part of the specimen .
the crosshead speed was set to 1 mm / min and the maximum load necessary to debond the wire was recorded .
after failure occurred , the composite over the wire was gently removed with a tungsten carbide bur .
the wire was then positioned on graph paper and its deflection was assessed under an optical stereomicroscope ( sz 40 ; olympus , tokyo , japan ) at 20 magnification .
we evaluated fracture mode on the side where the initial bond failure occurred using an optical stereomicroscope ( sz-40 ) at 20 magnification .
remnant adhesive on the enamel surface was coded by one investigator ( a.b . ) who was blind to treatment group .
we scored the fracture sites according to the adhesive remnant index ( ari ) . in this system , fractures are ranked from 0 to 3 , based on the amount of adhesive remaining after bracket removal17,18 : 0 , no adhesive remaining on the enamel surface ; 1 , less than 50% adhesive remaining on tooth ; 2 , more than 50% adhesive remaining on tooth ; 3 , all adhesive remaining on tooth surface .
we used the method reported by bearn et al.14 to test pull - out force . using molds , we prepared 60 cylindrical acrylic blocks that were 25 mm in diameter and 10 mm high .
a 3 2 mm hole was drilled in the center of each block ( figure 2 ) .
the drilled holes approximated the dimensions of the composite used clinically for lingual retainers.15 twenty acrylic blocks were assigned to each wire group .
the hole in each block was filled with composite ( transbond xt ) and one of the free ends of a 10 cm section of test wire was embedded in the composite .
a second block with the same dimensions as the test block was used to ensure the accuracy of test wire placement , and to remove any excess composite .
the placement block was fitted with a stainless steel alignment jig and a 1 mm hole through the center .
prepared test blocks were stored in distilled water at room temperature for 1 day before the test procedure . a testing machine ( instron corp .
, norwood , ma , usa ) was placed in tensile mode and the crosshead speed was set to 10 mm / min .
the test blocks were loaded into the machine and force was applied along the long axis of the wires .
chicago , il , usa ) . the shapiro - wilks normality test and levene 's variance homogeneity test were applied to the data .
detachment force and deformation data was not normally distributed and the groups did not have homogenous variances .
kruskal - wallis tests were used to evaluate the statistical significance of the differences between group detachment and deformation values .
when a kruskal - wallis test indicated an overall difference between groups , mann - whitney u tests were used to examine the differences between individual groups .
pull - out data was found to be normally distributed and there was homogeneity of variance among the groups .
therefore , we used one - way anova and tukey 's post hoc test to evaluate differences between the pull - out force of test groups .
we calculated descriptive statistics , including the mean , standard deviation , minimum values , and maximum values for these measurements .
embedded specimens were secured in a jig attached to the base plate of an instron testing machine ( instron corp . , norwood , ma , usa ) .
a chisel - edge plunger was mounted in the movable crosshead of the testing machine and positioned so that the leading edge was aimed at the marked midpoint of the wire ( figure 1 ) .
the chisel - edge was carefully placed so that it would not contact any part of the specimen .
the crosshead speed was set to 1 mm / min and the maximum load necessary to debond the wire was recorded .
after failure occurred , the composite over the wire was gently removed with a tungsten carbide bur .
the wire was then positioned on graph paper and its deflection was assessed under an optical stereomicroscope ( sz 40 ; olympus , tokyo , japan ) at 20 magnification .
we evaluated fracture mode on the side where the initial bond failure occurred using an optical stereomicroscope ( sz-40 ) at 20 magnification .
remnant adhesive on the enamel surface was coded by one investigator ( a.b . ) who was blind to treatment group .
we scored the fracture sites according to the adhesive remnant index ( ari ) . in this system , fractures are ranked from 0 to 3 , based on the amount of adhesive remaining after bracket removal17,18 : 0 , no adhesive remaining on the enamel surface ; 1 , less than 50% adhesive remaining on tooth ; 2 , more than 50% adhesive remaining on tooth ; 3 , all adhesive remaining on tooth surface .
we used the method reported by bearn et al.14 to test pull - out force . using molds , we prepared 60 cylindrical acrylic blocks that were 25 mm in diameter and 10 mm high .
a 3 2 mm hole was drilled in the center of each block ( figure 2 ) .
the drilled holes approximated the dimensions of the composite used clinically for lingual retainers.15 twenty acrylic blocks were assigned to each wire group .
the hole in each block was filled with composite ( transbond xt ) and one of the free ends of a 10 cm section of test wire was embedded in the composite .
a second block with the same dimensions as the test block was used to ensure the accuracy of test wire placement , and to remove any excess composite .
the placement block was fitted with a stainless steel alignment jig and a 1 mm hole through the center .
prepared test blocks were stored in distilled water at room temperature for 1 day before the test procedure . a testing machine ( instron corp . , norwood , ma , usa ) was placed in tensile mode and the crosshead speed was set to 10 mm / min .
the test blocks were loaded into the machine and force was applied along the long axis of the wires .
chicago , il , usa ) . the shapiro - wilks normality test and levene 's variance homogeneity test
detachment force and deformation data was not normally distributed and the groups did not have homogenous variances .
kruskal - wallis tests were used to evaluate the statistical significance of the differences between group detachment and deformation values .
when a kruskal - wallis test indicated an overall difference between groups , mann - whitney u tests were used to examine the differences between individual groups .
pull - out data was found to be normally distributed and there was homogeneity of variance among the groups .
therefore , we used one - way anova and tukey 's post hoc test to evaluate differences between the pull - out force of test groups .
we calculated descriptive statistics , including the mean , standard deviation , minimum values , and maximum values for these measurements .
group ii ( median = 3.5 mm ) and group iii ( median = 3.0 mm ) were significantly more deformed than group i ( median = 0.5 mm ; p < 0.001 ) .
anova indicated a significant difference between the pull - out forces for the 3 groups ( p < 0.001 ) .
the pull - out force was significantly higher for group i ( 74.68 8.15 n ) than for group ii ( 37.92 19.43 n ) and group iii ( 35.03 10.12 n ) .
group i : there was less deformation in this group than in the other two groups .
vertically applied force resulted in detachment of the wire from the composite resin ( figure 3a ) .
group ii : as the vertical force increased , the long edge of the wire tended to fold over the short edge ( figure 3b ) .
there was more deformation in this group than in group i. the wire broke during 2 tests and no detachment of the wire from the composite was observed in those samples .
group iii : the retainer wire tended to slip through the composite , resulting in " v " shaped deformations ( figure 3c ) .
these samples were more deformed than those in group i. the wire broke at the deepest point of the " v " in one sample . in this sample , no detachment was seen between the composite and wire .
group i : there was less deformation in this group than in the other two groups .
vertically applied force resulted in detachment of the wire from the composite resin ( figure 3a ) .
group ii : as the vertical force increased , the long edge of the wire tended to fold over the short edge ( figure 3b ) .
there was more deformation in this group than in group i. the wire broke during 2 tests and no detachment of the wire from the composite was observed in those samples .
group iii : the retainer wire tended to slip through the composite , resulting in " v " shaped deformations ( figure 3c ) .
these samples were more deformed than those in group i. the wire broke at the deepest point of the " v " in one sample . in this sample , no detachment was seen between the composite and wire .
bonded retainers are commonly used in order to prevent anterior lower arch crowding.19 patients with fixed retention show consistently better alignment at 5 and 10 years post - treatment than those patients without fixed retention , even though the peer assessment rating scores of these patients were higher before treatment than the scores of those patients who were not fitted with fixed retention.19 moreover , fixed retainers have no harmful effects on oral hard and soft tissues.19 many composite and wire combinations are used for bonded lingual retainer fabrication . in this study , we tested two types of dead - soft wires and a commonly used five - stranded stainless steel wire .
bearn11 recommended 0.0215-inch multistranded wires for fabricating fswrs , based on a review of the literature .
aldrees et al.20 found greater bond strength values with coaxial wire ( pentaone ) compared to a solid chain retainer and dahl and zachrisson8 stated that the results of their pentaone tests were " particularly encouraging .
" we selected five - stranded stainless steel wire as a control because it has been used in various studies of fixed retainers and there is copious information about fswrs constructed using this wire.8,9,14,20,21 the other two test wires were dead - soft wires .
manufacturers claim that dead - soft wire is superior to five - stranded stainless steel wire for the construction of fswrs because it is easily adaptable and minimizes the inadvertent tooth movement that is associated with active force wires .
the dead - soft wires we selected included a rectangular eight - braided dead - soft wire and a stainless steel coaxial dead - soft wire .
the manufacturer of the eight - braided wire states that intra - arch splinting with this wire prevents the torque control problems that can occur when round braided wires are used .
they also state that the flattened wire increases patient comfort . the coaxial wire is recommended as an initial arch wire because of it applies light and gentle force .
zachrisson9 recommended that fswrs wire be 0.0195 inch or 0.0215 inch in diameter . in a later pa per , he indicated a preference for five - stranded wire because distortions were observed when thinner wires ( 0.0195-inch and 0.0175-inch ) were used.21 moreover , zachrisson21 reported that 0.0215-inch multistrand dead - softened or heat - treated wires were unsafe for the maintenance of anterior tooth corrections , including rotations .
retainer wires should be flexible enough to allow some degree of physiologic movement of retained teeth .
this helps to maintain periodontal health and reduces the concentration of stress within the composite .
the pentaone group ( group i ) , had significantly less deformation than the dead - soft wire groups ( groups ii and iii ) .
the smaller deformation of the pentaone may cause force to be transferred to the teeth , thereby aiding periodontal health .
moreover , the forces of mastication or cleaning the area beneath the wire with dental floss may cause repetitious deformation that results in the breakage of the retainer wire .
one of the main questions following an in vitro study of this type is how well the tested forces match those that a retainer system must withstand in the oral cavity under clinical conditions . in this study ,
vertically directed force was applied to the interdental wire . according to cooke and sherriff,12 when a vertical force is applied to a bonded wire , tension , shear , and torsion forces
, bond strength studies are difficult to compare and interpret with previous studies.10 this is because there is no standard protocol for the preparation and testing of materials and measurements of bond strength are highly variable .
this is especially true for studies of lingual retainers , as there are few bond strength studies and testing models differ between them.12,14,22 the findings of the current study should therefore be interpreted cautiously . pull - out tests were performed in order to evaluate the micromechanical adhesion between the composite and the wires .
bearn et al.14 claimed that larger diameter wires with greater surface area require greater force to pull the wire out from composite .
however , we found that although it was not the wire with the largest diameter , pentaone wire had the highest mean resistance to displacement from composite . on the other hand , there may have been a lack of micromechanical adhesion between the composite and respond wire , as the wire in group iii slipped through the composite during testing .
however , we observed a non - significant tendency of the detachment force to increase as the wire diameter decreases .
this finding is consistent with the findings of cooke and sherriff12 and may be due to the greater flexibility of thinner wires as compared to thicker wires . while this flexibility may appear to be advantageous , zachrisson9 reported that the wire fracture incidence decreases as wire diameter increases .
failures have been found both at the composite - wire interface12 and at the composite - tooth interface.15 loosening of the wire , wire fractures , and abrasive wear over the composite bulk were also reported.8 we also found wire fractures in both dead - soft wire groups .
reynolds23 suggested that bonded orthodontic attachments should be able to support loads of 60 - 80 kg / cm , if they are to withstand both the normal occlusal forces and the forces generated by orthodontic appliances.10 these data are not applicable to bonded retainer wires.12 there is little information in the literature regarding the minimum clinically accepted bond strength for bonded retainer wires.12 we expressed force in newton ( unit of force ) , rather than in pascal ( unit of pressure ) , because the use of pascal implies that the applied force was homogenously distributed across the surface area of bonds.12 during the testing procedure , tension , shear , and torsion forces may occur simultaneously.12 according to cooke and sherriff,12 the age of the enamel , lingual morphology , and size of the tooth affect the forces exerted at the bonding interfaces .
the present study may have been limited by the use of human lower incisor teeth that differed from one another in morphology and donor age .
we chose to include teeth with various morphologies and donor ages in order to better mimic in vivo situations .
the ultimate success of a bonded retainer is determined by the size and quality of the teeth and the occlusal load on the retainer.10 large tooth crowns have large bonding areas , enabling the load to spread over a wide area of enamel.10 although the size and morphology of the teeth used in this study were different from one another , the composite bulk placed over the teeth and the wires tested were standardized with commercially available molders .
moreover , the favorable working environment during bonding should be taken into consideration when findings of in vitro studies are interpreted .
lie sam foek et al.16 stated that as the working conditions for in vitro studies are easier to manipulate than those experienced in vivo , any differences observed in in vitro studies are likely to be exacerbated in vivo .
a large range of composites and wires are available for lingual retainer fabrication . in this study ,
five stranded coaxial wires exhibited less deformation and higher micro - mechanical resistance than dead - soft wire .
use of dead - soft wires in fswrs may lead to problems in maintaining orthodontic treatment results . to evaluate the success rates of these wires , randomized controlled in vivo studies should be performed .
no significant differences were found between the three groups ( 0.0215-inch five - stranded wire , 0.016 0.022-inch dead - soft eight - braided wire , and 0.0195-inch dead - soft coaxial wire ) in detachment force or fracture mode . both dead wire groups exhibited greater deformation was than the 0.0215-inch five - stranded wire group . the 0.0215-inch five stranded wire group had greater mean pull - out force than either dead - soft wire group .
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### Summary:
: objectivewe evaluated the detachment force , amount of deformation , fracture mode , and pull - out force of 3 different wires used for bonded lingual retainer fabrication.methodswe tested 0.0215-inch five - stranded wire ( pentaone , masel ; group i ) , 0.016 0.022-inch dead - soft eight - braided wire ( bond - a - braid , reliance ;
group ii ) , and 0.0195-inch dead - soft coaxial wire ( respond , ormco ; group iii ) . to test detachment force , deformation , and fracture mode
, we embedded 94 lower incisor teeth in acrylic blocks in pairs .
retainer wires were bonded to the teeth and vertically directed force was applied to the wire . to test pull - out force ,
wires were embedded in composite that was placed in a hole at the center of an acrylic block .
tensile force was applied along the long axis of the wire.resultsdetachment force and mode of fracture were not different between groups .
deformation was significantly higher in groups ii and iii than in group i ( p < 0.001 ) . mean pull - out force was significantly higher for group i compared to groups ii and iii ( p < 0.001).conclusionsdetachment force and fracture mode were similar for all wires , but greater deformations were seen in dead - soft wires .
wire pull - out force was significantly higher for five - stranded coaxial wire than for the other wires tested .
five - stranded coaxial wires are suggested for use in bonded lingual retainers .
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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:
: pressure ulcers are localized injuries of the skin and underlying tissue due to capillary
circulation disturbance caused by prolonged pressure1 , and are usually located over bony prominences .
pressure ulcers
should be managed because they are difficult to treat once they have developed , and the
treatment can be expensive due to the increased length of hospitalization and pressure
ulcers can lead to complications , such as osteomyelitis and sepsis , in addition to pain .
extrinsic factors include direct pressure , pressure duration , shear , friction , temperature ,
and moisture ; and intrinsic factors include motor deficits , sensory deficits , muscular
atrophy , health and nutritional status , decreased tissue perfusion , and aging . those who are susceptible to pressure ulcers owing to intrinsic factors include individuals
with stroke , brain injury , spinal cord injury , circulatory disturbance , elimination
disorder , poor nutrition , and geriatric disease . based on studies of pressure ulcer
incidences among adults , song et al . and park et al .
reported that the pressure ulcer
incidence in residents at long - term care facilities in south korea was 9.8% and 5.2%2 , 3 ,
respectively . in older adults ,
the epidermis is thinning because of the loss of subcutaneous
fat that distributes the weight of the body , the skin is susceptible to dryness due to
decreased sweat and sebaceous gland activities , and the skin is susceptible to damage : and
recovery from injury is prolonged because of gradually decreasing replacement and
proliferation of epidermal cells4 .
furthermore , because older adults have two or more chronic degenerative diseases on average ,
and the majority of older adults have limited mobility due to cerebrovascular and
musculoskeletal diseases , hence , they are vulnerable to pressure ulcers , which require
prevention and management .
cushions have been designed for pressure ulcer prevention to relieve interface pressure in
the sitting position .
although existing cushions are mainly rubber products that are filled
with air , products using special materials , such as gel and foam , and those with a
combination of gel - air , gel - foam , or foam - air , have become commercially available in recent
years5 .
moreover , the long - term care
insurance scheme in south korea entitles beneficiaries to certain assistive products or
partially compensates and beneficiaries for fees paid to medical device , and cushions for
preventing pressure ulcers are also covered by this insurance scheme . with regard to the use
of assistive technology by rehabilitation workers at nursing facilities ,
the proportion of
those who use cushions for preventing pressure ulcers was reported to be 68.2% , and posture
and sitting assistive equipment have been identified as essential among assistive technology
devices that will be needed in the future6 .
continuous and proper positioning ( or continuously adjusting
individual posture ) to promote blood circulation in an area where pressure is concentrated ,
minimizing pressure in a localized area , such as the buttocks , and distributing pressure
more evenly throughout a contact surface are important interventions to prevent pressure
ulcers .
proper sitting posture and application of devices designed to maintain appropriate
sitting posture are also important as assistive technological approaches to distributing
pressure across areas where pressure is concentrated7 .
the cushions used for preventing pressure ulcers reduce the peak
sitting pressure over bony prominences and distribute pressure equally to the skin over a
large contact area ; and shear force that inhibits circulation can be also reduced by using
appropriately made cushions . in south korea , a long - term care insurance scheme for the elderly covers 20 types of
cushion for pressure ulcer prevention , among which , air cushion type is the most common
type . in the case of air cushions ,
. the dynamic stability of products using gel and foam is
excellent , but the pressure gradient , which is slightly high , is a disadvantage8 .
most previous studies have enrolled healthy adults and persons with disability , but studies
of older adults are scarce .
furthermore , because no study has investigated the effects of honeycomb cushions covered by
south korea s long - term care insurance on sitting pressure redistribution , there is limited
information for recommending an appropriate cushion types .
the purpose of this study was to
analyze the change in the sitting pressure redistribution of three different types of
pressure ulcer prevention cushions , honeycomb , air , and memory foam cushions , used byseniors
older than 60 years old and adults in their 20s .
the purpose of the present study was explained to all of subjects , and their
informed consent was obtained before they participated in the present study .
the
participants consisted of 49 males in their 20s , 62 females in their 20s , 50 elderly males
60 years or older , and 50 elderly females 60 years or older who had no neurological disease ,
were able to sit by themselves , and had sufficient visual acuity , hearing , and cognitive
function to answer general questions ( table
1table 1.general information of subjectselderly men ( n=50)elderly women ( n=50)young men ( n=49)young women ( n=62)age * ( years)78.2 5.8**74.6 4.919.7 1.419.6 1.1weight * ( kg)64.3 8.657.9 10.069.1 10.557.1 7.8height * ( cm)159.8 21.3150.7 4.8173.8 5.6158.9 4.5seat to footplate * ( cm)40.1 2.236.0 1.644.0 3.139.0
4.238.4 3.3total contact area * ( cm)661.7 197.7728.1 182.1829.5 162.9813.0 135.2hip ( )93.4 7.692.4 8.198.5 3.995.1 6.2knee ( )97.0
5.997.0 6.091.8 3.790.7 4.9ankle ( )91.7 5.193.0 4.489.9 3.491.2 4.3*p<0.05 , * * mean sd ) .
the conformat system was used for pressure mapping , and v.7.2 research software was used
for data acquisition ( both conformat and v7.2 were manufactured by tecksan inc . , ma , usa ) .
the horizontal axis has 32 sensors
numbered 1 to 32 , and the vertical axis has 32 sensors labeled a to ff ( 32 32 ) .
the
sitting pressure was measured in mmhg , and at a sampling rate of 1 hz . the conformat was
placed on each cushion during data acquisition , and one occupational therapist and two
university students collected the pressure data . after the participants height and weight
had been measured , the participants adjusted their posture in a sitting position using a
footstool .
while sitting on the cushions , participants were instructed to keep their chins
tucked in , spines straight , pelvis neutrally positioned , and place their hands placed on
their thighs .
they were also instructed to flex their hips , knees , and ankles to
approximately 90 , and to put their feet flat on the floor . the sitting position and each
joint angle
height , weight , foot height , and seat height ( seat to footplate ) , width ( seat width ) ,
length ( seat depth ) , total contact area ( total contact area ) , hip joint , knee angle , and
ankle joint were measured in the sitting position .
the posture was readjusted within joint
range of motion ( rom ) of 8595 , knee
ankle rom of 80100 , and hip joint rom of 80110
based on the angles from the no - cushion state .
when each cushion was changed , the subjects
posture was readjusted to avoid an angular difference of more than 10 in each rom .
after
the subjects general information has been recorded , sitting pressure - related variables were
measured .
the subjects were instructed to maintain their sitting state for 5 min , and the
researchers saved the data for 90 s after the subjects sitting posture had stabilized .
the
cushions were wrapped in black cloth after the measurements , and the subjects were
instructed to sit on the wrapped cushions in the following order : honeycomb , air , and memory
foam cushions .
each cushion was referred to as sitting states 1 , 2 , 3 , and 4 .
thus the
subjects were informed of only the changes of the cushions and were provided with no
information regarding the specific cushions .
after all measurements has been conducted , the
cushion preference was surveyed by instructing the subjects to select the most preferred
sitting state . after all measurements had been recorded ,
the pressure map was divided into four quadrants
( left hip , left thigh , right hip , and right thigh ) on the screen .
mergl s method was adapted
for quadrant division and analysis of pressure on the cushion9 .
a set of 60 frames were used for data analysis , excluding the data
of 10 s each at the beginning and end from the obtained data to exclude environmental
factors which might have affected the measurements .
after the sitting pressures had been measured , the mean and peak pressures in four
quadrants ( left hip / left thigh / right hip / right thigh ) were calculated .
the peak pressure was
determined as the mean of the maximum pressures measured by the four sensors in each
quadrant during sitting .
the mean pressure was the mean of the pressures measured by each
sensor on each quadrant .
the mean pressure ratio was calculated as a ratio = a mean/(a mean +
b mean + c mean + d mean ) 100 .
the ratio indicate the mean pressure ratio , and the mean can
be the mean pressure on the right or left hip area or the right or left thigh area , and b
mean , c mean , and d mean are the mean pressures of the remaining areas , respectively . the statistical package for the social sciences 20.0 was used for statistical analyses .
one - way analysis of variance was condected to determine the significance of differences
between groups , and tukey s post - hoc test was performed ( p<0.05 ) .
the males in their 20s showed significantly high pressures in all sitting positions when
the mean total pressure values were compared ( table
2table 2.comparisons of the total pressure mean among groups ( n=211 , mmhg)without cushionhoneycomb cushionair cushionmemory foam cushionmean sdtukey hsdmean sdtukey hsdmean sdtukey hsdmean sdtukey hsdtpma47.5 7.0c > a , b , d37.6 4.5c > a , b , d48.2 14.6c > a , b , d30.1 3.0c > a , b , db47.8 6.635.2 5.945.5 5.427.5 3.1c56.3 12.942.3 9.255.0 11.034.9 8.1d48.6 12.036.6 10.747.4 10.029.6 7.2tpm : total pressure mean , a : male ( 60 years and older ) , b : female ( 60 years and
older ) , c : male in their 20s , d : female in their 20s ) .
tpm : total pressure mean , a : male ( 60 years and older ) , b : female ( 60 years and
older ) , c : male in their 20s , d : female in their 20s significant differences were found in the right hip pressure mean , right hip pressure peak ,
left hip pressure peak , right hip pressure ratio , and left hip pressure ratio while sitting
without a cushion ( p<0.05 ) ( table
3table 3.comparisons of hip pressure variables among groups ( n=211 , mmhg)without cushionhoneycomb cushionair cushionmemory foam cushionmean sdtukey hsdmean sdtukey hsdmean sdtukey hsdmean sdtukey hsdrh pma71.0 13.8c > a , b , dc , a > b , d50.7 13.3c , a > d , bc > a , d > b59.1 10.5 - 42.4 8.7c > a , da > d , bb65.7 10.943.0 9.250.5 10.036.7 7.2c78.3 22.456.0 15.361.6 15.149.2 13.4d64.8 16.244.4
19.150.0 10.439.3 11.7lh pma83.0 73.7 - 45.4 11.9c > a , b , d47.9 11.1 - 42.0 9.2c > a , da > d , bb65.2 13.241.9 17.548.9 11.335.5 8.2c84.9 21.457.8 18.462.6 15.054.1 15.7d63.7 13.843.4 13.650.9 11.640.1 11.5rh ppa276.0 72.5c , b , a > d122.0 67.2c , a > ba , b > d110.1 49.5 - 143.7 64.1c , a > b , dc > a , b , db280.1 79.6100.2 37.4146.3 40.5126.8 55.9c304.7 88.7139.3 55.9150.8 49.5170.3 76.1d229.9 84.694.2 44.5114.3 35.7115.9 64.7lh ppa325.8 80.2c > a , b a > d100.6 43.4c > a , b , d97.5 35.2c , d , a > bc > d , a , b144.3 61.4c > a , d , bb269.0 77.186.6 35.8104.3 43.4119.4 69.0c325.8 80.2145.6 60.3142.8 47.6192.8 83.8d234.2 87.796.3 39.3118.0 44.2121.7 56.0rh pra36.4
6.3a > b , c , da , b , c > d35.5 6.5c , a , d > ba > d , b28.0 9.0 - 35.2 5.9-b34.6 4.930.7 5.527.7 3.833.3 4.7c34.7 4.733.1 5.928.0 3.435.1 3.8d33.6 3.930.0 5.826.5 3.334.1 4.9lh pra38.8 8.5a , c > b , d30.1 6.6a > c , b , d26.9 11.5 - 34.7 6.0c > a , d , bb34.1 4.929.2 6.626.7 3.732.2 5.6c37.7 4.133.9 6.728.5 3.438.5 4.4d33.2 4.729.9 6.726.9 3.333.9
5.3r / lhpm : right / left hip pressure mean , r / lhpp : right / left hip pressure peak , r / lhpr :
right / left hip pressure mean ratio , a : male ( 60 years and older ) , b : female ( 60 years
and older ) , c : males in their 20s , d : females in their 20s ) .
significant differences were found in the right hip pressure mean , left hip
pressure mean , right hip pressure peak , left hip pressure peak , right hip pressure ratio ,
and left hip pressure ratio of age groups on the honeycomb cushion ( p<0.05 ) .
significant
differences were found in the left hip pressure peak of age subjects on the air cushion
( p<0.05 ) .
significant differences were also found in the right hip pressure mean , left
hip pressure mean , right hip pressure peak , left hip pressure peak , and left hip pressure
ratio between subjects on the memory foam cushion ( p<0.05 ) .
r / lhpm : right / left hip pressure mean , r / lhpp : right / left hip pressure peak , r / lhpr :
right / left hip pressure mean ratio , a : male ( 60 years and older ) , b : female ( 60 years
and older ) , c : males in their 20s , d : females in their 20s significant differences were found in the left thigh pressure mean , left thigh pressure
peak , right thigh pressure ratio , and left thigh pressure ratio without cushion between the
age groups ( p<0.05 ) ( table 4table 4.comparisons of thigh pressure variables among groups ( n=211 , mmhg)without cushion ( n=211)honeycomb cushion ( n=211)air cushion ( n=211)memory foam cushion ( n=211)mean sdtukey hsdmean sdtukey hsdmean sdtukey hsdmean sdtukey hsdrt pma27.9 29.5 - 27.3 6.8 - 41.8 5.8c , d > a , bc > d , a , b18.1 4.1-b29.8 9.128.2 6.240.1 5.119.1 4.3c32.2 13.527.6 8.047.3 12.318.1 5.4d32.9 13.929.8 11.444.0 12.719.7 6.5lt pma22.7 7.1d , b , c >
a26.9 6.3 - 43.9 5.9c , d > a , bc > d , a , b17.9 4.0-b30.6 11.327.5 6.342.3 6.118.6 3.4c29.9 8.027.8 10.248.4 10.618.1 3.8d32.9 14.228.9
18.0d > b , a , cd , b , a > c99.0 43.6c > d , a , bc , d > a , b48.9 28.0-b72.3 42.668.0 21.6100.7 34.062.6 51.7c77.7 47.157.5 23.1114.1 30.349.7 41.6d81.6 53.764.4 27.4117.0 49.860.2 59.0lt ppa48.0 28.7c , d , b > ac , d > b , a56.9 17.7 - 99.2
28.3c > d , a , bc , d > a , b39.7 20.9-b61.3 20.757.0 18.694.2 23.243.3 19.2c74.8 50.859.4 28.7116.7 41.246.6 29.6d72.7 39.365.9 37.0112.9 58.049.1 29.4rt pra13.2
7.2d > b , c , ad , b , c > a18.3 4.6d , b , a > cb > a , c22.0 4.8 - 15.2 3.8b , d > ad , a > cb15.5 3.920.2 4.022.2 2.817.5 3.8c14.2 4.516.4 3.621.4 3.013.1 3.1d16.6 4.020.3 4.523.1 3.216.6 3.9lt pra11.6 3.4d , b > c , a18.1 4.3d , b , a > cd , b > a , c23.1 5.0 - 14.9 3.2b , d > ad , a > cb15.8 4.719.8 4.623.4 3.017.0 3.2c13.4 2.516.5 4.122.1 2.713.3 2.9d16.6 3.719.8 4.123.5
2.916.3 3.2r / ltpm : right / left thigh pressure mean , r / ltpp : right / left thigh pressure peak ,
r / ltpr : right / left thigh pressure mean ratio , a : male ( 60 years and older ) , b : female
( 60 years and older ) , c : males in their 20s , d : females in their 20s ) .
significant differences were found in the right thigh pressure peak , right
thigh pressure ratio , and left thigh pressure ratio of age groups sitting on the honeycomb
cushion .
significant differences were found in the right thigh pressure mean , left thigh
pressure mean , right thigh pressure peak , and left thigh pressure peak of age groups sitting
on the air cushion ( p<0.05 ) .
significant difference was found in the right and left thigh
pressure ratios between subjects on the memory foam cushion ( p<0.05 ) .
r / ltpm : right / left thigh pressure mean , r / ltpp : right / left thigh pressure peak ,
r / ltpr : right / left thigh pressure mean ratio , a : male ( 60 years and older ) , b : female
( 60 years and older ) , c : males in their 20s , d : females in their 20s the most preferred cushion was the honeycomb cushion with the highest preference rate of
42.4% , followed by the air cushion , 29.0% , the memory foam cushion , 28.1% , and without
cushion , 0.5% .
the second most preferred cushion was the memory foam cushion , followed by
the honeycomb , air , and without cushion with rate of 41.2% , 35.1% , 20.9% , and 2.8% ,
respectively .
the third most preferred cushion was the air cushion , followed by the memory
foam , honeycomb , and without cushion with preference rates of 40.3% , 28.0% , 22.7% , and 9.0% ,
respectively .
the fourth most preferred cushion was without a cushion , air , and memory foam
cushions with preference rates of 87.6% , 10.0% and 2.4% , respectively ( table 5table 5.cushion preference of entire subjects ( n=211 , score)without cushionhoneycomb cushionair cushionmemory foam cushion1st0.542.429.028.12nd2.835.120.941.23rd9.022.740.328.04th87.60.010.02.4 ) . the male subjects 60 years or older selected honeycomb ( 55.1% ) , memory foam
( 48.9% ) , air ( 46.9% ) , and without cushion ( 81.6% ) as the most , second , third , and fourth
most preferred cushions , respectively .
the female subjects 60 years or older selected
honeycomb ( 50.0% ) , memory foam ( 43.5% ) , air ( 48.4% ) , and without cushion ( 75.8% ) as the
most , second , third , and fourth most preferred cushion , respectively ( table 6table 6.cushion preference based on age and gender ( score)males in their 20s ( n=49)females in their 20s ( n=62)males 60 years and older ( n=50)females 60 years and older ( n=50)fhamfhamfhamfham1st2.030.042.026.00.034.040.026.00.055.122.422.40.050.014.535.52nd0.034.026.040.038.026.034.00.06.130.614.348.91.737.117.743.53rd0.036.030.02.028.034.038.00.012.214.346.926.521.014.548.416.14th98.00.02.034.00.00.02.098.081.60.016.32.075.80.019.44.8f : firm surface , h : honeycomb cushion , a : air cushion , m : memory foam cushion ) .
the male subjects in their 20s or older selected air ( 42.0% ) , memory foam
( 40.0% ) , honeycomb ( 36.0% ) , and without cushion as the most , second , third and fourth most
preferred cushions , respectively .
the female subjects in their 20s selected air ( 40.0% ) ,
honeycomb ( 38.0% ) , memory foam ( 38.0% ) , and without cushion as the most , second , third , and
fourth most preferred cushion , respectively .
f : firm surface , h : honeycomb cushion , a : air cushion , m : memory foam cushion
the present study analyzed changes in sitting pressure redistribution after adults 60 years
or older and young adults in their 20s sat on pressure ulcer prevention cushions , such as
honeycomb , air , and memory foam cushions along with no cushion .
first , this study compared changes in the sitting pressures of the male and female subjects
60 years or older , and male and female subjects in their 20s while sitting on each cushion .
a analysis of covariance ( ancova )
was performed to eliminate the effects of common variables
that are thought to affect sitting pressures , in addition to age and gender . in the ancova ,
height , weight , and contact surface area
were treated as covariates , and the mean total
pressure , the mean hip pressure , the peak hip pressure , and hip pressure ratio were compared
between groups divided by gender and age .
the results show that gender and age had
significant effects on the mean total pressure , mean hip pressure , and peak hip pressure .
weight affected on the mean total pressure and right hip pressure ratio , whereas height had
no effect on any variables .
the total contact surface area had significant effects on the
mean right hip pressure , peak right hip pressure , and right hip pressure ratio .
stinson
investigated the correlations between average pressure , maximum pressure , gender , and body
mass index ( bmi ) in 63 able - bodied subjects .
mean pressure , and maximum pressure were found
to be independent of gender , and no significant correlation was found between height or
weight and mean pressure , but a significant correlation was found between bmi and mean
pressure ( r=0.381 , p<0.01)10 . in a
study by cho , weight and bmi
were found to affect the mean pressure , total contact area , and
high - pressure area ratio ( p<0.05)11 .
according to reports ,
height is less correlated with pressure ; however , weight and bmi are
variables that significantly affect sitting pressure , and age and gender are also thought to
significantly affect sitting pressure . in future studies , it will be necessary to classify
weight as a variable and perform analysis by using bmi .
the group of males in their 20s had the highest hip pressure on all cushions excluding air
cushion , followed by females 60 years or older , males 60 years or older , and females in
their 20s ( p<0.05 ) .
the males in their 20s showed similar results to those in males
60 years or older , but a significant difference was found between the females in their 20s
and those 60 years or older .
the males 60 years or older showed a similar tendency to
females 60 years or older and those in their 20s .
the peak right hip pressure was the
highest for the males in their 20s , followed by females 60 years or older , males 60 years or
older , and females in their 20s , and was significantly higher in the other groups than that
of females in their 20s ( p<0.05 ) .
the left hip pressure was the highest for the males in
their 20s , followed by men 60 years or older , women 60 years or older , and women in their
20s .
significant differences were found between males in their 20s and all of the other
groups , and a significant difference was found between males 60 years or older and females
in their 20s , but no significant difference was found between females 60 years or older and
females in their 20s .
the mean pressure ratio was the highest for the males men aged
60 years or older , followed by males in their 20s , females 60 years or older , and females in
their 20s , and was found between males in their 20s and all of the other groups ( p<0.05 ) .
the mean hip pressure , peak hip pressure , and mean hip pressure ratio were higher for males ,
whereas the mean thigh pressure and mean thigh pressure ratio were higher for females .
this
is possibly because males generally weigh higher than females and thus , pressure applied by
body weight is also high .
this may be explained by differences in body composition pattern ,
such as age , body fat , and muscle mass .
the cushion preference was compared between males and females in their 20s , and the males
and females 60 years or older .
the most , second , third , and fourth preferred cushions were
honeycomb , memory foam , air , and without cushion , respectively .
when the correlations
between cushion preference and subjective sensibility evaluation regarding pressure
distribution and seats were investigated , statistically strong correlations were found12 . in this regard , the air cushion that had
higher mean pressure and peak thigh pressure compared with the other cushions was selected
as the third most preferred cushion
the reason why the honeycomb cushion was selected as
the most preferred cushion despite the fact that the memory foam cushion had the lowest mean
pressure seems to be because the honeycomb cushion had a relatively low mean pressure and
exhibited to the lowest peak pressure . by age group , the men and women in their 20s selected
the honeycomb cushion as the most preferred cushion , whereas the adults 60 years or older
selected the air cushion as the most preferred cushion . in addition , the men and women in
their 20s had a higher preference for without cushion than older adults , and indicated a
clearer preference among the cushions than the older adults . although similarities were
found in the cushion pressure distribution tendency between the young and older adults .
the
older adults were interpreted as preferring cushions with low peak pressures in a localized
area , compared to young adults . because interpreting cushion preference by using only
pressure has limitations , further studies regarding reasons for cushion preference are
necessary in the future .
|
### Summary:
: [ purpose ] the purpose of this study was to analyze the change in interface pressure
redistribution of three different types of cushions sat on by individuals in their 20s and
older than 60 years old .
[ subjects and methods ] one hundred and eleven college students
and 100 persons than 60 years old were recruited .
sitting pressure redistribution was
measured while subjects sat without cushions or on honeycomb , air , and memory foam
cushions in that order .
subsequently , the cushion preference was measured . after obtaining
all measurements , the mean total pressure and each quadrant s mean and peak pressure were
analyzed .
[ results ] the mean hip and the peak pressures were low in the group of females
aged 60 years or older , and the highest in the group of males in their 20s .
the hip
pressure ratio was low in the groups of females in their 20s and 60 years or older ,
whereas the thigh pressure ratio was high in the same groups .
the analysis of cushion
preference showed that the groups of males ( 42.0% ) and females ( 40.0% ) in their 20s mostly
preferred air cushion .
the men ( 55.1% ) and women ( 50.0% ) aged 20 years or older selected
honeycomb and air cushions as the first and third preferred cushions with a high response
rate .
[ conclusion ] our results indicate that gender and age should be considered when
recommending appropriate pressure redistribution cushions .
|
<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 rationale for the posterior palatal seal lies in completing peripheral seal along the posterior denture border .
it provides an effective barrier against the ingress of air or fluid during the functional movement of the soft palate or slight movement of denture during function.1 the available literature states that addition of posterior palatal seal markedly increases the retention of the denture . to test the retention of maxillary complete denture base both
caudally directed intra - oral and cranially directed extra - oral forces have been applied .
the following study was carried out for comparative evaluation of retention of complete maxillary denture bases with different posterior palatal seals .
the study was carried out in the department of prosthodontics crown and bridge of pmnm dental college and hospital , bagalkot , ethical committee reference number 2847 .
ten male patients with an average age of 60 years were selected for the study .
subjects who had been edentulous for varying periods of 6 months to 2 years were selected .
the subjects were without any systemic diseases and with good neuromuscular control for better cooperation .
the ridges were well - healed , round , smooth , and oral mucosa covering the ridges was firmly attached with average resiliency and thickness .
the primary impression was made with an impression compound ( y - dent , delhi , india ) and was border - molded to get the acceptable extension and border thickness ( figure 1 ) .
the uniform thickness of a 2 mm spacer was adapted over the cast and keeping it short by 2 mm all over the periphery and a tray was prepared with self - activated acrylic resin ( figure 2 ) .
a secondary impression was made with free - flowing zinc oxide eugenol paste ( dpi impression paste , dpi , mumbai , india ) with light pressure and border - molding ( figure 3 ) .
the posterior palatal seal area was marked by first locating the pterygomaxillary ( hamular ) notch with the t burnisher or moons probe and then marking the line 1.5 mm distal to hamular notches .
the posterior palatal seal area marking over the cast was slightly scraped with a sharp instrument to represent the posterior palatal seal area of subsequent casts .
dental stone ( dutt stone , 30:100 ) was poured into the molds over a vibrator to avoid the entrapment of air bubbles .
the casts were recovered after 1 hour and marked a , b , and c respectively ( figure 4 ) . on cast
a a v - shaped groove 1 to 1.5 mm deep and 1.5 mm at its base was carved 2 mm anterior to vibrating line - junction of hard and soft palate . on cast
b a groove of 1 to 1.5 mm deep and 1.5 mm wide was carved 1 mm anterior to the vibrating line , passing through the hamular notch .
an additional groove 1 mm deep and 1 mm wide at its base was carved just distal to anterior limit of posterior palatal seal area . on cast c a butterfly shaped design was carved as suggested by hardy and kapur1 with a groove of 1 mm deep and 1.5 mm wide at the base in the center of the posterior palatal seal area , passing through the hamular notch .
a , b , and c and prepared respectively.17 the four molds thus obtained were closed and packed with heat - cured acrylic resin ( dpi ) with a 1:3 volume to prepare the permanent denture base , the molds thus packed , with heat - cured acrylic resin , were trial closed twice , and excess flash was removed .
the polymerization was carried out under similar conditions for all flasks at a temperature of 74c for 2 hours and at 100c for 1 hour.7 after polymerization the flasks were allowed to bench cool for 1 hour .
the four denture bases were checked for accuracy and that they were identical in all respects , except for their posterior palatal seal .
the loop ( hook ) made of 19 gauge stainless steel wire was attached to the denture base with self - cured acrylic resin , exactly in the midline , the loops were placed 1 cm inwards to the anterior portion from the distal border of the denture base ( figure 6 ) . the denture bases
mo , and used to develop the posterior palatal seal with functional method by tracing the seal with low fusing compound ( figure 7 )
. thus the five denture bases were marked as : m without posterior palatal seal ; a
double bead posterior palatal seal ( scraped type ) ; c butterfly shaped posterior palatal seal ( scraped type ) ; mo posterior palatal seal with low fusing compound with functional method .
the five denture bases with different types of posterior palatal seals were subjected for evaluation of retention using a specialized t device in which a tipping force was developed extra - orally in a caudal direction to evaluate the retentive values of the denture bases ( figure 8) .
in this study the force required to dislodge the maxillary denture bases was measured in grams .
these forces were considered as the retentive values . for each of the ten patients , three readings
therefore , in the study of ten patients a total of 150 readings were taken .
analysis of variance ( anova ) test was applied to compare the retention valves and newman - keuls student test for the simultaneous comparison . a mean
value was calculated for statistical analysis from each set of the three readings for each of the five denture bases .
the mean retentive values are shown in table 1 and graphically represented in figure 9 .
the retention values of significance between a and c , mo , c and mo ( p<0.5 ) ; and those highly significant between m and c , mo , b and mo ( p<0.01 ) can be seen .
the highly significant values are recorded with the denture base with butterfly shaped posterior palatal seal and functionally developed posterior palatal seal with low fusing compound .
comparisons of retention between three different posterior palatal seals obtained with arbitrary scraping method are shown in tables 4 and 5 .
c ( p<0.01 ) and b c ( p<0.05 ) ; and the differences between a b were found to be insignificant . when comparing the scraped type of posterior palatal seals with each other , the butterfly shaped posterior palatal seal and double beaded posterior palatal seal showed highly significant retentive values .
percentage increase in retention values of denture bases with different types of posterior palatal seals when compared to
the results showed that there is a consistent increase in retention of denture bases with different types of posterior palatal seals when compared to denture bases without posterior palatal seals .
the posterior palatal seal obtained by functional method provided greater retention value than those obtained with the scraping method when compared with each other and with a denture base without a posterior palatal seal .
the fact that posterior palatal seal plays an important role in enhancing the retention and stability of complete maxillary denture is well recognized.2,3 by providing intimate contact with the posterior palatal tissue , it reduces the gagging reflex .
further , it partly compensates for the palatal discrepancy occurring as a result of curing shrinkage of acrylic resins.4 the available literature shows that the displacement of the soft tissue is a critical factor in developing the posterior palatal seal.5 skinner and chung3 demonstrated the importance of posterior palatal seal experimentally .
several methods are used to develop the posterior palatal seal,1,613 namely in the arbitrary method , by scraping the cast at the distal border of the denture depending on the compressibility of the tissue .
hamrick12 stated that an upward extra - oral force to test the retention of maxillary denture was closer to a functional situation .
avant15 stated that in extra - oral caudally directed forces , some patients feel pain and discomfort in the anterior ridge .
t shaped device which could be used to apply tipping forces , where the anterior ridge acts as fulcrum .
antolino16 showed the application of forces to dislodge the denture at the posterior border of denture was closer to the dislodging pattern of denture during function .
the most obvious finding in the present study was that irrespective of the type of posterior palatal seal employed there occurred a consistent and substantial increase in the retention of denture base .
since the denture bases are similar to each other except for the posterior palatal seal .
retention was checked at constant leverage action , the salivary flow and the degree of mouth opening was maintained constant throughout the study .
the variability in the retention value of the test bases could only be attributed to the varied situation of the posterior palatal seal.14 comparison of retention between different types of posterior palatal seals shows significant to highly significant retentive values when compared to a denture base without a posterior palatal seal .
the findings of the present study were found to be at par with past studies made by other investigators .
mean retentive value of m was 577.3 grams against values of a , b , c , and
mo bases , which were 679.6 , 790.4 , 940.1 , and 1,200 grams respectively . the percentage increase in retention of denture base when compared to denture base m showed an increased retentive value of 108% , 63% , 37% , and 18% with the denture bases mo , c , b , and a , respectively .
within the limit of this in vivo study , it was concluded that the incorporation of posterior palatal seal is essential for obtaining optimum retention of maxillary complete denture .
all types of posterior palatal seals evaluated provided a consistent and substantial increase in the retention of denture base .
the retention of denture base varied with the type of posterior palatal seal . among the scraped type of posterior palatal seal evaluated , the butterfly shaped posterior
the functional type of posterior palatal seal developed by the addition of low fusing compound provided higher retentive values when compared to the scraped type of posterior palatal seal .
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### Summary:
: aimto evaluate retention of complete denture base with different types of posterior palatal seals.material and methodsten male patients between the age group of 50 years to 60 years were selected for the study . after the primary and secondary impressions were taken , five casts were made including a cast without posterior palatal seal , a cast with single bead posterior palatal seal , a cast with double bead posterior palatal seal , a cast with butterfly shaped posterior palatal seal , and a cast with posterior palatal seal with low fusing compound by functional method.resultsit was observed that retention increased up to 108% in the posterior palatal seal with low fusing compound with functional method and the posterior palatal seal that was obtained by using functional method provided greater retention than a denture base without posterior palatal seal.conclusionit was concluded that the incorporation of a posterior palatal seal is important for obtaining optimum retention of the maxillary complete 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:
: the burden of tuberculosis ( tb ) caused by drug - resistant mycobacterium tuberculosis is increasing . as a result ,
the standard treatment directly observed therapy , short course ( dots ) , composed of 2 months of a four - drug regimen ( isoniazid [ inh ] , rifampicin [ rif ] , pyrazinamide [ pza ] , and ethambutol [ emb ] ) followed by 4 months of treatment with rif and inh is failing in many settings .
while any degree of drug resistance might worsen the prognosis of a tb patient [ 1 , 2 ] , there are two definitions of m. tuberculosis drug resistance that are particularly relevant in the clinic .
the first refers to strains resistant to both inh and rif and is termed multidrug - resistant ( mdr ) tb .
treatment of patients with mdr - tb takes up to 2 years , and currently relies on fluoroquinolones ( fq ) and injectable aminoglycosides ( ag ) to compensate for the loss of two of the most potent drugs .
the acquisition of resistance to these classes of antibiotics defines extensively drug - resistant ( xdr ) tb .
xdr - tb requires even longer treatment with drugs that are much more costly and show limited efficacy and increased side effects .
the global genetic diversity of drug - resistant m. tuberculosis [ 410 ] indicates that drug resistance evolved on multiple occasions in geographical hotspots characterized by a high incidence of tb and inappropriate drug treatment .
the latter is mostly driven by a lack of resources resulting in two important failures : an inability to detect drug resistance and a systemic failure to deploy effective treatments [ 1113 ] .
the ongoing evolution of m. tuberculosis in these settings [ 14 , 15 ] , provides an excellent opportunity to explore the genetic determinants of drug resistance in this microbe . unlike most other bacterial pathogens , resistance plasmids and horizontal gene transfer play no role in the acquisition of drug resistance in m. tuberculosis .
moreover , efflux mechanisms appear to serve only as a stepping stone to high - level resistance .
they allow the bacteria to tolerate higher levels of drug but do not per se result in clinically relevant levels of resistance to multiple antibiotics in m. tuberculosis [ 14 , 1618 ] . instead
, the evolution of strains resistant to multiple antibiotics is driven by the sequential acquisition and accumulation of resistance - conferring mutations on the bacterial chromosome .
these mutations primarily interfere with drug - target binding ( e.g. rif - rpob , fq - gyra ) , compromise prodrug activation ( e.g. inh - katg , pa-824-fgd ) , or cause over - expression of the target ( inh / eth promoter region of inha ) .
the elucidation of the mechanisms of action for many antimycobacterials led to the identification of key determinants of resistance ( see zhang and yew and almeida da silva and palomino for reviews ) , and the realization that the corresponding genetic mutations can be used as reliable molecular markers for drug susceptibility testing ( dst ) .
the application of this knowledge to the clinic has resulted in the development of diagnostic tools based on nucleic acid amplification ( naa ) that overcome many of the shortcomings of phenotypic dst ; these include a long turnaround time , outcome variability , and infrastructure requirements [ 2629 ] .
recently , one of these tools , known as xpert mtb / rif , has been the subject of a policy update published by the world health organization .
their recommendation for xpert mtb / rif to replace microscopy in hiv - positive patients , patients suspected of mdr - tb , and those suspected of tb meningitis follows its successful implementation in many countries [ 31 , 32 ] .
the instrument is designed to analyse sputum directly , hence bypassing the need for primary bacterial culture .
it simultaneously tests for the presence of m. tuberculosis and rif resistance . even though this technology is having a positive impact on tb control by offering high sensitivity and reducing the time to tb diagnosis
, the associated costs and infrastructural requirements ( e.g. a constant power supply , machine maintenance ) remain limiting for many high - burden countries [ 32 , 33 ] .
hence , on - going efforts in product development focus on cheaper and simpler so - called point - of - care diagnostics . nonetheless , dst without bacterial culturing will continue to require naa .
it should be based on detailed knowledge of the relationship between strain genotype , drug resistance phenotype , and the patient treatment outcome in terms of relapse rate and treatment failure .
whole genome sequencing ( wgs ) of clinical drug - resistant strains of m. tuberculosis should be combined with the analysis of clinical information from patients infected by these strains to yield valuable new insights into the biology of drug resistance . in this review
we focus specifically on results that shed light on why the acquisition of individual drug resistance - conferring mutations is only part of the problem .
we then use specific examples to illustrate how understanding more broadly the evolutionary mechanisms that drive drug resistance can inform the development of improved diagnostic tools as well as better strategies to preserve both existing and new treatment regimens .
the evolutionary path leading through drug resistance is strongly influenced by two factors : epistasis and bacterial fitness [ 3538 ] .
we define epistasis as a set of genetic interactions where the phenotypic effect of one mutation is determined by the presence of one or more other mutations . for example
, resistant strains carrying the same resistance mutations vary in their capacity to transmit from patient to patient [ 3942 ] , showing that the strain genetic background can determine the course of evolution of drug resistance . bacterial fitness , on the other hand , is a function of growth rate , virulence , and transmissibility [ 15 , 43 ] .
any mutation that reduces it in relation to the wild - type strain is said to carry a
fitness cost. the most immediate way to estimate the relative fitness is to measure the growth rate of bacteria in culture . on average ,
3 ) whose magnitude positively correlates with the frequency of different resistance mutations in the clinic ; resistant strains with the smallest fitness defect are most abundant [ 45 , 46 ] .
furthermore , the fitness of resistant mutants is not fixed ; evolution is an ongoing process , and a comparison between clinical and laboratory strains carrying the same drug - resistance mutation shows that clinical strains often successfully bypass any fitness cost imposed by resistance .
the acquisition of such compensatory mutations is also an example of epistasis and is key in the evolution of transmissible drug - resistant strains that pose the greatest risk to public health [ 6 , 10 , 4751 ] .
unfortunately , we do not currently have sufficient knowledge to predict epistatic interactions a priori , so we must rely on detecting them empirically by studying the genetics of drug resistance .
a number of recent studies used wgs to address the evolution of drug - resistant m. tuberculosis [ 7 , 9 , 51 , 53 , 54 ] .
the authors of these studies used approaches based on phylogeny , molecular epidemiology [ 9 , 51 , 53 ] , and mutation frequency analyses to compare drug - susceptible and drug - resistant clinical strains of m. tuberculosis .
the shared aim of these studies was the identification of bacterial genes under positive evolutionary selection by drug pressure .
the detailed discussion of the merits and shortcomings of the analytical approaches used in these studies is beyond the scope of this review , but it is important to note that there is considerable overlap in the findings of these studies .
in addition to known drug targets , all studies identified novel bacterial genes and intergenic regions whose function may be ancillary to drug - resistance mutations ( see fig . 1 ) .
in particular , several genes involved in lipid metabolism , cell wall homeostasis , purine metabolism , and transcriptional control appear to be positively selected in presence of anti - tb drugs [ 7 , 54 ] .
however , with the exception of just a few mutations ( e.g. pona1 , and the promoters of thya and thyx [ 7 , 54 ] ) , the actual role of these genes remains unclear , essentially offering an extended list of genes of interest that require further investigation .
consequently , it is currently not possible to evaluate the role of these genes in the development of future diagnostics or therapies.fig .
key genes in m. tuberculosis drug resistance have been plotted , taking into account their approximate position in the genome .
lines denote putative epistatic interactions ; connecting genes involved in the physiology of a drug as well as more broad / indirect mechanisms referred to as
ancillary to drug resistance. this categorization is meant to include factors mediating complex aspects of cell physiology , such as cell permeability and mutation - induced physiological changes .
bold lines connecting rpob to rpoc and embb to rv3972 refer to in vitro validated compensatory mechanisms .
figure based on information from the following references : [ 6 , 7 , 24 , 46 , 47 , 49 , 51 , 54 , 9194 ] .
ag aminoglycosides , emb ethambutol , eth ethionamide , fq fluoroquinolones , inh isoniazid , pas para - aminosalicylic acid , pza pyrazinamide , rif rifampicin , str streptomycin .
see original papers for a more comprehensive list [ 7 , 54 ] a web of epistasis mediates drug resistance in m. tuberculosis .
key genes in m. tuberculosis drug resistance have been plotted , taking into account their approximate position in the genome .
lines denote putative epistatic interactions ; connecting genes involved in the physiology of a drug as well as more broad / indirect mechanisms referred to as
ancillary to drug resistance. this categorization is meant to include factors mediating complex aspects of cell physiology , such as cell permeability and mutation - induced physiological changes .
bold lines connecting rpob to rpoc and embb to rv3972 refer to in vitro validated compensatory mechanisms .
figure based on information from the following references : [ 6 , 7 , 24 , 46 , 47 , 49 , 51 , 54 , 9194 ] .
ag aminoglycosides , emb ethambutol , eth ethionamide , fq fluoroquinolones , inh isoniazid , pas para - aminosalicylic acid , pza pyrazinamide , rif rifampicin , str streptomycin .
see original papers for a more comprehensive list [ 7 , 54 ] in addition to the above genes , there are a growing number of novel genes for which experimental evidence is available to support a role of epistasis in adaptation to resistance .
these genes were identified through recent studies aimed at elucidating the evolutionary trajectory of drug - resistant m. tuberculosis in the clinic [ 6 , 47 ] and include rpoc , which mediates the adaptation to rif resistance , and rv3806c , which appears to have a role in emb resistance .
rif resistance is caused by mutations of the beta subunit of rna polymerase encoded by rpob .
mutated amino acids are normally involved in drug binding and are usually restricted within a short stretch of the protein termed the rifampicin resistance determining region ( rrdr ) .
many of these mutations carry a fitness cost [ 45 , 49 ] that appears to be negatively correlated with the activity of the mutant enzyme . the importance of this aspect of rna polymerase physiology is clearly illustrated by the fact that one of the most frequent resistance mutations observed in the clinic , s450l , ( equivalent to s531l in escherichia coli ) also carries the lowest fitness cost .
moreover , this mutation appears to be almost ubiquitous among mdr strains of m. tuberculosis [ 6 , 9 , 10 , 48 , 51 ] , and perhaps more importantly , is shown to be strongly associated with the acquisition of compensatory mutations within rna polymerase genes ( rpoa , rpob , and rpoc ) .
this combination of mutations is strongly associated with improved transmissibility of strains as evidenced by clonal expansion of m. tuberculosis strains carrying these particular mutations in patient populations [ 9 , 48 , 51 ] .
the role of these compensatory mutations ( see koch et al . for a more comprehensive review ) appears to be to restore wild - type function of mutant rna polymerase , probably on the level of enzymatic activity [ 49 , 50 ] .
alternatively , these compensatory mutations maybe also restore the baseline gene expression profile of cells .
specifically , rpob mutants were shown to have a modified lipid profile as well as a modified expression of many proteins involved in lipid metabolism , particularly phthiocerol dimycocerosates ( pdims ) .
interestingly , lipid metabolism genes , including those for pdim metabolism , seem to be under positive selection during the evolution of drug resistance [ 7 , 54 ] . because pdims and other mycobacterial lipids play an important role in virulence [ 59 , 60 ] ,
this argues that global physiological consequences of drug - resistance mutations could provide a contextual framework , within which the compensatory mechanisms mediated by mutations in ancillary genes can be explored [ 7 , 51 , 54 ] .
demonstrate the effect of epistasis in the progressive increase of minimal inhibitory concentration ( mic ) for a drug . focusing their study on emb
, they observed that acquisition of high - level resistance to emb is a multistep process .
embb m306v they identified nonsynonymous mutations in rv3806c and a synonymous mutation in rv3792 as important contributors to emb resistance in vitro .
they proceeded to show that rv3806c is involved in modulating the availability of embb substrates , while the synonymous single nucleotide polymorphism in rv3792 apparently stabilized embc rna , leading to a de facto over - expression of the gene , resulting in reduced susceptibility to emb .
investigations into the interaction between mutations resulting in resistance to disparate drugs have suggested that positive epistasis may drive multidrug resistance .
our group recently published a report showing that specific resistance mutations in rpob and gyra can compensate for each other s fitness defects , to the point that some strains carrying both mutations are fitter than either single mutant .
moreover , the particular combinations of mutations conferring resistance to rif and ofloxacin ( ofx ) associated with the highest overall fitness appear to be positively selected in high - burden settings .
the examples listed here are not designed to offer a comprehensive overview of all reported examples of epistasis in drug - resistant m. tuberculosis ; we have tried to sketch a more complete picture in fig . 1 . instead , they were chosen to illustrate important concepts brought to light by recent studies : in the first place , based on current data , it appears that compensatory mutations occur most frequently in strains that already harbor the least costly mutation .
second , epistatic interactions occur between specific mutations [ 46 , 47 , 49 ] , and in some cases these can be mutually exclusive ; for example , a strain harboring an rpoa mutation does not then also acquire an rpoc or additional rpob mutations [ 6 , 50 , 51 , 62 ] . continued exposure to a drug seems to impose constraints on evolution that facilitate the acquisition of compensatory mutations in strains that are already resistant [ 36 , 50 ] .
once generated , these strains are more likely to be transmitted than strains carrying the resistance mutation alone [ 48 , 51 ] .
a further consequence of continued drug exposure is the stepwise accumulation of mutations that result in an increased level of resistance to a drug ; a factor that is already influencing inh resistance in xdr strains and may contribute to higher levels of resistance to fq [ 64 , 65 ] .
moreover , epistasis can occur between drug - resistance mutations [ 46 , 61 , 66 ] , implicating individual resistance determinants as drivers of polydrug resistance .
combined , these observations clearly indicate that continued inappropriate treatment , in part caused by misdiagnosis of resistance , drives the evolution of more transmissible , increasingly drug - resistant strains [ 10 , 51 ] .
a further set of factors , not considered hitherto , is involved in the generation of protein heterogeneity in the cell .
the primary source of this is mutations , and mutation rates were shown to vary between different phylogenetic lineages of m. tuberculosis .
the beijing family of strains in particular seems to have a higher mutation rate [ 6769 ] .
the exact consequences of this remain to be determined , but differences in mutation rate have been used to explain the correlation between this genotype with a higher rate of drug - resistance acquisition .
, who argue that protein variability driven by errors in the central information - processing pathway ( dna - rna - protein ) may provide a phenotypic stepping - stone to resistance akin perhaps to other ancillary mechanisms shown in fig . 1 .
while intellectually appealing , the clinical relevance of such a scenario remains to be substantiated .
the translational potential of the knowledge gained from the above studies lies in the implementation of molecular tools in tb control ( see table 1 for a summary ) .
wells et al . offer an excellent review of current and future needs for the clinical management of tb , addressing diagnostics , surveillance , and programmatic approaches .
it is useful to take advantage of their conceptual framework to discuss the impact of the themes that emerge from evolutionary studies .
they place capabilities available to tb control programs onto a continuum that spans from community - based physicians to supranational reference laboratories ( see fig . 2 ) .
accordingly , the available resources combined with the specific needs of each level will dictate the contribution that molecular approaches can offer.table 1implications of understanding evolutionary mechanisms of drug resistance for tuberculosis controlexperimental observationphysiological consequenceimplicationsresistant strains gain compensatory mutations that change the basic physiology , e.g. rif - rpoc
increased transmissibility , increased propensity to acquire additional resistancefocus surveillance on mutations that correlate with transmissible , highly resistant strainsuse spent biosamples to establish wide catchment area for wgs - based surveillancecontinued exposure to rif directs evolution towards the acquisition of compensatory mutationsmore rapid evolution of compensatory mutationsuse molecular tools to probe the genotype of strains and stop administering ineffective drugs immediatelyepistasis exists between drug - resistance mutations for a single drug : e.g. emb , fq , inh , rifmulti - step acquisition of high level of drug resistancedefine clinical breakpoint concentrations based on specific susceptibility profiles for a drugpositive epistasis between rpob and gyra mutationsstrains with specific combinations of resistance mutations ( e.g. gyra d94 g and rpob h445y ) are fitter than the wild typedrug regimens containing both rif and fq may fail more quickly .
assess current clinical trials for evidenceevaluate if the order in which drugs are administered might enhance negative epistatic interactionssome mutations conferring resistance to fq and bedaquiline have no fitness costs attachedno need to compensate for specific resistance mutationsenforce appropriate administration of drugs to avoid adding these antibiotics to failing regimens or use as monotherapyexplore the spectrum of resistance mutations , identify low cost and frequent mutations before releasing the drug into the marketmutation rates vary between m. tuberculosis lineagesbeijing family strains acquire resistance to inh and rif at a higher rate and are 22 times more likely to develop into mdr than the laboratory - adapted strainincrease frequency of phylogeny - based surveillance and focus monitoring on areas with high rates of beijing strains
emb ethambutol , fq fluoroquinolones , inh isoniazid , rif rifampicin , wgs whole genome sequencingfig .
2the healthcare continuum . a diagrammatic representation of the current healthcare continuum as described in wells et al .
the resources dimension encompasses a breadth of parameters , from access to infrastructure and apparatus , to technical proficiency of staff and financial resources that are available .
different diagnostic and dst technologies are shown as bars with the arrows indicating the levels at which we would ideally deploy them in the future .
wgs whole genome sequencing , lpa line probe assay , mgit mycobacterial growth indicator tube : phenotypic dst using the bactec mgit 960 instrument , automated nat automated nucleic acid amplification technology implications of understanding evolutionary mechanisms of drug resistance for tuberculosis control
emb ethambutol , fq fluoroquinolones , inh isoniazid , rif rifampicin , wgs whole genome sequencing the healthcare continuum .
the resources dimension encompasses a breadth of parameters , from access to infrastructure and apparatus , to technical proficiency of staff and financial resources that are available .
different diagnostic and dst technologies are shown as bars with the arrows indicating the levels at which we would ideally deploy them in the future .
wgs whole genome sequencing , lpa line probe assay , mgit mycobacterial growth indicator tube : phenotypic dst using the bactec mgit 960 instrument , automated nat automated nucleic acid amplification technology in the clinic , the main goal is rapid and effective treatment of infected individuals .
this relies on quick and reliable case detection , and , given the need for speed , is likely to depend on molecular diagnostics in the future .
in this setting , focusing on drug - resistance mutations offers high sensitivity and specificity for key first - line drugs . including compensatory mutations
( e.g. in rpoc or rpoa , discussed above ) as diagnostic markers is unlikely to provide additional clinical benefit , because mutations in rpob already display a high sensitivity and specificity for detecting mdr - tb in individual patients [ 33 , 72 ] .
in contrast , a key area in which evolutionary lessons could be brought to bear in a significant manner is surveillance . consider the reproductive number of a pathogen ( r0 , see fig .
two dimensions are paramount to the outcome of transmission cycles ; one is pathogen transmissibility ( t ) and the other is time to effective treatment ( c d ) . strain fitness plays a role in the former , while drug resistance considerably influences the latter .
it is in the interest of public health to identify and eradicate transmissible drug - resistant strains quickly .
we are currently failing on this front in 2012 , fewer than one - quarter of estimated mdr - tb cases were detected , and only 23 % of those had dst results reported for pza and fq . to this end
, there is scope for the implementation of molecular diagnostics for public health. screening for the emergence of compensatory mutations in a population , perhaps by focusing on re - treatment cases to pinpoint areas with evolved highly transmissible strains as they emerge [ 48 , 51 ] , would aid the public health official to prioritize resource allocation and interrupt the spread of these strains .
examples of such measures include targeted delivery of individualized , albeit expensive treatments , resource - intensive active case finding , and , in extreme cases , isolation [ 75 , 76 ] . in line with the described differences in mutation rates between m. tuberculosis lineages [ 67 , 68 ] , the public health official may include phylogenetic markers to focus monitoring on areas with a high incidence of beijing strains .
mutations conferring intermediate resistance , namely , below that of empirically determined resistance breakpoints , play a potentially pivotal role in the spread of resistance .
we have used the fitness - mic space to illustrate these concepts in fig .
it is also important to stress at this point , that strains harboring mutations conferring low - level resistance can often be treated effectively with existing drugs , either by increasing the dosage of the same drug , or by using alternative drugs from the same class , as is the case of fq .
conversely , the use of ineffective drugs should be stopped immediately to avoid directing the evolution of a strain [ 36 , 50 ] towards a more transmissible phenotype.fig .
the relative fitness of strains carrying key drug - resistance mutations grown in the absence of drug was plotted against their contribution to mic to illustrate the relationship between genotype and phenotype for important drug - resistance mutations .
lines connecting individual mutations denote strains carrying two mutations , while arrows denote estimates of the fitness of double / triple - mutants ( three different types of arrows are used to illustrate different evolutionary trajectories ) . reproductive number ( r
0 ) defined as
the number of secondary cases caused by an infected individual is roughly equal to the product of an organism s transmissibility ( t ) , number of contacts ( c ) , and the duration of infection ( d ) .
we were unable to find true relative fitness measurements for katg s315 t and gyra a90v ; these were estimated from pym et al . and poissy et al .
[ 47 , 100 , 101 ] , plinke et al . [ 47 , 100 , 101 ] , and starks et al .
[ 94 , 102105 ] , duong et al . [ 94 , 102105 ] , and malik et al .
bdq bedaquiline , emb ethambutol , fq fluoroquinolones , inh isoniazid , mic minimum inhibitory concentration , rif rifampicin evolutionary trajectories of epistasis - driven resistance .
the relative fitness of strains carrying key drug - resistance mutations grown in the absence of drug was plotted against their contribution to mic to illustrate the relationship between genotype and phenotype for important drug - resistance mutations .
lines connecting individual mutations denote strains carrying two mutations , while arrows denote estimates of the fitness of double / triple - mutants ( three different types of arrows are used to illustrate different evolutionary trajectories ) . reproductive number ( r
0 ) defined as the number of secondary cases caused by an infected individual is roughly equal to the product of an organism s transmissibility ( t ) , number of contacts ( c ) , and the duration of infection ( d ) .
( emb , m. tuberculosis ) , and huitric et al . ( bdq , m. tuberculosis ) .
we were unable to find true relative fitness measurements for katg s315 t and gyra a90v ; these were estimated from pym et al . and poissy et al .
safi et al . [ 47 , 100 , 101 ] , plinke et al . [ 47 , 100 , 101 ] , and starks et al . [ 47 , 100 , 101 ] for emb ; aubry et al . [ 94 , 102105 ] , matrat et al . [ 94 , 102105 ] , cheng et al . [ 94 , 102105 ] , duong et al . [ 94 , 102105 ] , and malik et al .
[ 94 , 102105 ] for fq ; and huitric et al . for bdq .
bdq bedaquiline , emb ethambutol , fq fluoroquinolones , inh isoniazid , mic minimum inhibitory concentration , rif rifampicin in addition to surveillance , knowledge of epistasis should be applied to the design and deployment of future drug regimens .
given the genetic interaction between mutations in rpob and gyra , it may be dangerous to administer rif and fq simultaneously , and should perhaps be avoided .
a number of current clinical trials are testing an iteration of such a combination , and their outcomes should be carefully scrutinized by using wgs for evidence of epistasis - driven drug resistance [ 74 , 8082 ] . protecting new drug classes is equally important .
bedaquiline is the first new antimycobacterial to be approved by the us fda for over 40 years [ 83 , 84 ] .
given the availability of bedaquiline resistance mutations with no fitness cost , or even a fitness benefit ( see fig .
3 ) , it is key that the guidelines for the administration of the drug are adhered to [ 86 , 87 ] , especially in light of the fact that no standardized regimen exists for it yet .
most importantly , bedaquiline should not be used to rescue a failing regimen , and should always be administered with other effective drugs to minimize the emergence of resistance .
consensus is growing that biological parameters such as the frequency of resistance mutations , the occurrence of low- or no - cost drug - resistance mutations , epistasis between resistance mutations , as well as host genetics should be considered when deciding on future treatment protocols .
efficient inclusion of all of these factors for drug - resistance surveillance requires broader implementation of wgs .
the world health organization is currently analyzing the results of a surveillance effort looking for underlying resistance to pza and fq where phenotypic dst was paired with dna sequencing ( zignol , unpublished ) .
the timing of the study is crucial in view of the fact that many of the new treatment regimens under investigation rely on these two drugs , and underlying resistance may severely compromise their success . applying wgs to clinical trials
can also contribute important information on the success of a new treatment , as well as sorely needed data for new - in - class antibiotics such as pa-824 , delamanide , bedaquiline , and sq109 .
together , this knowledge should be used to build an accurate picture of how the genetic makeup of a strain ultimately determines the success of treatment . due to high costs and logistical requirements
, wgs technology might not find its way into many of the most affected and often resource - poor countries in the short term .
however , applied at a supranational or national level with a wide - spread community - based catchment area , wgs would allow high - throughput analysis of known but also unknown mutations .
healthcare officials would thus obtain surveillance data and essential information for the development of new diagnostic tests adjusted to the prevailing resistance pattern [ 39 , 40 , 42 , 90 ] .
for example , one could imagine an approach in which used sputum - microscopy slides from primary tb - diagnostic centers are recycled as a source of m. tuberculosis dna for pooled dna sequencing to measure the frequency of drug - resistance alleles in a particular patient population .
similarly , spent dst samples , such as mycobacterial growth indicator tubes ( mgit ) and loewenstein jensen slopes , would provide an excellent source of dna for wgs - based surveillance .
the application of wgs and evolutionary principles to drug resistance in m. tuberculosis has been furthering our understanding of the challenges faced in the clinic as well as contributing key data for developing tools and strategies to control drug - resistant tb . as new treatment regimens containing new drugs
are implemented , we will have to establish the spectrum of epidemiologically relevant mutations as soon as possible .
this will help us track the emergence of strains resistant to these drugs in real - time , thereby prolonging the life span of the new regimens a fundamental concern given how precious new drugs are .
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### Summary:
: drug - resistant tuberculosis is a growing threat to global public health .
recent efforts to understand the evolution of drug resistance have shown that changes in drug target interactions are only the first step in a longer adaptive process .
the emergence of transmissible drug - resistant mycobacterium tuberculosis is the result of a multitude of additional genetic mutations , many of which interact , a phenomenon known as epistasis .
the varied effects of these epistatic interactions include compensating for the reduction of the biological cost associated with the development of drug resistance , increasing the level of resistance , and possibly accommodating broader changes in the physiology of resistant bacteria .
knowledge of these processes and our ability to detect them as they happen informs the development of diagnostic tools and better control strategies .
in particular , the use of whole genome sequencing combined with surveillance efforts in the field could provide a powerful instrument to prevent future epidemics of drug - resistant tuberculosis .
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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:
: coupled plasma filtration adsorption ( cpfa ) is an extracorporeal blood purification therapy that uses a plasma filter to separate plasma from the blood , a sorbent cartridge that removes various substances from the separated plasma and a haemofilter .
the aim of this treatment is to reduce the levels of inflammatory mediators in patients with acute inflammatory diseases [ 1 , 2 ] .
this technique has been proposed as a blood purification therapy in the course of sepsis and multiple organ dysfunction syndrome . however , as yet , its role in treating patients with acute diseases but without the traditional criteria for sepsis has not been defined . in this case report , we describe the potential usefulness of cpfa in association with conventional drug therapy in treating a patient with acute kidney injury ( aki ) and acute respiratory distress syndrome ( ards ) , possibly mediated by the removal of pro - inflammatory cytokines .
a 43-year - old male was admitted to our nephrology unit for dyspnoea and fever .
a biopsy diagnosis of membranous glomerulonephritis with chronic kidney disease not requiring dialysis ( estimated glomerular filtration rate of 18 ml / min , serum creatinine 7.1 mg / dl ) had been made in our unit 3 months earlier .
the patient was in treatment with cyclophosphamide ( 1 mg / kg po daily ) and prednisone ( 0.5 mg / kg po daily ) .
ten days prior to the present hospitalization , his serum creatinine was 5.0 mg / dl . at the time of admission , the patient was dyspnoic , disoriented , tachycardic ( 110 beats / min ) and febrile ( 37.8c ) with an oxygen saturation of 86.7% while breathing room air .
chest auscultation revealed scattered , coarse crepitations and rubbing at the right side of the chest and diminished air entry into both lung bases .
an arterial blood gas ( abg ) test showed the presence of type 1 acute respiratory failure .
laboratory investigations revealed lymphocytopoenia and a deterioration of renal function . the acute physiology and chronic health evaluation ( apache ) ii scored 18 .
blood cultures and tests for pneumotropic microbial agents ( cytomegalovirus , legionella pneumophila , mycoplasma pneumoniae , chlamydia pneumoniae , epstein - barr virus and adenovirus ) were negative .
approximately 48 hours after hospitalization , abg test while breathing through a venturi mask ( fio2 = 0.4 ) confirmed the presence of chronic metabolic acidosis , with a compensatory respiratory alkalosis . a high - resolution - computed tomography ( hrct ) scan of the chest showed bilateral patchy areas of ground - glass consolidation ( figure 1a ) .
a diagnosis of ards was made and continuous positive airway pressure ( cpap ) ventilation was started .
the worsening of respiratory function was followed by the onset of atrial fibrillation and by the further increase of serum creatinine levels ( 8 mg / dl ) ( apache ii score : 24 ) .
the severity of the clinical picture induced us to additionally apply blood purification therapy with cpfa .
the procedure was performed for 68 h ( daily , for three consecutive days ) with a four - pump blood - purification machine ( lynda ; bellco , mirandola , italy ) and a kit ( abl814 ; bellco spa ) including a polyethersulfone plasmafilter ( 0.5 m ) , an adsorbent cartridge containing styrene resin with macroporous structure ( 50 000 m / cartridge ) , and a highly permeable polyethersulfone haemofilter ( 1.4 m ) where convective exchanges may be applied to the reconstituted blood in a post - dilutional mode .
blood flow rate was set to 180 ml / min , plasma separation rate was adjusted to 15% in the plasmafilter and haemofiltration was performed at the ultrafiltration rate of 2530 ml / kg / h , aiming to a weight loss of 1 kg per session .
pro - inflammatory cytokines [ interleukin ( il)-6 , tumour necrosis factor ( tnf)- , interferon- , monocyte chemotactic protein ( mcp)-1 ] , pro - calcitonin ( pct ) and c - reactive protein ( crp ) were measured before every cpfa session and after the last one .
the following day , the patient was not confused and converted back into sinus rhythm .
after 4 days , the oxygen saturation was 97% while breathing in room air . during the 3 days in which cpfa treatments were carried out , serum levels of pro - inflammatory cytokines , pct and crp decreased progressively ( figure 2a e ) .
apache ii progressively decreased , reaching a score of 9 five days after the first cpfa session ( figure 2f ) .
a control chest hrct was performed after 9 days from the admission , confirming a substantial improvement of the acute respiratory disease ( figure 1b ) .
main clinical and laboratory data registered at the admission , before each cpfa session and 48 h after the last one while breathing room air .
hrct scan of the chest before ( a ) and after ( b ) cpfa treatments .
trend of apache ii score and of cytokines , pct and crp levels from admission .
cpfa has been proposed as an emerging treatment aimed at restoring immune function in patients with sepsis - related multiorgan dysfunction by non - selectively reducing the circulating levels of inflammatory mediators [ 4 , 5 ] . however , evidence - based data about the clinical efficacy of this technique are still lacking [ 6 , 7 ] not only in the course of sepsis but even in less acute inflammatory conditions that do not fulfill the traditional criteria for sepsis . we report the case of a critically ill patient with ards and aki in which cpfa was successfully used as part of the treatment .
ards is a severe disease characterized by diffuse inflammation of lung parenchyma which determines a large release of cytokines and other pro - inflammatory mediators secreted by local endothelial and epithelial cells , such as tnf- , il-6 and mcp-1 , that in turn determine the release of acute - phase reactants ( mainly crp and pct ) . in particular , it has been reported that high plasmatic levels of il-6 are associated with increased morbidity and mortality in patients with acute lung injury .
if ards is not promptly treated , the amount of inflammatory mediators released by the lungs may result in systemic inflammatory response syndrome or sepsis .
in fact , he developed ards and an acute deterioration of renal function but was immediately treated with antimicrobial agents and cpfa .
the decision of employing cpfa as renal replacement technique was taken because the patient showed fluid overload and appeared at high risk of sepsis . in the days in which cpfa was performed , we observed a progressive reduction of serum pro - inflammatory cytokines , in particular il-6 and tnf- ( figure 2a and b ) .
such decrease was associated with a parallel decline in the serum levels of crp and pct ( and thus of the systemic inflammatory state ) ( figure 2d and e ) and with a rapid improvement of the clinical conditions and a decrease of the apache ii score ( figure 2f ) .
however , it is well known that the mortality in patients with ards is very high and that the therapeutic measures , which attenuate the inflammatory state and maintain a slightly negative fluid balance , can improve the outcome in these patients [ 11 , 12 ] .
steroids are part of the therapy , but our patient was already on steroid treatment before developing pneumonia and this therapy was maintained throughout the course of the acute disease so that the fall in plasma cytokines that we observed after cpfa was started can not be entirely ascribed to steroids . of course
, we can not exclude that the observed changes in cytokine levels reflect merely an antibiotic - related improvement of the disease , but the rapidity of the cytokine decline and the temporal association with cpfa therapy strongly suggest a beneficial role for this procedure in our patients . in conclusion
, cpfa may have played a role in the favourable outcome of our patient with aki and ards by reducing inflammation and fluid overload .
this case report also suggests that starting cpfa early as part of the treatment of severe acute inflammatory diseases could help improve the survival of critically ill patients , possibly preventing the onset of sepsis , although this hypothesis needs to be verified in specifically designed trials .
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### Summary:
: coupled plasma filtration adsorption ( cpfa ) is an extracorporeal blood purification therapy based on non - specific pro- and anti - inflammatory mediator adsorption on a special resin cartridge coupled with continuous veno - venous haemofiltration or continuous veno - venous haemodiafiltration and is one of the emerging treatments for septic patients . however , in the literature , there are limited data about its efficacy in treating patients with acute diseases but without the traditional criteria for sepsis .
we describe the case of a 43-year - old male who developed acute respiratory distress syndrome secondary to pneumonia and acute kidney injury , whose clinical conditions rapidly improved after early cpfa 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:
: vasoactive neuropeptides ( vns ) ( e.g. , pituitary adenylate
cyclase - activating polypeptide ( pacap ) and vasoactive intestinal peptide ( vip ) ) are widely distributed in the central nervous
system ( cns ) and peripheral nervous system ( pns ) including autonomic nervous
system ( ans ) and peripheral tissues including heart , lung , pancreas , adrenal gland ,
gonads , and gastrointestinal tract as well as immune cells and lymphatic
system .
vns have critical roles and functions as neurotransmitters and
neuroregulators , neurotrophic stimulators , hormonal regulators , vasodilators ( including
perfusion and hypoxia regulators ) , as well as immune and nociception
modulators .
they have key roles in blood vessel function in the cns and contribute to high - level neurological
functions including memory and learning .
they have a well - described neuroprotective role and act as
inflammatory mediators in microglial activation .
vns exert potent effects in metabolism as they have a vital role in
cyclic adenosine monophosphate ( camp ) production and regulation through
adenylate cyclase ( ac ) activation .
immunological dysregulation of vital
biochemical and/or epigenetic mechanisms affecting vns resulting in down - regulation
of camp are possible pathways by which disease entities become manifest .
their
role along with other neurotrophic factors in maintaining camp levels
may be of vital importance for the integrity of blood brain barrier ( bbb ) and blood
spinal barrier ( bsb ) . bbb and bsb
have
traditionally been regarded as the main barriers between the brain and spinal
cord parenchyma and the intravascular compartment and are , therefore , important
in keeping immune cells and macromolecules from interfering with brain and
spinal neurological processes . however , disruption of bbb and bsb is well known in certain pathological states
suggesting that they function more as a sieve rather than an absolute
barrier .
virchow - robin
spaces ( vrss ) are compartments surrounding small vessels within the cns
which contain interstitial fluid and , while some functional contact with
subarachnoid spaces may occur for solute exchange , they may not contain csf as
commonly thought .
vrss have important connections with lymphatic
drainage of the head and neck , having
intricate pial relations and providing a surface for
activity of neuropeptides , hormones , and cytokines .
pial cells may have a role in protecting the brain from exogenous
catecholamines , and vrs may have a complex role in leukocyte recruitment
across the bbb .
vns are known to have neuroprotective effects through hypoxia
protection on passage through the bbb via a transport mechanism which enables
the intact peptides to enter the parenchymal space of the brain .
vns may
have a significant role in blood bbb / bsb function and likely assist in immune regulation of vrs in the brain and spinal
cord .
the present paper asserts that in view of the many vital roles of vns in cns neuroregulatory and immunological function
including bbb function , autoimmunity to vns or vn receptors will have
significant effects on homeostasis resulting in disease states .
vns exert influence over inflammatory control mechanisms including influencing
th1 to th2 shift , and the suppression of tnf alpha has been established in
camp participation in vascular dysfunction involving endothelial cells .
the vrs has been identified as a location for immunoreactive lymphocytes in
penetration of neuronal parenchyma .
also , vip has been identified in connection with neuronal function and vrs suggesting that
vip may have a regulatory function
associated with vasodilatation .
we assert that important immunoregulation
occurs in vrs and that this may involve vn regulation .
many regulatory
functions are dependent on il-10 and il-4 , these may be compromised in vn
failure .
moreover , leakiness in bbb and bsb functions may encourage development or relapses in neurological conditions ,
such as multiple sclerosis ( ms ) . regulatory t cells ( tregs )
moreover , treg function is substantially influenced by
vns and may also have influence over th17 direction .
loss of treg
function in vrs will , therefore , have significant implications for inflammatory
control .
moreover , th17 development occurs under il-6 and tgf beta influence ,
and this may be a key switching point from a protective treg to an autoimmune
th17 phenotype .
certainly , th1 and th17 ratios are important in brain and spinal
inflammation regulation .
interestingly , a number of seemingly unrelated disorders may be
implicated in this postulated pathology .
for example , crohn 's disease ( cd ) and ms
are inflammatory disorders with known th1-directed cytokines and loss of foxp3
treg function [ 24 , 25 ] . as vrs have important roles in controlling macrophage and perivascular
infiltrates in ms ,
complement - fixing myelinolytic antigens have been
identified in the vrs in early ms , indicating the possible involvement of
vrs in immune activity .
vn autoimmunity has been postulated as a contributing cause for some
fatigue - related conditions .
the
present paper explores the possible role vn immune dysregulation may have on
vrs function and cns activity as
this anatomical pathway may have a significant bearing on disease aetiology .
because vns are widely distributed in the cns ,
neurovascular , and immune systems , they exert extraordinary influence on
neurological , vascular , and immunological functions .
significantly , vns exert
mostly anti - inflammatory activities and loss of their function , for example ,
through autoimmune compromise , could become manifest as unmodulated activation
of immune responses .
autoimmunity directed at vn guanine protein - coupled
receptors ( gpcrs ) is currently unproven and loss - of - function autoimmunity to
gpcrs generally is not widely documented .
however , parallels exist with other
conditions such as sjogren 's syndrome which has t cell and/or b cell antibody
targeting of acetylcholine gpcrs .
the role of vns in linking the innate
and acquired immune systems suggests that there would be significant effects
on homeostasis if compromised .
pain , fatigue , and dysregulation of nociception may be prominent
features in these syndromes as a result of vn compromise in the cns .
pain and nociception are mediated through
spinal and cerebral pathways particularly via spinothalamic , spinoreticular ,
and spinomesencephalic structures .
the periaqueductal grey ( pag ) region surrounding the third ventricle and
cerebral aqueduct is a key area for regulation of noxious stimuli .
this area
has high - density vn presence and may be a prominent target for vn autoimmune
compromise . similarly , vrs have a critical role in maintaining the interstitial
fluid immunological milieu and may be a vulnerable area for vn compromise .
it is likely that bbb , bsb , and vrs play an important role in
immunological maintenance and homeostasis within the cns .
macrophages in vrs express mhc class ii antigens and interact with lymphocytes from the blood in initiating
and promoting immune responses to foreign antigens in the brain .
immunological
activity within vrs may have a role in a number of neurological conditions .
moreover ,
sites deficient in bbb include the subarachnoid space and pial surface , and circumventricular
organs may be more prone to macromolecule penetration of csf , and this may have
implications regarding autoimmune dysfunction within the cns .
collections
of macrophages may occur in vrs following trauma in a proinflammatory context and pathological dilatation of vrs may
occur from a variety of causes including ischaemia .
for example , vrs in the nucleus
tractus solitarius in the dorsal medulla oblongata suggests they may have a
role in viscerosensory and autonomic functions .
capillary diversity within the subfornical organ ( sfo ) and area
postrema ( ap ) may function as low - resistance pathways for the rapid dispersion
of blood - borne hormones inside their organ boundaries and this may have a role
in the regulation of blood pressure and body fluids .
hence , these
functions linked to vrs microanatomy may be particularly susceptible to vn
compromise .
vascular compromise within the cns possibly as a result of vn compromise may give rise to features consistent with
certain forms of dementia . fronto - temporal dementia ( ftd )
is a
neurodegenerative disease in which a vascular component is suggested and
immunoreactivity of bax , a proapoptotic protein regulated in part by vns in
astrocytes , suggests a role for autoimmunity in the pathology of ftd .
astrogliosis in ftd corresponds with
spect hypoperfusion , suggesting that astrocyte disruption may be related to disturbances
of cerebral perfusion in ftd .
cognitive dysfunction is associated with
reduced cerebral blood flow in different types of dementia . moreover
, vrs
dilatation associated with microvessel abnormality may contribute to the diagnosis
of vascular dementias .
changes
in social behaviour occur in cerebrovascular comprise and may result from an
ftd - like syndrome .
similarly , reduction in cortical blood flow has been
identified in cfs patients [ 41 , 42 ] ;
however , these findings were not replicated in a study of twins with cfs .
astroglial water channel aquaporin ( aqp4 ) is essential for the
maintenance of blood - brain barrier integrity .
antibodies to aqp4 have a
highly specific role in neuromyelitis optica ( nmo ) and characteristically bind
to cerebral microvessels , pia mater , and vrss .
secretin receptor - null mice , for
example , have reduced renal expression of aqp2 and aqp4 .
interestingly , vip , which is related to secretin , also has a
relationship with aquaporin distribution and function .
an association with vrs
has been identified supporting the view that cortical nerve cells release vip in the perivascular space during periods of
activity and thus contribute to local vasodilatation associated with neuronal
function .
there is an important relationship whereby atp over expression has a
down - regulatory impact on aqp4 expression .
adenylate cyclase compromise could have an impact on atp levels by
failure to convert to camp , arguably maintaining high levels of atp with
adverse consequences for aqp4 function .
neurological conditions often present with fatigue and other
symptoms including memory and concentration loss , emotional lability , and
confusion .
multisystem involvement including cerebrospinal effects of these
conditions may be explained in part through vn compromise . in particular , cerebrovascular
and spinovascular compromise
acting at the ultra - microscopic level involving
bbb and bsb may contribute to these
disorders .
compromise of vn receptors critical to bbb and bsb functioning may have a role in these disorders
and should be the subject of further research .
this paper asserts that cns vascular compromise including immunological dysfunction of the vrs may be
linked to postulated vn autoimmunity .
evidence for compromise of vn receptors
at different levels including vn receptor mrna , protein transcription , cellular
migration and trafficking , cell membrane localisation , as well as possible
antibody or t cell targeting will be required to support this hypothesis .
vns ,
such as pacap and vip , exert potent effects in metabolism as they have a vital
role in camp production and regulation through ac activation .
phosphodiesterase
( pde ) enzymes metabolise camp as a
means of feedback regulation of camp levels .
thus ,
phosphodiesterase inhibitors ( pdeis ) , novel therapeutic substances used to
promote camp levels , may have a role in treatment of vn autoimmune conditions .
proof of this hypothesis will require demonstration of pathological
antibodies or t cells specific to vn immunological pathology .
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### Summary:
: vasoactive neuropeptides ( vns ) such as pituitary
adenylate cyclase - activating polypeptide ( pacap ) and vasoactive intestinal peptide
( vip ) have critical roles as neurotransmitters , vasodilators including perfusion
and hypoxia regulators , as well as immune and nociception modulators .
they have key roles in blood vessels in the central nervous system ( cns )
including maintaining functional integrity of the blood brain barrier ( bbb )
and blood spinal barrier ( bsb ) .
vns are potent activators of adenylate cyclase and thus
also have a key role in cyclic amp production affecting regulatory t cell and
other immune functions .
virchow - robin spaces ( vrss ) are perivascular compartments
surrounding small vessels within the cns and contain vns .
autoimmunity of vns or vn receptors may affect bbb and vrs function and ,
therefore , may contribute to the aetiology of neurological - related conditions
including multiple sclerosis , parkinson 's disease , and amyotrophic lateral sclerosis .
vn autoimmunity will likely affect cns and immunological homeostasis .
various pharmacological and immunological treatments including phosphodiesterase inhibitors
and plasmapheresis may be indicated .
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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:
: spleen is a vulnerable organ and frequently sustains injury from the abdominal trauma in all age groups . in civilian practice frequency of splenic injury due to blunt trauma
far exceeds than that due to penetrating trauma , road traffic accidents , steering wheel injuries and seat belt injuries .
penetrating injuries of the left thorax should also arouse suspicion of splenic injury.[13 ] after blunt injury to the spleen , splenectomy was the preferred method of management till late seventies .
contemplations for the splenic salvage operations and nonoperative treatment for splenic injuries was increasingly been suggested for its invaluable functions .
the drift to the concept of splenic salvage ushered in response to king and schumacher 's report of overwhelming sepsis in children after splenectomy .
the idea of nonoperative treatment of selected pediatric patients with splenic injury was introduced in 1968 .
still , it was not until the development of better diagnostic modalities in two subsequent decades that nonoperative management ( nom ) became a more common treatment strategy in children . currently , the standard of care for a hemodynamically stable child with a splenic injury documented by computed tomography scan is nonoperative treatment with close monitoring by an experienced surgical team.[911 ] morbidity and mortality are further compounded by the life - long risk of overwhelming postsplenectomy sepsis that is estimated to occur 85 times the rate of the normal population . even in regions with organized trauma systems , a significant number of children are likely managed at the general hospitals .
no previous study has systematically examined the treatment of children with splenic injury at the nontrauma centers in sikkim .
the objectives of our study were to find out the risk factors , the presentations , the severities and the outcomes of the interventions of splenic injuries in the children and adolescents .
a retrospective blinded review was designed of the records of147 children and adolescents with history of abdominal trauma with splenic injury spanning over a 5-year period from january 2005 to december 2009 admitted in the department of surgery of a tertiary care teaching hospital in sikkim .
the study included all children and adolescents with a diagnosis of blunt injury to the spleen .
adolescent age was defined by world health organization as a person between 10 and 19 years of age .
the splenic injuries were graded with the american association for the surgery of trauma splenic injury scale .
all the cases were evaluated with detail history of the mode of injury , prehospital care , time interval between the incident and arrival in this hospital , hemodynamic stability , routine investigations ( hematological : hemoglobin , total leukocyte count , blood grouping and cross match , platelet count ; biochemical : bun , serum creatinine , plasma sugar , serum sodium and potassium ; radiological : x - ray chest and abdomen , ultrasound of abdomen , intravenous contrast - enhanced ct scan of abdomen and ultrasound guided diagnostic peritoneal tap .
standard clinical criteria allowed triage of patients to immediate surgery or in the initial nonsurgical intervention groups .
eighty - seven cases among 147 enrolled cases were hemodynamically unstable and went directly to surgery without ct evaluation due to hypotension or following focused abdominal sonography for trauma ( usg ) criteria .
the second group ( n= 60 ) cases underwent ct evaluation with contrast ; of them eight cases were decided for splenectomy , 19 cases underwent surgical salvage and 33 were closely observed with a by the conservative approach with both clinical and ct criteria .
the clinical criteria included morphological grade of the injury , the hemodynamic instability , the requirement of the transfusion and the abdominal rigidity .
ct criteria included the extent of the splenic injury , the active extravasations , and the amount of hemopenitoneum .
the operative managements included total splenectomy and salvage operation ( partial splenectomy and splenorraphy ) .
nom was done with abdominal rigidity and girth measurements , serial ct assessment , hemodynamic status evaluation , etc .
postoperative vaccination was provided to all cases with polyvalent pneumococcal vaccine 0.5 ml , hemophilias influenza type b vaccine and quadrivalent meningococcal vaccine ( the latter for those 2 years of age ) .
the statistical analysis was done using graph pad 3 and the comparison between cases and control was calculated by using student 's t - test .
test and trend was used to compare the outcomes in relation to the ages of the cases .
one - way anova and bonferroni multiple comparison test was applied to compare multiple independent and dependant variables .
the statistical analysis was done using graph pad 3 and the comparison between cases and control was calculated by using student 's t - test .
test and trend was used to compare the outcomes in relation to the ages of the cases .
one - way anova and bonferroni multiple comparison test was applied to compare multiple independent and dependant variables .
out of the 147 patients of splenic injury 87 cases were considered for immediate surgical interventions .
other 60 patients underwent ct evaluation of them , active extravasations of blood was identified in 10 patients ; all of them underwent surgical interventions ( splenectomy in 8 , splenornhaphy in two ) .
fifty cases were earmarked for nom ; 17 cases , with no demonstrated extravasations at ct , underwent salvage surgery for splenic injuries at a later date in accordance with both the clinical and ct criteria , while 33 were closely followed up by the conservative approach . in the demographic and clinical characteristics of the study population ,
nearly three - fourths were adolescents ; preponderance of cases were above 16 years [ 57(38.77% ) ] ; 117(79.59% ) were male.mean age of the splenic injury cases was 13.210.46.a great majority [ 91(61.90% ) ] were due to fall from heights and others were due to road traffic accidents .
prehospital care i.e. , the treatment before shifting from scene of trauma to our center was received by 59(40.14% ) cases and a gender bias was observed in favor of males ; these differences were statistically significant ( p=0.0453 ) .
the mean time interval in hours between the incidence and arrival in this hospital was estimated at 7.67 hours as only 31(21.09% ) cases reached our center within an hour .
nonpalpable peripheral pulse and a nonrecordable systolic blood pressure were noted in 53(36.06% ) cases .
the hemoglobin level of more than 10 gm% was noted in 23(15.65% ) cases . in our series
the diagnostic accuracy of ultrasound imaging was in 80.27% , while in computerized tomography the comparable data was 98.33% [ table 1 ] .
clinicopathological correlates of splenic injury in children and adolescent population in sikkim ( n=147 ) in our study we noted that 37(25.17% ) cases had grade - iii , followed by 35(23.81% ) with grade - ii , 31(21.09% ) with grade - i , 25(17.01% ) in grade iv and 19(12.92% ) in grade v splenic injuries .
we observed that total number of cases in grade iii and above was significantly higher than with lower grades of injuries ( p=0.0038 ) . in males ,
a significant linear trend was noted when we compared cases with grade iii and above with lower grades of splenic injury ( p<0.0001 ) . however , linear trend could not be delineated in females . in total , 95(64.63% )
cases were managed with total splenectomy ; while 19(12.93% ) cases in the initial nonsurgical group underwent salvage operation ( partial splenectomy and splenorraphy ) and 33(22.45% ) cases had received nom in surgical intensive critical care unit .
we sought for the enhanced understanding on the risk and the outcome of splenic injury in children .
so we compared total splenectomy and salvage operation with nom in children below the age of 10 years with those in the adolescents .
overall it was noted that children recovered in significantly higher number with nom ( p=0.0349 ) .
blood transfusion was needed in all cases ; more than 5 u were provided to 89(60.54% ) cases . in comparison ,
the recipients of more than 5 u of blood transfusion were significantly higher than those receiving less ( p<0.0001 ) .
but when the transfusion analysis was compared we did not note any significant difference between nom and operative management ( om ) ( p=0.067 ) .
postoperative complications were observed in 98(66.67% ) cases though we could not find any significant difference in age groups in relation to infection , shock , atelectasis or anemia ( p>0.05 ) . from the analysis of the records of this review ,
sikkim is a hilly state in the himalayan range in the north - eastern part of india ; a bit of plane land or a valley is a rare scene in the whole state .
further , sikkim is a peaceful state in india with rare documented cases of violence .
we observed 147 cases of splenic injury ; majority was due to fall from heights and others from road traffic accidents .
blunt trauma is the second commonest mode of abdominal trauma and spleen is the most commonly injured organ after blunt trauma .
the overall mortality rate from splenic injury was reported as 6 - 7% or high in many series and this mortality rate is secondary to associated injuries.[21619 ] researchers noted that the most common cause of splenic injury was blunt abdominal trauma .
most of the blunt abdominal traumas were secondary to falls from heights and road traffic accidents .
our results are similar with world literature.[2022 ] in our series the diagnostic accuracy of ultrasound imaging was in 80.27% in splenic injury cases , while in computerized tomography the comparable data was 98.33% . in a comparable study ,
patients with hyperattenuating foci were much more likely to need laparotomy or splenic artery embolization than were patients without hyperattenuating foci . among the patients with hyperattenuating foci , a significant difference in the type of management
was also shown on the basis of whether the hyperattenuating foci represented active splenic hemorrhage or contained injury based on dual - phase ct findings .
patients with active splenic hemorrhage were more likely than patients with contained injuries to undergo splenectomy .
intravenous contrast - enhanced ct has been shown to be accurate in the evaluation of splenic injuries resulting from blunt trauma.[2426 ] there is a general trend toward nonsurgical management of abdominal traumatic injuries as well as the confidence our surgeons have in our ability to accurately stage splenic injuries , including evidence of active bleeding , and to exclude with confidence other visceral injuries that would necessitate surgery .
others also reported in that grade iii splenic injury was the most frequent that corroborated our findings . in our series we had performed total splenectomy in 64.63% patients .
other similar study also concluded that the need for splenectomy was most significantly correlated with higher grades of splenic injury .
a study was conducted on the children and adolescents were admitted to all acute care hospitals in pennsylvania and had a diagnosis of blunt injury to the spleen .
researcher in this field reported that , 23.2% of children with blunt splenic injury in their study were treated operatively .
of the 752 patients who were treated operatively , 56(7.4% ) were characterized as having had a partial splenectomy , 208(27.7% ) as a repair / plastic operation of the spleen , 484(64.4% ) as a total splenectomy and 4(0.5% ) as other operations on the spleen . in our study ,
the success rates in treating blunt splenic injury in children had been reported to be over 90% . in the nigerian study ,
23 cases were managed for splenic injuries that consisted of 21(91.3% ) males and two ( 8.7% ) females within the age range of 1658 years .
the risk factors were blunt injury in 21 cases and penetrating in two cases with motor vehicle accident being the most commonest .
challenges identified in the management of patients with splenic injuries in nigeria include delayed presentation , underutilization of ct , unavailability of interventional radiology , inadequate icus , limited vaccination , discharge against medical advice and poor follow - up . in the hemodynamically stable blunt splenic injury
researchers noted significant difference in mean time of healing among all grades when followed up to us - documented complete injury healing on nonsurgical management on children and adolescents with splenic injuries grade 1 - 3 .
there was a clear relationship between the severity of blunt splenic injury and adolescents and the time course .
in a recent extensive review for the ptolemy monthly reviews in canada , iribhogbe summarised that nom of blunt splenic injuries has become the norm in the developed countries for children . in the absence of rcts
, nom has shown itself superior to laparotomy , through practice , in terms of mortality rates , blood transfused and splenic preservation .
the management protocols used abdominal ct scanning to diagnose the degree of splenic injury and to rule out associated abdominal injuries requiring surgery .
the strength of the study was that there was no report of management of splenic injury from this part of india on children and adolescents .
further , the reasons for surgical intervention in the nonoperative group varied within the surgical panel responsible for the decisions that included both clinical and ct criteria .
firstly , in our resource poor setting , we are yet to establish a specialized pediatric and adolescent trauma care unit . hence even with our best efforts we had to compromise 27 patients from nom group to surgical salvage . secondly , intravenous contrast used for the ct diagnosis could not be done in hemodynamically unstable patients .
globally researchers have shown that hemodynamic stability is the key factor for consideration of nom and injury severity score is optimally related with the outcome.of the ct criteria , active extravasations usually correlated best with the need for splenic surgery .
yetmanagement had evolved from splenectomy to splenic salvage and nom in selective patients for preserving the valuable functions of spleen .
nom had replaced splenorrhaphy as the most common method of splenic salvage and the main goal of salvage , preservation of 35 - 50% of spleen is required .
future researches has to be directed to solve several important unanswered questions dealing with the diagnosis and the treatment of the splenic trauma in growing ages on the degree of splenic injury of prognostic importance by assessing clinical outcome , determination of active hemorrhage by ct , clinical and ct criteria to predict optimum nom and many more .
the management strategies such as the nom of blunt splenic injury are more likely to be adopted and sustained in pediatric trauma care centers with high volume of experience .
results of this study suggest the need for regionalized trauma care systems to implement evidence - based guidelines and to identify resources that are required to optimize care of the injured child across all types of hospitals .
to sum up , the practice of the interventions of splenic injury in children and adolescents differ broadly in spite of the well - documented benefits of nom .
ct criteria especially in the absence of active extravasations can help predict successful nom of splenic injuries .
it is important for the dedicated trauma management groups to identify the appropriate patients for nom as controversy still exist in the selection of the cases in the prediction of failure of nom .
the relative advantages of nom for children and adolescents with blunt splenic injury necessitated for widespread and standardized adoption of this intervention .
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### Summary:
: background : the contemplation for the salvage operations and the nonoperative treatment for the pediatric splenic injuries had increasingly been suggested as the standard case management.objectives:the study was carried out to identify the risk factors , the presentations , the severities and outcome of the interventions of blunt splenic injuries in the children and adolescents.materials and methods : this retrospective review was carried out in a tertiary care hospital in sikkim on the children and adolescents admitted with splenic injury from january 2005 to december 2009 .
splenic injuries were graded with the american association for the surgery of trauma splenic injury scale followed by the operative and nonoperative managements ( nom).results : overall 147 cases with the abdominal trauma were diagnosed with splenic injury . of them , males reported in higher numbers ; three - fourths were adolescents with preponderance above 16 years of age .
majority of the cases [ n=91(61.90% ) ] were due to fall from heights and others from road traffic accidents .
immediate surgical interventions was instituted in the hemodynamically unstable cases ( n=87 ) nom failed in 27 patients ; of them eight cases underwent splenectomy , and 19 underwent surgical salvage ; 33 were closely followed up by conservative approach with both clinical and ct criteria .
total number of cases in grade iii and above was significantly higher than with lower grades of injury.conclusions:in total 95(64.63% ) of the cases were managed with total splenectomy ; 19 cases in the initial nonsurgical group underwent salvage operation and 33 cases received nom .
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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:
: acanthosis nigricans ( an ) is characterized by symmetric , hyperpigmented , velvety thickening of the skin predominantly over the flexors .
the word an ( acantho , greek for thorn and nigricans , latin for becoming black ) was first proposed by unna in 1890 .
an is usually benign in children , and the generalized form is very rare in this age group .
lesions are more severe and extensive and may be accompanied by skin tags , multiple seborrhoeic keratoses or tripe palms .
a 1-year - old female child born of non - consanguineous marriage with normal growth and developmental milestones presented to us with progressive generalized darkening and thickening of the skin .
her mother had first noticed the darkening around the axillae and groin at about 2 months of age . the darkening gradually progressed to involve the other body parts , including the palms and soles .
the skin was more hyperpigmented , thickened , velvety and rugosed over the neck , axillae , cubital fossae , wrists , groin , buttocks , knees and ankles .
anterior ( a ) and posterior ( b ) view of the infant showing generalized hyperpigmentation and thickening of the skin along with velevety and rugose texture tripe palms ( a ) ; velvety changes and rugosities on the dorsum of the hands ( b ) ; plantar keratoderma ( c ) routine laboratory tests including serum biochemistry panel , urinalysis , thyroid profile , growth hormone , insulin level and oral glucose tolerance test were within normal limits .
the dermal papillae showed upward finger - like projections and the valleys between the papillae were filled with keratotic material .
based on the clinical and histological findings , a diagnosis of generalised benign acanthosis nigricans was made .
dermal papillae showing upward finger - like projections and the valleys between the papillae filled with keratotic material ( hematoxylin and eosin , 40 )
age of onset more than 40 years , sudden onset , rapid progression , mucosal involvement and tripe palms are clinical indicators of malignancy .
tripe palms ( acanthosis palmaris ) are characterized by thickened velvety palms with prominent dermatoglyphics .
type ii or familial an is inherited in an autosomal - dominant manner , which presents at birth or may develop during childhood .
type iii or an associated with obesity , insulin - resistant states and endocrinopathy is the most common type .
various endocrinopathies include diabetes mellitus , acromegaly , addison 's disease , cushing syndrome , hypothyroidism , stein - leventhal syndrome and hypogonadal syndrome .
insulin - resistant states are lipoatrophic diabetes , leprechaunism , pinealoma and acral hypertrophy syndrome - type a and type b syndrome .
syndromic an is associated with various congenital syndromes like bloom syndrome , crouzon disease , rud syndrome , prader - willi syndrome , ataxia telangiectasia , costello syndrome , mental retardation , overgrowth , remarkable face , acanthosis nigricans syndrome ( morfan ) and wilson 's disease .
drugs causing an are nicotinic acid , diethyl stilbesterol , testosterone , oral contraceptives , systemic corticosteroids and fusidic acid .
an is likely caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation . in the benign form , the factor is probably insulin or an insulin - like growth factor that incites the epidermal cell propagation .
other proposed mediators include other tyrosine kinase receptors , epidermal growth factor receptor or fibroblast growth factor receptor . in malignant
an , the stimulating factor is hypothesized to be a substance secreted either by the tumor or in response to the tumor . transforming growth
factor - alfa is structurally similar to epidermal growth factor and is a likely candidate .
differential diagnoses considered in our case were addison 's disease , hemochromatosis and epidermolytic hyperkeratosis ( ehk ) .
consistent with our case , histopathology of acanthosis nigricans ( an ) reveals hyperkeratosis , papillomatosis but only slight , irregular acanthosis and usually no hyperpigmentation .
weight reduction , withdrawal of offending drugs , treatment of endocrinopathies and removal of underlying tumor may lead to improvement .
keratolytics including retinoid , calcipotriol , oral retinoids , co2 laser and long - pulsed alexandrite laser may be successful in individual cases . in conclusion , the generalized form and palmoplantar involvement ,
although indicators of malignant an , can represent benign an also , especially in the childhood period .
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### Summary:
: the generalized form of acanthosis nigricans , especially in infants , is extremely rare .
herein we report a 1-year - old female child who developed generalized acanthosis nigricans without any evidence of internal malignancy or endocrine disorder .
this case is being reported for its rarity .
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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:
: this phenomenon has been both a bane and a boon to the dental profession . despite technological advances ,
polymerization shrinkage of composites still remains a challenge and imposes limitations in their clinical use .
the setting of dental composites is accompanied by significant polymerization contraction , resulting in the generation of stresses within the material and at the tooth - restoration interface .
microleakage is defined as the passage of bacteria , fluids or molecules between a cavity wall and the restorative material applied to it .
besides pulpal irritation and secondary caries , microleakage also results in marginal discoloration . restoring cervical lesions with resin composites
has always been a problem , especially where a very thin layer of enamel is present in the gingival margin for bonding .
the higher organic content , tubular structure , fluid pressure and the low surface energy of dentin make bonding more critical .
in addition , because of abfraction and debonding of restoration at this area , a proper and accurate method of restoration is needed . for the past several years , different techniques and materials
incremental placement of light - cured composite resin has been suggested to reduce polymerization shrinkage and also improve marginal adaptation .
microleakage is commonly assessed in vitro using dye penetration studies to detect bond failure at the enamel resin interface .
confocal laser scanning microscopy ( clsm ) is a non - destructive technique for visualizing subsurface tissue features .
one of its advantages is the clear indication of leakage limits due to a lens focus that can occur some microns beneath the observed surface .
this eliminates the stain spread caused by specimen sectioning and also avoids polishing artifacts that exaggerate dye penetration .
the aim of the present study was to compare microleakage of silorane - based resin composite in class v cavities with split incremental and oblique layering technique using clsm .
this experimental study was done on 40 intact human premolars extracted for orthodontics reasons , with no crack , decay , fracture , abrasion , previous restorations , or structural deformities , which all were stored in normal saline and used within 2 weeks after extraction . after removing residual tissue tags ,
the specimens were cleaned with pumice . in the buccal surfaces of all the teeth ,
the gingival margin of the cavity extended 1 mm above the cementoenamel junction ( cej ) .
the cavity dimensions were 3 mm in length , 2 mm in width and 1.5 mm in depth .
the cavities were cleaned using pumice paste and then were rinsed with a water spray and gently dried . after the preparations were completed ,
this group consisted of 20 specimens obturated with a silorane restorative material ( filtek p90 silorane low shrink restorative , 3 m espe ) and its relevant adhesive .
silorane system adhesive self - etch primer was applied to the enamel and dentin surfaces . after waiting for 20 seconds , the excess solvent
was evaporated with a gentle blast of air for 10 seconds , and the primer was light cured for 10 seconds .
one flat 1.5-mm - thick composite resin increment was used to restore the cavity . prior to light curing ,
one diagonal cut was made in this increment using a plastic filling instrument with a blunt blade to split it into two triangular - shaped flat portions .
the diagonal cut was first half filled with the composite and light cured for 20 seconds . following this ,
the remaining half of the diagonal cut was filled with resin composite and cured for 20 seconds .
following the same procedures applied in group i , an oblique incremental technique was used for this group .
the resin material was inserted into the cavity using an oblique incremental technique . due to the limited depth of cavity ,
the number of oblique layers was limited to two oblique layers of 1.5 mm each .
the specimens were stored at 100% relative humidity at 37c for 24 hours and were then submitted to 1000 thermal cycles at 5c and 55c with a dwell time of 1 minute at each temperature .
the specimens were then covered with two layers of nail varnish , except the resin composite restoration and 1 mm area around it , followed by immersion in 0.6% aqueous rhodamine dye for 48 hours .
the specimens were rinsed and sectioned buccolingually through the center of restorations with a slow speed diamond disk .
the specimens were polished using alumina paste in decreasing order of granulation , followed by an ultrasonic bath .
microleakage was measured using confocal microscopy at 10 magnification ( confocal fluorescence imaging microscope , leica tcs - sp5 , dm6000-cfs ) and in the fluorescent mode .
approximately , six photographs of each specimen were taken to obtain the full perimeter of the restoration . with a digital scale ( snagit digital scale ) , the width of interface between restoration and tooth surface was calculated .
the microleakage score was also recorded using the scoring method , as per alavi and kianimanesh .
the scores are as follows .
no dye penetration.dye penetration within one - half of occlusal or gingival wall.dye penetration extending to the end of occlusal or gingival walls.dye penetration through the gingival or occlusal wall to one - third of axial wall.dye penetration through the gingival or occlusal wall to two - thirds of axial wall.dye penetration throughout the axial wall
dye penetration within one - half of occlusal or gingival wall .
dye penetration through the gingival or occlusal wall to one - third of axial wall .
dye penetration through the gingival or occlusal wall to two - thirds of axial wall .
dye penetration throughout the axial wall the results were subjected to statistical analysis by using paired
after the preparations were completed , the teeth were randomly assigned to two groups of 20 teeth each .
this group consisted of 20 specimens obturated with a silorane restorative material ( filtek p90 silorane low shrink restorative , 3 m espe ) and its relevant adhesive .
silorane system adhesive self - etch primer was applied to the enamel and dentin surfaces . after waiting for 20 seconds , the excess solvent
was evaporated with a gentle blast of air for 10 seconds , and the primer was light cured for 10 seconds .
one flat 1.5-mm - thick composite resin increment was used to restore the cavity . prior to light curing ,
one diagonal cut was made in this increment using a plastic filling instrument with a blunt blade to split it into two triangular - shaped flat portions .
the diagonal cut was first half filled with the composite and light cured for 20 seconds . following this ,
the remaining half of the diagonal cut was filled with resin composite and cured for 20 seconds .
following the same procedures applied in group i , an oblique incremental technique was used for this group .
the resin material was inserted into the cavity using an oblique incremental technique . due to the limited depth of cavity ,
the number of oblique layers was limited to two oblique layers of 1.5 mm each .
the specimens were stored at 100% relative humidity at 37c for 24 hours and were then submitted to 1000 thermal cycles at 5c and 55c with a dwell time of 1 minute at each temperature .
the specimens were then covered with two layers of nail varnish , except the resin composite restoration and 1 mm area around it , followed by immersion in 0.6% aqueous rhodamine dye for 48 hours .
the specimens were rinsed and sectioned buccolingually through the center of restorations with a slow speed diamond disk .
the specimens were polished using alumina paste in decreasing order of granulation , followed by an ultrasonic bath .
microleakage was measured using confocal microscopy at 10 magnification ( confocal fluorescence imaging microscope , leica tcs - sp5 , dm6000-cfs ) and in the fluorescent mode .
approximately , six photographs of each specimen were taken to obtain the full perimeter of the restoration . with a digital scale ( snagit digital scale ) , the width of interface between restoration and tooth surface was calculated .
the microleakage score was also recorded using the scoring method , as per alavi and kianimanesh .
the scores are as follows .
no dye penetration.dye penetration within one - half of occlusal or gingival wall.dye penetration extending to the end of occlusal or gingival walls.dye penetration through the gingival or occlusal wall to one - third of axial wall.dye penetration through the gingival or occlusal wall to two - thirds of axial wall.dye penetration throughout the axial wall
dye penetration within one - half of occlusal or gingival wall .
dye penetration through the gingival or occlusal wall to one - third of axial wall .
dye penetration through the gingival or occlusal wall to two - thirds of axial wall .
dye penetration throughout the axial wall the results were subjected to statistical analysis by using paired
microleakage was seen along the entire perimeter of restoration , irrespective of the layering technique used [ table 1 ] .
graph depicting mean width of the interface , as measured by confocal microscopy in different layering techniques has been shown [ figure 1 ] .
microleakage score evaluated in two different techniques mean width of the interface , as measured by confocal microscopy in different layering techniques .
microleakage in specimens restored with split incremental technique and oblique layering technique , visualized by confocal microscopy .
the width of interface in restorations prepared with split incremental technique was significantly lesser than the one restored with oblique layering technique , as presented in table 2
. statistical analysis of width of interface in specimens restored with two layering techniques by using the mann
resin dentin interface sealing is a desirable property of dentin bonding system in preventing the pulp dentin complex from being exposed to bacteria and their toxins .
polymerization stresses developed at the adhesive interface play an important role in the marginal adaptation of resin composite restorations .
contraction stress values can exceed the bond strength , leading to the formation of openings and gaps .
they are considered deleterious because they allow the transfer of fluid between the oral environment and the pulp through the dentin tubules .
control of such stresses improves the bond strength and marginal seal of composite resin to dentin .
different incremental layering techniques , c factor analysis , low shrink materials and a combination of different restorative materials have been used in efforts to prevent this problem .
one approach to minimize the effects of curing shrinkage is the insertion of resin composite in increments , which lowers the configuration factor .
the configuration factor ( c factor ) is the ratio between the bonded and free surfaces of the cavity .
high c factor can cause adhesion breakdown between the restorative system and the cavity wall .
moezyzadeh and kazemipoor found that oblique ( gingivo - occlusal ) technique showed less microleakage in gingival margins of the restorations compared to bulk technique . in the present study , the authors used oblique and split incremental techniques that have lower c factor values to reduce shrinkage stress in class v cavities .
dentin junction was used as a parameter to assess the polymerization shrinkage occurring at resin dentin interface , as the width is directly proportional to the amount of resin polymerization . in the current study ,
the width of interface was significantly less with split incremental technique . in the split incremental technique ,
the actual number of increments needed depends on the volume of space undergoing restoration , with larger lesions requiring more incremental applications of composite resin .
relief of such stresses was achieved through the use of diagonal cut to split each flat increment into two triangular - shaped portions before light curing .
the free , unbonded composite surfaces created by the diagonal cut would convert the restricted shrinkage occurring on the cavity walls prior to splitting to unrestricted shrinkage .
this serves as a reservoir for flow or plastic deformation in the initial stage of polymerization . in the present study
, the authors made only one diagonal cut , as the volume of the cavity to be restored was less .
composite filling and light curing of 1.5-mm - wide diagonal cuts in each increment were performed ; so , one diagonal cut was completely filled and light cured , followed by filling and curing of one - half of the second diagonal cut at a time .
this sequence would prevent composite resin from connecting two opposing cavity walls at the same time , thereby minimizing the development of the detrimental polymerization shrinkage stresses on adhesive interfaces at cavity walls and margins .
since the type of composite and bonding system can influence the amount of polymerization shrinkage and the resulting microleakage , silorane - based resin composite ( filtek p90 silorane low shrink restorative , 3 m espe ) was used as a restorative material in our study .
palin and others used experimental silorane and an experimental silorane bonding system in their study .
all tested mesioocclusodistal restorations exhibited microleakage in the palin study , but the microleakage of experimental silorane - based composite restorations was lesser than commercial methacrylate - based composite restorations .
showed that the silorane - based microhybrid resin composite system had no microleakage for wide class ii mod restorations with oblique and vertical layering techniques .
the present study showed that microleakage was present in both the groups , but significantly reduced with split incremental technique .
clsm was used to assess the extent of microleakage , which is considered to be a more reliable tool . the present study measured microleakage using confocal microscopy at low magnification ( 10 ) , differing from other microleakage studies .
one of its advantages is the clear indication of leakage limits , due to a lens focus that can occur some microns beneath the observed surface .
this eliminates the stain spread caused by specimen sectioning and also avoids polishing artifacts that exaggerate dye penetration .
subsequent observation of clsm is made possible by elimination of scattered , reflected and fluorescent light from planes other than the plane from which the image is created , the focal plane .
the laser scanning microscope scans the sample sequentially point by point and line by line and assembles the pixel information into one image .
the main problem and important limitation of microleakage studies is that microleakage only reveals a minor aspect of adhesion . in the present study
, all the experimental groups showed extensive leakage and , although significant differences were found among them , the clinical relevance of these differences remains questionable .
based on the limitations of this study , it may be concluded that in class v restorations , microleakage is observed regardless of the technique used and split incremental technique shows lesser microleakage than the oblique layering technique .
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### Summary:
: aims : this in vitro study compared the effects of different layering techniques on the microleakage of silorane - based resin composite using confocal laser scanning microscope.materials and methods : forty caries free premolars extracted for orthodontic reasons were used .
a class v cavity was prepared on the buccal surface in each of the premolars , with the gingival margin of the cavity being 1 mm above cementoenamel junction .
the cavities were restored with a silorane - based resin composite ( filtek p90 silorane low shrink restorative , 3 m espe ) using two different layering techniques split incremental and oblique layering technique .
all samples were subjected to 1000 thermal cycles of 5c/55c in water with a 30 second dwell time , and after the procedure , the teeth were immersed in 0.6% aqueous rhodamine dye for 48 hours .
sectioned samples were examined under a confocal fluorescence imaging microscope ( leica tcs - sp5 , dm6000-cfs ) at 10 magnification , and microleakage scores were analyzed statistically using paired
t
test and mann whitney test .
width of interface between the tooth surface and resin composite was measured using a digital scale ( snagit digital scale).results : microleakage was seen along the entire perimeter of restoration irrespective of the layering technique used .
the microleakage score was same in both the groups .
statistical analysis of width of interface showed significant difference between the two layering techniques .
the width was significantly less in split incremental technique , indicating less polymerization shrinkage.conclusions:this in vitro study showed that the silorane - based resin composite shows microleakage irrespective of the layering technique used for class v cavities .
however , this problem can be minimized significantly by using split incremental technique for restoration of class v lesions .
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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:
: oral submucous fibrosis ( osmf ) is a chronic , premalignant condition of the oral mucosa which was first described by schwartz in 1952 .
pindborg ( 1966 ) defined osmf as follows : an insidious , chronic disease affecting any part of the oral cavity and sometimes the pharynx .
although occasionally preceded by and/or associated with vesicle formation , it is always associated with juxta - epithelial inflammatory reaction followed by fibroelastic change of the lamina propria , with epithelial atrophy leading to stiffness of the oral mucosa and causing trismus and inability to eat .
paymaster first described the malignant potential of osmf in 1956 , the rate of which has been estimated to be 713% recently .
the disease is seen in those from the indian subcontinent and from many parts of south - east asia , such as taiwan .
mid upper arm circumference ( muac ) is a useful tool for a fast assessment of the nutritional status .
it is an easy and inexpensive way to detect nutritional status and is used in developing countries for rapid and extensive nutrition surveillance and screening programs .
muac is the circumference of the right upper arm measured at the midpoint between the tip of the shoulder and the tip of the elbow ( olecranon process and the acromium ) .
the other anthropometric parameters include skin - fold thickness at defined sites , muscle circumference , and waist : hip ratio .
muac is a useful indicator of malnutrition that can be used in ill patients ( normal muac > 23 cm in males , > 22 cm in females ) .
the study was undertaken to evaluate the correlation of muac as a nutritional status indicator with osmf patients .
the patients for the study were selected randomly among the outpatients who visited during the period october 2011august 2013 in the department of oral medicine and radiology of our institute . a detailed case history of the patients with emphasis on their habits ( chewing betel nut , various brands of chewing tobacco available in market , smoking , alcohol consumption , etc . ) was taken .
fifty patients ( 39 males and 11 females ) in the age group 1545 years , diagnosed of osmf based on the history and clinical features , with the diagnosis confirmed through histopathological examination were included in the study .
a formal ethical clearance to conduct this study was obtained from the ethical committee of the institute .
patients selected for the study were explained in detail about the condition affecting their oral cavity and the procedure that they would be subjected to .
a detailed case history was recorded for all patients with special reference to their habits , their nature , duration , and frequency of use .
all patients were subjected to a thorough general physical and oral clinical examination and details were recorded on standard proforma . after establishing the clinical diagnosis of osmf , the patients were subjected to routine hemogram to rule out any systemic ailment .
the patients were clinically categorized according to the classification given by bose and balan , 2007 into mild , moderate , and severe cases . only occasional symptoms , pallor , vesicle formation , presence of one or two solitary palpable bands , loss of elasticity of mucosa , variable tongue involvement with protrusion beyond vermillion border ; mouth opening > 3 cm . symptoms of soreness of mucosa or increased sensitivity to chillies , diffuse involvement of the mucosa , blanched appearance , tough and inelastic fibrous bands palpable in buccal mucosa , considerable restriction of mouth opening ( 1.53 cm ) and variable tongue movement .
symptoms more severe , broad fibrous bands palpable , blanched opaque mucosa , rigidity of mucosa , very little opening of mouth ( less than 1.5 cm ) , depapillated tongue , and protrusion of tongue very much restricted .
this was followed by a histopathological confirmation of diagnosis by performing an incisional biopsy of the lesion . following the establishment of the diagnosis ,
the patient was then advised to discontinue the use of areca nut in all preparations .
the right upper arm was measured at the midpoint between the tip of the shoulder and the tip of the elbow ( olecranon process and the acromium ) [ figure 1 ] .
subject position for upper arm length and midpoint ( http://www.cdc.gov/nchs/data/nhanes/nhanes_07_08/manual_an.pdf ) data analysis and database management were done using statistical package for social sciences ( spss ) version 16.00 ( ibm spss modeler ) .
only occasional symptoms , pallor , vesicle formation , presence of one or two solitary palpable bands , loss of elasticity of mucosa , variable tongue involvement with protrusion beyond vermillion border ; mouth opening > 3 cm .
symptoms of soreness of mucosa or increased sensitivity to chillies , diffuse involvement of the mucosa , blanched appearance , tough and inelastic fibrous bands palpable in buccal mucosa , considerable restriction of mouth opening ( 1.53 cm ) and variable tongue movement .
symptoms more severe , broad fibrous bands palpable , blanched opaque mucosa , rigidity of mucosa , very little opening of mouth ( less than 1.5 cm ) , depapillated tongue , and protrusion of tongue very much restricted .
this was followed by a histopathological confirmation of diagnosis by performing an incisional biopsy of the lesion . following the establishment of the diagnosis ,
the patient was then advised to discontinue the use of areca nut in all preparations .
the right upper arm was measured at the midpoint between the tip of the shoulder and the tip of the elbow ( olecranon process and the acromium ) [ figure 1 ] .
subject position for upper arm length and midpoint ( http://www.cdc.gov/nchs/data/nhanes/nhanes_07_08/manual_an.pdf ) data analysis and database management were done using statistical package for social sciences ( spss ) version 16.00 ( ibm spss modeler ) .
all patients in the present study gave a positive history of areca nut chewing either in raw form as a quid or in a commercial preparation such as gutkha and paan masala .
out of 50 subjects , 76% ( 38 ) were having muac value < 23 cm , which shows an inverse relation between muac and clinical staging .
table 1 and graph 1 show that 20 patients were in mild category , out of which 13 were having muac value < 23 cm with the p value being 0.04 ; 25 were in moderate category , out of which 20 were having muac value < 23 cm with the p value being 0.05 ; and 5 were in severe category with all 5 having muac value < 23 cm and a p value of 0.03 . a p value of < 0.05 reveals the significance of muac with the severity of the disease .
distribution of muac of patients having osmf according to clinical staging distribution of muac of patients and severity of the disease
the incidence of osmf is increasing like an epidemic among youngsters in the indian and south - east asian population .
the etiology for osmf is still obscure and various factors have been proposed , arecanut chewing being the most important .
the lack of awareness , aggressive marketing strategies of these products , and failure to impart primary preventive measures have also contributed to a considerable increase in the incidence of osmf among the rural and urban younger population .
measurements of adult muac have long been known to reflect changes in adult body weight , and the major determinants of muac , arm muscle and subcutaneous fat , are both important determinants of survival in starvation . in the present study , out of 50 subjects ,
76% ( 38 ) were having muac value < 23 cm , which shows an inverse relation between muac and clinical and histological staging .
's study was the only cross - sectional study that we found on the elderly using muac as the method to assess the nutritional status of adults . in a study carried by shetty et al . , serum and salivary ascorbic acid level and iron level consistently decreased with the progression of osmf . in a similar study carried out by guruprasad et al .
, the levels of serum vitamin c and iron were significantly decreased in osmf patients . in another similar study carried out by balpande et al .
these studies attributed poor nutritional status and oxidative stress in precancerous lesions and conditions as being responsible for the decrease in serum and salivary vitamin c and vitamin e levels . as in the present study all the subjects were from same socioeconomic status , decreased muac appears to be the outcome of the disease .
thus , it can be suggested that the lack of consumption of normal diet could be the cause of decreased muac .
thus , it is concluded from the present study that the patients with osmf become unable to eat due to burning , ulcers , and inability to open their mouth , which affects the health of the individual .
thus , it is important to assess the nutritional status to improve the survival rate of patients .
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### Summary:
: background : oral submucous fibrosis ( osmf ) is always associated with juxtaepithelial inflammatory reaction followed by fibroblastic changes in lamina propria , with epithelial atrophy leading to stiffness of oral mucosa and causing trismus and inability to eat .
mid upper arm circumference ( muac ) is a useful tool for a fast assessment of the nutritional status.aims:the study was undertaken to evaluate the correlation of muac as a nutritional status indicator in osmf patients.patients and methods : the study group comprised 50 clinically diagnosed and histopathologically confirmed cases of osmf .
muac was recorded using a plastic measuring tape .
the right upper arm was measured at the midpoint between the tip of the shoulder and the tip of the elbow ( olecranon process and the acromium).results : out of 50 subjects , 76% ( 38 ) were having muac value < 23 cm , which shows an inverse relation between muac and clinical staging .
the relation of muac with clinical staging was significant.conclusion:the patient with osmf becomes unable to eat due to burning , ulcers , and inability to open mouth , which affects the health of the individual .
thus , it is crucial to access the nutritional status to improve the survival rate of 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:
: urinary tract infection ( uti ) is one of the most common causes of febrile infectious disease in children [ 1 , 2 ] .
it is a risk factor for progressive renal damage , hypertension and end stage renal failure [ 36 ] .
vesicoureteral reflux ( vur ) is the most common predisposing factor for uti and 25 - 40% of children with uti have vur [ 7 , 8 ] . voiding cystourethrography ( vcug ) is the method of choice for detection of vur in children with uti .
but this is an invasive procedure , the risk of irradiation is high and patients and their parents show poor compliance for medical care of the disease [ 1012 ] . for detection of vur , it is very important to choose procedures that are safe , noninvasive and accepted by the patients and their parents [ 13 , 14 ] . to evaluate urinary tract system , ultrasonography
( us ) and technetium 99 m - labeled dimercaptosuccinic acid scan ( dmsa ) are used for detection of urological abnormalities and renal parenchymal damage .
also there are some studies for prediction of vur by these methods [ 10 , 1517 ] .
although significant or high grade vur were predicted by dmsa in some studies [ 15 , 1819 ] , it is ruled out by others [ 16 , 20 ] . according to these disagreements ,
this study was done to evaluate the prediction of vur by dmsa scan and ultrasonography .
all children who were referred to our center ( amirkola children hospital , babol , iran ) with first time acute pyelonephritis were enrolled .
acute pyelonephritis was diagnosed in children with fever ( higher than 38.5c ) , having more than 5 white blood cells in urinalysis and more than 10 colony count of one micro organism in urine culture .
ultrasonography , dmsa renal scan and vcug were done during 2 - 5 days after diagnosis when urine cultures were negative .
children with congenital abnormality , ureteroplevic junction obstruction , ureterovesical junction obstruction and posterior urethral valve in final diagnosis were excluded .
abnormal ultrasonography finding was defined if the patient had hydronehrosis , dilatation of ureter , increase of cortical echogenecity , decreased cortical thickness and increased kidney size .
also decrease of radioisotope uptake in dmsa renal scan was defined abnormal [ 2122 ] . according to the classification of international reflux study committee ,
vur was graded to i - v . the positive predictive value ( ppv ) , negative predictive value ( npv ) , sensitivity , specificity , confidence interval ( ci ) and likelihood ratio of ultrasonography and dmsa for prediction of vur were assessed .
the local ethics committee approved the study and informed consent was obtained from all patients or their parents .
the data were analyzed by spss and fisher exact test and p<0.05 was considered significant .
among 100 children with diagnosis of uti , 88 ( 88% ) patients were girls and others were boys .
mean age was 38 ( 37 ) months ( range 1 - 147 months ) .
vur was detected in 39 ( 39% ) patients and was bilateral in 22 ( 22% ) cases of these children .
sixty three ( 31.5% ) kidney unites ( 34 right and 29 left side ) had vur . among 200 kidney units that were evaluated by vcug , 137(68.8% ) units
had no vur and 3 ( 1.5% ) , 29 ( 14.5% ) , 29 ( 14.5% ) and 2 ( 1% ) had vur grade i - iv , respectively .
dmsa scan was abnormal in 86 ( 86% ) patients and 17 ( 17% ) children had bilateral involvement .
thirty ( 30% ) patients had abnormal ultrasonography and bilateral involvement was detected in 11% .
one hundred three ( 51.5% ) units were abnormal in dmsa scan of which 45 ( 44% ) units had vur .
also , 79 ( 81% ) units with normal dmsa renal scan had no vur ( table 1 ) .
sensitivity , specificity , positive predictive value , negative predictive value , positive likelihood ratio and negative likelihood ratio values for prediction of vur by dmsa scan and us in children with urinary tract infection dmsa : dimercaptosuccinic acid ; us : ultrasonography ; vur : vesicoureteral reflux ; ci : confidence interval one hundred fifty nine kidney units were normal in ultrasonography of which 44 ( 28% ) units had vur but in 41 units with abnormal ultrasonography , 19 ( 46% ) units had vur ( table 1 ) .
all children were divided into three age groups of less than 2 years , 2 - 5 years and more than 5 years old . in the first group , among 56 abnormal units in dmsa or ultrasonography , 23 ( 41% ) units had vur . in 48 normal units in both studies ,
year - olds27 units were abnormal in dmsa or ultrasonography , 59.3% of units had vur and in 11 normal units , 81.1% of units had no vur . in children
more than 5 years old , 63.6% of units with abnormal dmsa scan or ultrasonography had vur whereas 92% had no vur when dmsa scan or ultrasonography was normal ( p<0.05 )
. of 116 kidney units that were abnormal in ultrasonography or dmsa scan , 51 ( 44% ) units had vur ( table 1 ) , whereas 72 ( 86% ) units with normal ultrasonography or dmsa had no vur .
twenty eight units were abnormal in both ultrasonography and dmsa scan of which 13 units had vur ( ppv= 46.7% ) .
to predict high grade vur ( i.e. grade iii and higher ) by dmsa scan , ppv and npv were 84% and 94% respectively compared to units without vur .
prediction of high grade vur by dmsa scan and ultrasonography ( without low grade vur ) in children with urinary tract infection dmsa : dimercaptosuccinic acid ; ; vur : vesicoureteral reflux ; vcug : voiding cystourethrography dmsa scan was abnormal in 55% of units with grade ii vur ; 72.5% of units in this group had abnormal ultrasonography or dmsa scan ( table 3 ) . in grade iii vur
, 83% of units had abnormal dmsa scan and 86.2% of units were abnormal in ultrasonography or dmsa scan ( table 3 ) .
prediction of vesicoureteral reflux ( vur ) by dimercaptosuccinic acid ( dmsa ) scan and ultrasonography ( us ) in children with urinary tract infection according to grading of vur
in the study , sensitivity , specificity , ppv and npv of dmsa scan for prediction of vur were 71% , 58% , 44% and 81% , respectively .
thirty nine percent of children with pyelonephritis had vur and 51.5% of all renal units were abnormal in dmsa renal scan .
vcug is the golden standard for detection of vur . but this procedure is invasive and causes anxiety in the patients and their parents .
so , recommendation of any procedure instead of vcug is desirable for the patients and their parents . in tseng study , sensitivity , specificity , ppv and npv for prediction of vur by dmsa were 71% , 58% , 44% and 88% , respectively .
camacho reported 48% and 88% of ppv and npv for prediction of vur by dmsa scan .
it seems that abnormal dmsa instead of vcug can not be used for prediction of vur because it is expected that about 40% of uti children have vur and the ppv of dmsa scan is not as high as this value ( 44% ) . but with normal dmsa , we can except that the probability of vur is low ( npv=88% ) . in this study , 19 ( ppv=46% ) units with abnormal ultrasonography had vur and 15 ( npv=72.3% ) units with normal ultrasonography had no vur .
sensitivity , specificity , ppv and nvp of ultrasonography for prediction of vur was 40% , 76% , 32% and 82% respectively in mahant and alshamsa studies [ 25 , 26 ] .
so , using ultrasonography for predication of vur is not recommended and for detection of vur , vcug is preferred to ultrasonography . among 115 units with abnormal ultrasonography or dmsa scan , 51 units had vur ( ppv=44% ) and npv was 86% .
kass reported 77% npv for prediction of vur by abnormal ultrasonography or dmsa scan and does not recommend the ability of them for prediction of vur .
although according to our study , the probability of vur is low , when both dmsa and ultrasonography are normal .
the sensitivity of ultrasonography and dmsa alone and ultrasonography plus dmsa for prediction of vur were 67.2% , 65.5% and 83.3% , respectively in another study , although the vurs were of grade iii and higher in this study . in our study , sensitivity and specificity of ultrasonography for prediction of grade iii and more of vur were 29% and 84% .
the sensitivity of dmsa for prediction of grade iii - iv vur was 60% , 79% and 95% respectively in ajdinovi 's study .
npv for ultrasonography and dmsa for prediction of absent high grade vur in our study was 84% and 94% respectively .
also npv for high grade vur by ultrasonography plus dmsa is reliable for prediction of absent vur , ppv was not of high value for predicting the existence of vur .
urinary tract infection is more important in children less than 2 years old , therefore detection of vur and prevention of uti is of great importance . in our study ppv and npv for prediction of vur by dmsa scan in children less than 2 years old
also , in other study of this age group , lin reported 32.7% and 94.35% ppv and npv of dmsa scan for prediction of vur [ 17 , 30 ] .
also , in study by lee et al , the prediction of vur by ultrasonography were 41.7% and 86% in low and high grade vur by ultrasonography , respectively , and 62.5% and 95% by dmsa .
also preda et al reported 96% of infants less than 1 year old with dilatation of pelvicalyceal system ( by ultrasonography ) and vur had abnormal dmsa scan .
also 72% of children with low grade vur had abnormal dmsa scan . in our study , there were no significant differences between ppv and npv in this age group and older children , although , the npv is more reliable for ruling out the vur .
ultrasonography , dmsa scan and ultrasonography plus dmsa scan can not predict the low grade vur , whereas vcug is more reliable and the standard method for detection of vur . although according to npv , with dmsa scan plus ultrasonography , the absence of vur can be predicted especially in high grade vur .
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### Summary:
: objectiveurinary tract infection ( uti ) is one of the most common causes of febrile pediatric diseases . also , vesicoureteral reflux ( vur ) is a significant risk factor for uti .
voiding cystourethrography ( vcug ) is the method of choice for evaluation of vur .
this study was done to predict vur by dmsa scan ( technetium 99 m - labeled dimercaptosuccinic acid ) and ultrasonography ( us).methodsin a prospective study , all children with first time acute pyelonephritis were selected and evaluated by dmsa scan and us .
then vcug was done with negative urine culture .
all children with final diagnosis of obstructive congenital anomaly were excluded .
the sensitivity , specifity , positive predictive values , negative predictive values , confidence interval of dmsa scan and us were calculated for prediction or exclusion of vur.findingsamong 100 children with uti diagnosis , vur was detected in 39 children and 63 ( 31.5% ) kidneys .
dmsa scan was abnormal in 103 ( 51.5% ) units , 45 units had vur ( ppv=44% ) , 79 units with normal dmsa scan had no vur ( npv=81% ) . of kidney units that were abnormal by dmsa or us ,
51 units had vur .
ppv and npv were 44% and 56% , respectively.conclusiondmsa scan alone or with us can not predict vur ( especially low grade vur ) . but according to npv , it seems that absence of vur can be predicted .
so , more studies are needed to determine the usefulness of dmsa scan and us instead of vcug for detection of vur .
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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:
: thromboembolic occlusion of major cerebral arteries is usually a very serious condition and successful recanalization improves outcomes .
unfortunately , such lesions are often refractory to intravenous ( iv ) and/or intra - arterial ( ia ) thrombolysis1,15,25,28 ) .
endovascular intervention offers good result in the treatment of acute ischemic stroke in patients presenting beyond the 4.5-hour time window , as well as in patients presenting in less than 4.5-hours who are ineligible for tissue plasminogen activator ( tpa ) or have failed to respond to iv tpa .
however , these agents are known to frequently cause symptomatic intracranial hemorrhage ( sich)3,7,25 ) .
several reports about mechanical thrombolysis in acute ischemic stroke have been published over the past decade including a new technique with the solitaire ab / fr device ( ev3 , irvine , ca , usa ) with favorable outcomes5,19,20 ) .
even with the new technique , some cases of large artery occlusion were not resolved with retrievable stent therapy alone .
we collected data from 28 consecutive patients with acute ischemic stroke who were treated with the solitaire ab / fr stent device .
data were analyzed from interventional database at our stroke center between march 2011 and december 2011 .
all patients treated with solitaire retrievable stent for acute cerebral artery occlusion were included in this study .
as a protocol for acute stroke patient in our stroke center , all patients who present with symptoms suspicious of acute ischemic stroke are initially examined with a ct scan .
in addition to plain ct , ct angiography and perfusion ct are done at the same session .
if intracranial hemorrhage was excluded by ct , diffusion magnetic resonance ( mr ) and 4-vessel angiography were performed .
inclusion criteria for mechanical recanalization in this study were as follows : 1 ) clinical diagnosis of acute stroke by a stroke neurologist ; 2 ) baseline national institutes of health stroke scale ( nihss ) score 4 , except for isolated aphasia or hemianopsia ; 3 ) exclusion of hemorrhage as determined by cranial ct ; 4 ) large vessel occlusion [ intracranial internal carotid artery ( ica ) , a1 of anterior cerebral artery , m1-m2 of middle cerebral artery ( mca ) , vertebrobasilar artery ] with correlating neurological deficits ; 5 ) large perfusion - diffusion mismatch between perfusion ct and diffusion mr ; and 6 ) initiation of treatment within 8 hours after symptom onset for hemispheric stroke and 12 hours for vertebrobasilar stroke .
all patients who were included in these criteria went through recanalization with solitaire stent during study period .
diagnostic cerebral angiography was performed to assess the site of vessel occlusion and collateral circulation .
collateral flow was graded based on the system proposed by the american society of interventional and therapeutic neuroradiology / society of interventional radiology13 ) : grade 0 , no collateral visible to the ischemic site ; grade 1 , slow collateral to the periphery of some of the defect and to only a portion of the ischemic territory ; grade 2 , rapid collaterals to the periphery of the ischemic site with persistence of some of the defect and to only a portion of the ischemic territory ; grade 3 , collateral with slow but complete angiographic blood flow to the ischemic bed occurring by the late venous phase ; grade 4 , complete and rapid collateral blood flow to the vascular bed of the entire ischemic territory by retrograde perfusion . for the endovascular procedure , a 6- to 7-french ( fr ) guiding catheter
the guiding catheter was continuously flushed with heparinized saline ( 10 iu / ml ) .
using standard cerebral catheterization techniques , the microcatheter was guided into the occluded vessel and passed through the occluded area .
the length and shape of the occlusion segment was assessed with selective angiography using a microcatheter ( excelsior sl-10 , stryker , natick , ma , usa ) to distal portion of occlusion segment .
another larger microcatheter ( rebar-18 , ev3 , irvine , ca , usa ) replaced along the long type microwire ( transcend-300 , stryker , natick , ma , usa ) .
the solitaire stent was advanced through the microcatheter and fully deployed in the occluded segment .
stents were slightly oversized to allow proper adjustment to the vessel wall ( 4 to 6 mm diameter , 15 to 20 mm length ) .
one assistant compressed the common carotid artery to block the anterograde flow of the ica and another assistant aspirated the guiding catheter gently with a 50 cc syringe to prevent thrombus migration during stent retrieval .
when occlusion persisted , the procedure was repeated once again with the re - captured stent .
the results of recanalization were assessed by angiography immediately after the procedure according to the thrombolysis in cerebral infarction ( tici ) criteria13 ) .
demographic , clinical and laboratory data including neurological and physical examinations , nihss , routine blood analysis and 12-lead ecg were recorded for each patient . when successful recanalization ( tici of 2 or 3 ) was still not achieved with second stent retrieval , balloon angioplasty
the distal artery was selected with a microcatheter , and the microwire was exchanged with a longer microwire ( transcend-300 , stryker ) .
the gateway balloon ( stryker , natick , ma , usa ) , an over - the - wire type , was used .
the balloon diameter was 2/3 to 3/4 normal vessel diameter and the length was 5 - 10 mm longer than the occluded segment .
after positioning the balloon at the occluded segment , the balloon was inflated slowly up to nominal pressure and maintained for 120 seconds .
although permanent stent deploy was avoided as much as possible , it was used if sufficient recanalization could only be obtained with the stent deployment .
in such cases , aspirin ( 300 mg ) and clopidogrel ( 300 mg ) were administered using a levin tube before stent placement .
immediately after recanalization , systolic blood pressure was controlled between 100 - 120 mm hg using continuous iv nicardipine to prevent hyperperfusion injury .
all patients underwent ct immediately after the procedure to verify the absence of hemorrhagic transformation .
after exclusion of hemorrhage , long - term aspirin ( 100 mg / d ) was prescribed .
ct angiography and perfusion ct were performed within 72 hours and again 90 days after intervention .
the occurrence of sich was defined as clinical deterioration ( 4-point increase or more in the nihss or 1-point deterioration in the level of consciousness ) combined with a space - occupying brain hematoma on the ct or mr image3,9,14 ) .
clinical outcomes were evaluated with 90-day modified rankin scale ( mrs ) , nihss , and 90-day mortality .
an mrs of 0 to 2 was defined as a good outcome , 3 as moderate and 4 - 6 as poor .
patients were sedated with 50 - 100 ug of fentanyl . diagnostic cerebral angiography was performed to assess the site of vessel occlusion and collateral circulation .
collateral flow was graded based on the system proposed by the american society of interventional and therapeutic neuroradiology / society of interventional radiology13 ) : grade 0 , no collateral visible to the ischemic site ; grade 1 , slow collateral to the periphery of some of the defect and to only a portion of the ischemic territory ; grade 2 , rapid collaterals to the periphery of the ischemic site with persistence of some of the defect and to only a portion of the ischemic territory ; grade 3 , collateral with slow but complete angiographic blood flow to the ischemic bed occurring by the late venous phase ; grade 4 , complete and rapid collateral blood flow to the vascular bed of the entire ischemic territory by retrograde perfusion . for the endovascular procedure , a 6- to 7-french ( fr ) guiding catheter
the guiding catheter was continuously flushed with heparinized saline ( 10 iu / ml ) . using standard cerebral catheterization techniques ,
the length and shape of the occlusion segment was assessed with selective angiography using a microcatheter ( excelsior sl-10 , stryker , natick , ma , usa ) to distal portion of occlusion segment .
another larger microcatheter ( rebar-18 , ev3 , irvine , ca , usa ) replaced along the long type microwire ( transcend-300 , stryker , natick , ma , usa ) .
the solitaire stent was advanced through the microcatheter and fully deployed in the occluded segment .
stents were slightly oversized to allow proper adjustment to the vessel wall ( 4 to 6 mm diameter , 15 to 20 mm length ) .
one assistant compressed the common carotid artery to block the anterograde flow of the ica and another assistant aspirated the guiding catheter gently with a 50 cc syringe to prevent thrombus migration during stent retrieval .
when occlusion persisted , the procedure was repeated once again with the re - captured stent .
the results of recanalization were assessed by angiography immediately after the procedure according to the thrombolysis in cerebral infarction ( tici ) criteria13 ) .
demographic , clinical and laboratory data including neurological and physical examinations , nihss , routine blood analysis and 12-lead ecg were recorded for each patient . when successful recanalization ( tici of 2 or 3 ) was still not achieved with second stent retrieval , balloon angioplasty
the distal artery was selected with a microcatheter , and the microwire was exchanged with a longer microwire ( transcend-300 , stryker ) .
the gateway balloon ( stryker , natick , ma , usa ) , an over - the - wire type , was used .
the balloon diameter was 2/3 to 3/4 normal vessel diameter and the length was 5 - 10 mm longer than the occluded segment .
after positioning the balloon at the occluded segment , the balloon was inflated slowly up to nominal pressure and maintained for 120 seconds .
although permanent stent deploy was avoided as much as possible , it was used if sufficient recanalization could only be obtained with the stent deployment . in such cases , aspirin ( 300 mg ) and
immediately after recanalization , systolic blood pressure was controlled between 100 - 120 mm hg using continuous iv nicardipine to prevent hyperperfusion injury .
all patients underwent ct immediately after the procedure to verify the absence of hemorrhagic transformation .
after exclusion of hemorrhage , long - term aspirin ( 100 mg / d ) was prescribed .
ct angiography and perfusion ct were performed within 72 hours and again 90 days after intervention .
the occurrence of sich was defined as clinical deterioration ( 4-point increase or more in the nihss or 1-point deterioration in the level of consciousness ) combined with a space - occupying brain hematoma on the ct or mr image3,9,14 ) .
clinical outcomes were evaluated with 90-day modified rankin scale ( mrs ) , nihss , and 90-day mortality .
an mrs of 0 to 2 was defined as a good outcome , 3 as moderate and 4 - 6 as poor .
after initial ct , two patients who were within 3 hours of symptom onset were treated with iv tpa ( 0.9 mg / kg ) without clinical improvement over one hour .
baseline characteristics and demographic data are listed in table 1 . by the end of thromboembolectomy with a retrievable stent , 24 patients demonstrated grade 2 or 3 recanalization according to the tici grading system .
new occlusion of a distal artery from migration of the lost clot was observed in two patients with no neurologic deterioration .
balloon angioplasty was performed in four patients who showed insufficient recanalization ( tici of 0 - 1 ) after a second attempt of thromboembolectomy with solitaire .
it took an additional 7 - 10 minutes from balloon catheter preparation to 1st angiography after balloon angioplasty .
the location of occlusion was m1 in three cases and distal ica ( ophthalmic segment ) in one case .
successful recanalization was achieved after balloon angioplasty in two patients and after additional stent retrieval in one patient with m1 occlusion .
recanalization was failed even after stent retrieval and balloon angioplasty in one patient with distal ica occlusion , and recanalization was achieved after permanent stent deployment .
1 . finally , we successfully recanalized all patients with single solitaire or combined balloon angioplasty .
no patient showed re - occlusion or severe stenosis ( > 70% of normal vessel ) at 90-day follow up .
the nihss score before recanalization and at 90-day follow - up is presented in fig .
twenty - four of 28 patients showed an nihss decrease of more than three points in three days and nine showed a decrease of more than five points .
definite neurologic improvement was not seen in the other three patients , even after successful recanalization .
one patient died from progression of the mca territory infarction and severe brain edema , despite successful recanalization . at three - month follow - up , 17 patients had a good outcome ( mrs of 0 to 2 ) , 6 moderate ( mrs of 3 ) , and 5 poor ( mrs of 4 to 6 ) .
by the end of thromboembolectomy with a retrievable stent , 24 patients demonstrated grade 2 or 3 recanalization according to the tici grading system .
new occlusion of a distal artery from migration of the lost clot was observed in two patients with no neurologic deterioration .
balloon angioplasty was performed in four patients who showed insufficient recanalization ( tici of 0 - 1 ) after a second attempt of thromboembolectomy with solitaire .
it took an additional 7 - 10 minutes from balloon catheter preparation to 1st angiography after balloon angioplasty .
the location of occlusion was m1 in three cases and distal ica ( ophthalmic segment ) in one case .
successful recanalization was achieved after balloon angioplasty in two patients and after additional stent retrieval in one patient with m1 occlusion .
recanalization was failed even after stent retrieval and balloon angioplasty in one patient with distal ica occlusion , and recanalization was achieved after permanent stent deployment .
1 . finally , we successfully recanalized all patients with single solitaire or combined balloon angioplasty .
no patient showed re - occlusion or severe stenosis ( > 70% of normal vessel ) at 90-day follow up .
the nihss score before recanalization and at 90-day follow - up is presented in fig .
twenty - four of 28 patients showed an nihss decrease of more than three points in three days and nine showed a decrease of more than five points .
definite neurologic improvement was not seen in the other three patients , even after successful recanalization .
one patient died from progression of the mca territory infarction and severe brain edema , despite successful recanalization . at three - month follow - up , 17 patients had a good outcome ( mrs of 0 to 2 ) , 6 moderate ( mrs of 3 ) , and 5 poor ( mrs of 4 to 6 ) .
early recanalization of acute thromboembolic occlusions of intracranial arteries can remarkably improve the life quality of patient9,21,29 ) .
the tpa trials of ninds suggested that treatment within 3 to 4.5 hours from symptom onset was beneficial despite an increased risk of symptomatic hemorrhage22,25,26 ) .
unfortunately , presentation beyond the narrow therapeutic time window is the leading cause of treatment disqualification4,10 ) . over the past decade ,
thrombolytic agents like urokinase , tirofiban and abciximab were commonly used in ia thrombolysis and some resulted in a good prognosis .
even so , ia thrombolysis always has a risk of sich , especially when a large amount of thrombolytic agent is used3,7,25 ) .
compared to ia fibrinolytic strategies , mechanical thromboembolectomy offers the advantage of a potential reduction in the rate of hemorrhagic transformation .
the merci trials demonstrated that endovascular mechanical thromboembolectomy is technically efficacious in achieving recanalization in patients within 8 hours of stroke onset10,11,23,24 ) .
the penumbra system has shown promising clinical outcome , with successful recanalization in 82 to 100% of cases2,12,17 ) . nevertheless , these instruments have some flaws , such as occasional difficulty passing a carotid siphon due to its relatively large profile , especially in elderly patients with tortuous vessels .
the repetitive push and pull action of the separator wire also increases the possibility of vessel injury or perforation resulting in reocclusion or hemorrhage . in real practice ,
the solitaire ab / fr stent has recently been considered as a part of the standard care for acute intracranial artery occlusion .
this device advances in the microcatheter and can approach almost every vessel that is selected with the microcatheter .
the solitaire device is an intracranial stent that is fully retrievable after full deployment and there is no need for aggressive antiplatelet therapy .
several recent studies suggested a good revascularization rate with the solitaire stent6,16,18,27 ) . despite promising results , thromboembolectomy with solitaire
recanalization can fail in cases when severe stenosis is accompanied by occlusion , when an occlusive clot is attached firmly to the endothelium , or when the clot is too hard to be opened by a self - expandable stent strut , or when severe vasospasm happens after thromboembolectomy .
in such situations , the occlusive clot can not be removed efficiently and balloon angioplasty can be an effective secondary method .
a balloon can dilate the stenosis or spasm , loosen the endothelial - clot attachment , and shatter hard clot , enabling efficacious clot removal and recanalization . in our consecutive case - review series with the solitaire stent alone
the other patients , who failed recanalization after stent retrieval , also achieved successful recanalization after balloon angioplasty or permanent stent deployment .
complete revascularization was achieved in 60% ( tici of 3 ) . though our study is limited by small sample size
, our results suggest that most patients with failed solitaire thromboembolectomy can achieve successful recanalization with subsequent balloon angioplasty .
we utilized an over - the - wire type gateway balloon , which is more easily advanced to the distal vessel than the same sized monorail type .
although we avoided permanent stent deploy if possible , successful recanalization was failed in one patient even after stent retrieval and balloon angioplasty , and sufficient blood flow was achieved after permanent stent deploy . with this single or combined procedure
, we achieved a recanalization rate of 100% ( tici of 2 or 3 ) .
the mean time from femoral puncture to recanalization was only 38 mins ( range 20 - 62 ) .
after recanalization , 85% of the patients experienced a 4-point improvement on the nihss score at discharge and 60% of patients achieved a good clinical outcome at three months .
the lack of sich after recanalization in our patient series may be explained by several factors , including proper sedation during the procedure , non - excessive angioplasty , strict blood pressure control , and above all , avoidance of ia thrombolytic agents .
the mortality during study period in this consecutive series was 3.5% , as one patient had died at three - month follow - up .
there are , however , some drawbacks to the use of intracranial stents and balloons for acute recanalization in ischemic stroke .
clot migration was observed in only two cases in our consecutive case analysis perhaps because most of the clot was removed with aspiration of the guiding catheter during stent retrieval .
there was no aggravation of the neurological deficit or enlargement of infarction size in these two cases .
another concern with our procedure is the possibility of causing endothelial injury or dissection during stent retrieval or angioplasty , which can lead to secondary stenosis or blood leakage .
finally , the risk of hyperperfusion also increases if there is preexisting , severe and chronic stenosis .
it is important not to attempt full recovery of vessel diameter as even small increases in radius greatly increase the volume of flow according to poiseuille 's law . in our opinion , 50 - 70% restoration of the normal diameter is sufficient for saving the penumbra and preventing hyperperfusion . if a perfusion defect is discovered on follow - up study , it is not too late to carry out additional angioplasty or stent deployment .
the solitaire device is technically safe and effective in clearing cerebral thrombi and restoring flow to the neurovasculature .
also , balloon angioplasty is an effective secondary procedure when sufficient restoration of blood flow is not achieved with stenting alone .
although our case number is small and a larger scale study is required , the combination of a retrievable stent and balloon is a promising first - line therapy for acute occlusion of intracranial artery due to its high success rate and low complication rate .
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### Summary:
: objectivesudden major cerebral artery occlusion often resists recanalization with currently available techniques or can results in massive symptomatic intracranial hemorrhage ( sich ) after thrombolytic therapy . the purpose of this study was to examine mechanical recanalization with a retrievable self - expanding stent and balloon in acute intracranial artery occlusions.methodstwenty-eight consecutive patients with acute intracranial artery occlusions
were treated with a solitaire retrievable stent .
balloon angioplasty was added if successful recanalization was not achieved after stent retrieval .
the angiographic outcome was assessed by thrombolysis in cerebral infarction ( tici ) and the clinical outcomes were assessed by the national institutes of health stroke scale ( nihss ) and the modified rankin scale ( mrs).resultsat baseline , mean age was 69.4 years and mean initial nihss score was 12.5 .
a recanalization to tici 2 or 3 was achieved in 24 patients ( 85% ) after stent retrieval .
successful recanalization was achieved after additional balloon angioplasty in 4 patients . at 90-day follow - up , 24 patients ( 85% )
had a nihss improvement of 4 and 17 patients ( 60% ) had a good outcome ( mrs 2 ) .
although there was sich , there was one death associated with the procedure.conclusionmechanical thromboembolectomy with a retrievable stent followed by additional balloon angioplasty is a safe and effective first - line therapy for acute intracranial artery occlusions especially in case of unsuccessful recanalization after stent thrombectomy .
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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:
: male sprague - dawley rats ( 8 weeks old , 200250 g ) and c57/b6 mice ( 8 weeks old ) were housed in air - conditioned rooms ( 2224c ) under a 12/12-h light / dark cycle and fed standard chow .
p53-null ( 810 weeks old , mixed background c57bl/6j and 129/sv ) mice were described previously ( 19 ) .
homozygous wild - type ( wt ) and knockout ( ko ) mice were originated from heterozygous mating , so only littermate wt and ko animals were compared in each experiment .
animals were treated and killed when they were 12 to 14 weeks of age before any sign of morbidity resulting from tumor development occurred .
animals were killed by decapitation between 1000 and 1200 h. animal experiments were conducted in accordance with the standards approved by the faculty animal committee at the university of santiago de compostela , and the experiments were performed in agreement with the rules of laboratory animal care and international law on animal experimentation . rats ( n = 8/group ) , were assigned to one of the following groups : fed ad libitum , deprived of food for 48 h , and fasted during 48 h and refed during 24 h. all animals had free access to tap water .
rats were anesthetized by an intraperitoneal injection of ketamine ( 100 mg / kg body wt)/xylazine ( 15 mg / kg body wt ) .
mice were anesthetized by an intraperitoneal injection of tribromoethanol ( 480 mg / kg ; sigma - aldrich , st louis , mo ) .
intracerebroventricular cannulae were implanted stereotaxically in rats ( 20 ) or mice ( 21 ) , as described previously .
rats received an intracerebroventricular administration of 5 l of vehicle or ghrelin ( 5 g ; bachem , bubendorf , switzerland ) .
for the inhibition of sirt1 , we used two potent specific inhibitors of sirt1 : ex527 ( 1 to 5 - 10 g in a total volume of 5 l ; tocris bioscience , st .
louis , mo ) ( 22 ) and sirtinol ( 1 to 5 - 10 g in a total volume of 5 l ; tocris bioscience ) ( 23 ) before ghrelin administration .
for the experiments involving only two groups ( vehicle versus ghrelin ) , the vehicle was saline .
for the experiments involving sirt1 inhibitors , the vehicle was dmso , because ex527 and sirtinol were both diluted in dmso .
mice received an intracerebroventricular administration of vehicle , ghrelin ( 5 g ) , or aicar ( 3 g ; sigma - aldrich a9978 ) in a total volume of 2 l .
for the experiments involving vehicle versus ghrelin and vehicle versus aicar , the vehicle was saline .
we used the same dose of ghrelin for both rats and mice because this dose has been demonstrated to be effective in both species ( 2 ) .
we used eight rats per group , and the experiments were repeated at least twice .
hypothalami were homogenized in ice - cold lysis buffer containing 50 mmol / l tris - hcl ( ph 7.5 ) , 1 mmol / l egta , 1 mmol / l edta , 1% triton x-100 , 1 mmol / l sodium orthovanadate , 50 mmol / l sodium fluoride , 5 mmol / l sodium pyrophosphate , 0.27 mol / l sucrose , 0.1% 2-mercaptoethanol , and complete protease inhibitor cocktail ( 1 tablet/50 ml ; roche diagnostics , mannheim , germany ) .
homogenates were centrifuged at 13,000 g for 10 min at 4c , supernatants were removed , and aliquots were snap - frozen in liquid nitrogen .
hypothalamus lysate ( 40 g ) was subjected to sds - page on 6% polyacrylamide gels and electrotransferred on a polyvinylidene fluoride membrane .
membranes were blocked for 1 h in tbs - tween 20 ( tbst : 50 mmol / l tris - hcl [ ph 7.5 ] , 0.15 mol / l nacl , and 0.1% tween 20 ) containing 5% skimmed milk or 3% bsa ( for pampk thr and pacc ser ) and probed for 16 h at 4c in tbst , 5% skimmed milk , or 3% bsa ( for pampk thr , pacc ser , sirt1 , and acetyl - p53-lys ) with the appropriate dilution of the indicated antibodies ( acetyl - coa carboxylase [ acc ] : 1:1500 ; pacc : 1:2000 ; ampk1 : 1:1000 ; ampk2 : 1:1000 ; pampk : 1:2000 ; -actin ( loading control ) : 1:2000 ) .
acc was detected using horseradish peroxidase ( hrp)-conjugated coupled streptavidin ( amersham biosciences , little chalfont , u.k . ) .
detection of proteins was performed using hrp - conjugated secondary antibodies and an enhanced chemiluminescence reagent ( amersham biosciences ) .
acc , pacc-ser , ampk1 , and ampk2 were obtained from upstate biotechnology ( temecula , ca ) ; pampk-thr from cell signaling ; fatty acid synthase ( fas ) , pcreb , and foxo1 from santa cruz biotechnology ( santa cruz , ca ) ; and -actin from abcam ( cambridge , u.k . ) , as described previously ( 6 ) . for the blotting assays , the experiments constituted by two groups : sprague - dawley rats and mice ( wt and p53 ko ) treated with ghrelin or aicar and analyzed using a nonparametric mann
constituted by four groups ( sprague - dawley rats treated with vehicle , ghrelin , ex527 , and ex527 + ghrelin , or with vehicle , ghrelin , sirtinol , and sirtinol + ghrelin ) , the data were analyzed by two - way anova , followed by a post hoc multiple comparison test ( tukey s test ) .
coronal hypothalamic sections ( 16 m ) were cut on a cryostat and immediately stored at 80c until hybridization . for agrp , npy , and bsx mrna detection
these probes were 3-end labeled with [ s]deoxy - atp using terminal deoxynucleotidyl transferase .
the specificity of the probes was confirmed by incubating the sections with an excess of the unlabeled probes , as reported previously ( 24,25 ) . in situ hybridizations
antisense oligonucleotides for in situ hybridization analysis the frozen sections were fixed with 4% paraformaldehyde in phosphate buffer ( 0.1 mol / l , ph 7.4 ) at room temperature for 30 min .
they were dehydrated using 70% , 80% , 90% , 95% , and 100% ethanol for 5 min each .
the hybridization solution contained 5 10 ( agrp and bsx ) or 1 10 cpm ( npy ) per slide of the labeled probe , 4 standard saline citrate ( ssc ) , 50% deionized formamide , 1 denhardt s solution , 10% dextran sulfate , and 10 g / ml sheared , single - stranded salmon sperm dna . afterward , the hybridization sections were sequentially washed in 1 ssc at room temperature , four times in 1 ssc at 42c ( 30 min / wash ) , and once in 1 ssc at room temperature ( 1 h ) and then rinsed in water and ethanol . finally , the sections were air - dried and exposed to hyperfilm -max ( amersham biosciences ) at room temperature for 4 to 6 days for agrp and npy and for 21 days for bsx .
the slides were developed in kodak d-19 developer ( eastman kodak co. , rochester , ny ) , fixed ( kodak fixer ) , and counterstained with methylene blue . to compare anatomically similar regions ,
the slides from control and treated animals at each treatment time were always exposed to the same autoradiographic film .
all sections were scanned , and the specific hybridization signal was quantified by densitometry using the molecular analyst digital imaging system ( bio - rad laboratories inc . , richmond , ca ) .
the optical density of the hybridization signal was determined and subsequently corrected by the optical density of its adjacent background value .
for this reason , a rectangle with the same dimensions in each case was drawn enclosing the hybridization signal over each nucleus and over adjacent brain areas of each section ( background ) .
we used 16 to 20 sections for each animal ( 45 slides , 4 sections / slide ) .
the mean of these 16 to 20 values was used as the densitometry value for each animal .
chronic intracerebroventricular and intracardiac cannulae were implanted under ketamine / xylazine anesthesia , as described above .
after surgery , the animals were placed directly in isolation test chambers for 5 days and were given free access to regular rat chow and tap water .
on the day of the experiment , blood samples ( 0.3 ml ) were withdrawn at the appropriate times . the animals ( n = 79 rats / group ) received vehicle , ghrelin ( 12 nmol / kg i.v . ) , ex527 ( 1 g i.c.v . ) , or ex527 + ghrelin .
plasma growth hormone ( gh ) concentrations were determined by double - antibody radioimmunoassay using materials supplied by the national hormone pituitary program , as described previously ( 27 ) .
values are expressed in terms of the gh reference preparation ( gh - rp-2 ) .
the experiments constituted by two groups : sprague - dawley rats and mice ( wt and p53 ko ) treated with ghrelin or aicar and analyzed using a nonparametric mann whitney test . in the experiments constituted by four groups ( sprague - dawley rats treated with vehicle , ghrelin , ex527 , and ex527 + ghrelin , and vehicle , ghrelin , sirtinol , and sirtinol + ghrelin ) ,
the data were analyzed by two - way anova , followed by a post hoc multiple comparison test ( tukey s test ) .
data are expressed as mean sem and analyzed using pasw statistics 18.0 software ( spss inc . ,
chicago , il ) . a value of p < 0.05 was considered as being significant .
male sprague - dawley rats ( 8 weeks old , 200250 g ) and c57/b6 mice ( 8 weeks old ) were housed in air - conditioned rooms ( 2224c ) under a 12/12-h light / dark cycle and fed standard chow .
p53-null ( 810 weeks old , mixed background c57bl/6j and 129/sv ) mice were described previously ( 19 ) .
homozygous wild - type ( wt ) and knockout ( ko ) mice were originated from heterozygous mating , so only littermate wt and ko animals were compared in each experiment .
animals were treated and killed when they were 12 to 14 weeks of age before any sign of morbidity resulting from tumor development occurred .
animals were killed by decapitation between 1000 and 1200 h. animal experiments were conducted in accordance with the standards approved by the faculty animal committee at the university of santiago de compostela , and the experiments were performed in agreement with the rules of laboratory animal care and international law on animal experimentation .
rats ( n = 8/group ) , were assigned to one of the following groups : fed ad libitum , deprived of food for 48 h , and fasted during 48 h and refed during 24 h. all animals had free access to tap water .
rats were anesthetized by an intraperitoneal injection of ketamine ( 100 mg / kg body wt)/xylazine ( 15 mg / kg body wt ) .
mice were anesthetized by an intraperitoneal injection of tribromoethanol ( 480 mg / kg ; sigma - aldrich , st louis , mo ) .
intracerebroventricular cannulae were implanted stereotaxically in rats ( 20 ) or mice ( 21 ) , as described previously .
rats received an intracerebroventricular administration of 5 l of vehicle or ghrelin ( 5 g ; bachem , bubendorf , switzerland ) .
for the inhibition of sirt1 , we used two potent specific inhibitors of sirt1 : ex527 ( 1 to 5 - 10 g in a total volume of 5 l ; tocris bioscience , st .
louis , mo ) ( 22 ) and sirtinol ( 1 to 5 - 10 g in a total volume of 5 l ; tocris bioscience ) ( 23 ) before ghrelin administration . for the experiments involving only two groups ( vehicle versus ghrelin ) ,
for the experiments involving sirt1 inhibitors , the vehicle was dmso , because ex527 and sirtinol were both diluted in dmso .
mice received an intracerebroventricular administration of vehicle , ghrelin ( 5 g ) , or aicar ( 3 g ; sigma - aldrich a9978 ) in a total volume of 2 l .
for the experiments involving vehicle versus ghrelin and vehicle versus aicar , the vehicle was saline .
we used the same dose of ghrelin for both rats and mice because this dose has been demonstrated to be effective in both species ( 2 ) .
we used eight rats per group , and the experiments were repeated at least twice .
hypothalami were homogenized in ice - cold lysis buffer containing 50 mmol / l tris - hcl ( ph 7.5 ) , 1 mmol / l egta , 1 mmol / l edta , 1% triton x-100 , 1 mmol / l sodium orthovanadate , 50 mmol / l sodium fluoride , 5 mmol / l sodium pyrophosphate , 0.27 mol / l sucrose , 0.1% 2-mercaptoethanol , and complete protease inhibitor cocktail ( 1 tablet/50 ml ; roche diagnostics , mannheim , germany ) . homogenates were centrifuged at 13,000 g for 10 min at 4c , supernatants were removed , and aliquots were snap - frozen in liquid nitrogen .
hypothalamus lysate ( 40 g ) was subjected to sds - page on 6% polyacrylamide gels and electrotransferred on a polyvinylidene fluoride membrane .
membranes were blocked for 1 h in tbs - tween 20 ( tbst : 50 mmol / l tris - hcl [ ph 7.5 ] , 0.15 mol / l nacl , and 0.1% tween 20 ) containing 5% skimmed milk or 3% bsa ( for pampk thr and pacc ser ) and probed for 16 h at 4c in tbst , 5% skimmed milk , or 3% bsa ( for pampk thr , pacc ser , sirt1 , and acetyl - p53-lys ) with the appropriate dilution of the indicated antibodies ( acetyl - coa carboxylase [ acc ] : 1:1500 ; pacc : 1:2000 ; ampk1 : 1:1000 ; ampk2 : 1:1000 ; pampk : 1:2000 ; -actin ( loading control ) : 1:2000 ) .
acc was detected using horseradish peroxidase ( hrp)-conjugated coupled streptavidin ( amersham biosciences , little chalfont , u.k . ) .
detection of proteins was performed using hrp - conjugated secondary antibodies and an enhanced chemiluminescence reagent ( amersham biosciences ) .
acc , pacc-ser , ampk1 , and ampk2 were obtained from upstate biotechnology ( temecula , ca ) ; pampk-thr from cell signaling ; fatty acid synthase ( fas ) , pcreb , and foxo1 from santa cruz biotechnology ( santa cruz , ca ) ; and -actin from abcam ( cambridge , u.k . ) , as described previously ( 6 ) .
for the blotting assays , the experiments constituted by two groups : sprague - dawley rats and mice ( wt and p53 ko ) treated with ghrelin or aicar and analyzed using a nonparametric mann whitney test . in the experiments constituted by four groups ( sprague - dawley rats treated with vehicle , ghrelin , ex527 , and ex527 + ghrelin , or with vehicle , ghrelin , sirtinol , and sirtinol + ghrelin ) , the data were analyzed by two - way anova , followed by a post hoc multiple comparison test ( tukey s test ) .
coronal hypothalamic sections ( 16 m ) were cut on a cryostat and immediately stored at 80c until hybridization . for agrp , npy , and bsx mrna detection
these probes were 3-end labeled with [ s]deoxy - atp using terminal deoxynucleotidyl transferase .
the specificity of the probes was confirmed by incubating the sections with an excess of the unlabeled probes , as reported previously ( 24,25 ) . in situ hybridizations
antisense oligonucleotides for in situ hybridization analysis the frozen sections were fixed with 4% paraformaldehyde in phosphate buffer ( 0.1 mol / l , ph 7.4 ) at room temperature for 30 min .
they were dehydrated using 70% , 80% , 90% , 95% , and 100% ethanol for 5 min each .
the hybridization solution contained 5 10 ( agrp and bsx ) or 1 10 cpm ( npy ) per slide of the labeled probe , 4 standard saline citrate ( ssc ) , 50% deionized formamide , 1 denhardt s solution , 10% dextran sulfate , and 10 g / ml sheared , single - stranded salmon sperm dna .
afterward , the hybridization sections were sequentially washed in 1 ssc at room temperature , four times in 1 ssc at 42c ( 30 min / wash ) , and once in 1 ssc at room temperature ( 1 h ) and then rinsed in water and ethanol .
finally , the sections were air - dried and exposed to hyperfilm -max ( amersham biosciences ) at room temperature for 4 to 6 days for agrp and npy and for 21 days for bsx .
the slides were developed in kodak d-19 developer ( eastman kodak co. , rochester , ny ) , fixed ( kodak fixer ) , and counterstained with methylene blue . to compare anatomically similar regions ,
the slides from control and treated animals at each treatment time were always exposed to the same autoradiographic film .
all sections were scanned , and the specific hybridization signal was quantified by densitometry using the molecular analyst digital imaging system ( bio - rad laboratories inc . , richmond , ca ) .
the optical density of the hybridization signal was determined and subsequently corrected by the optical density of its adjacent background value .
for this reason , a rectangle with the same dimensions in each case was drawn enclosing the hybridization signal over each nucleus and over adjacent brain areas of each section ( background ) .
we used 16 to 20 sections for each animal ( 45 slides , 4 sections / slide ) .
the mean of these 16 to 20 values was used as the densitometry value for each animal .
chronic intracerebroventricular and intracardiac cannulae were implanted under ketamine / xylazine anesthesia , as described above .
after surgery , the animals were placed directly in isolation test chambers for 5 days and were given free access to regular rat chow and tap water .
on the day of the experiment , blood samples ( 0.3 ml ) were withdrawn at the appropriate times .
the animals ( n = 79 rats / group ) received vehicle , ghrelin ( 12 nmol / kg i.v . ) , ex527 ( 1 g i.c.v . ) , or ex527 + ghrelin .
plasma growth hormone ( gh ) concentrations were determined by double - antibody radioimmunoassay using materials supplied by the national hormone pituitary program , as described previously ( 27 ) .
values are expressed in terms of the gh reference preparation ( gh - rp-2 ) .
the experiments constituted by two groups : sprague - dawley rats and mice ( wt and p53 ko ) treated with ghrelin or aicar and analyzed using a nonparametric mann whitney test . in the experiments constituted by four groups ( sprague - dawley rats treated with vehicle , ghrelin , ex527 , and ex527 + ghrelin , and vehicle , ghrelin , sirtinol , and sirtinol + ghrelin ) , the data were analyzed by two - way anova , followed by a post hoc multiple comparison test ( tukey s test ) .
data are expressed as mean sem and analyzed using pasw statistics 18.0 software ( spss inc . ,
chicago , il ) . a value of p < 0.05 was considered as being significant .
rats fasted during 48 h exhibited a loss of body weight , whereas the refeeding during 24 h partially led to a substantial recovery ( fig .
acetyl - p53 levels , a marker of sirt1 activity in vivo ( 28 ) , were decreased in the hypothalamus of fasted rats ( f2,18 = 3.651 , p < 0.05 ) , whereas those levels were similar to baseline in rats after refeeding ( fig .
because ghrelin is a key player for increasing feeding behavior , we tested the hypothesis that central ghrelin administration might stimulate hypothalamic sirt1 activity
. as previously reported , ghrelin increased food intake after 2 h ( f1,13 = 24.161 , p < 0.001 ; fig .
1c ) and 6 h ( f1,13 = 36.14 , p < 0.001 ; fig .
1e ) ( 29 ) and decreased hypothalamic acetyl - p53 levels after 2 h ( f1,13 = 7.915 , p < 0.01 ; fig .
1d ) and 6 h ( f1,13 = 7.645 , p < 0.05 ; fig .
a : fasting for 48 h caused a significant ( p < 0.001 ) decrease in body weight , whereas refeeding during 24 h partially recovered the weight loss .
b : hypothalamic acetylated p53 levels decreased in fasted rats and recovered in refed rats .
effects of intracerebroventricular ghrelin injection ( 5 g / rat ) after 2 h on food intake ( c ) , and hypothalamic acetylated p53 levels ( d ) .
effects of intracerebroventricular ghrelin injection ( 5 g / rat ) after 6 h on food intake ( e ) , and hypothalamic acetylated p53 levels ( f ) .
values were normalized to those of the internal control -actin , and the results are expressed as arbitrary units .
values are the mean sem . * p < 0.05 , * * p < 0.01 , * * * p < 0.001 .
we next studied the functional relevance of these findings by assessing whether the pharmacologic blockade of sirt1 activity might regulate the orexigenic action of ghrelin .
first , we observed that the central injection of ex527 , a potent inhibitor of sirt1 activity , increased hypothalamic acetyl - p53 levels at different doses ( 1 , 5 , and 10 g ; supplementary fig .
we then centrally administered ghrelin , ex527 , and ex527 + ghrelin to the rats .
we found that ghrelin increased food intake at 2 h ( data not shown ) and 6 h ( f3,27 = 12.282 , p < 0.001 ; fig .
2a ) , but when the sirt1 inhibitor was administered 20 min before ghrelin , the orexigenic action of ghrelin was markedly blunted after 6 h ( fig .
2a ) . because ghrelin increases food intake through its effects on hypothalamic fatty acid metabolism ( 5,6 ) , we next assessed the levels of several key enzymes for the synthesis of lipids .
we found that 6 h after an intracerebroventricular ghrelin injection , pampk levels were increased ( f3,28 = 2.455 , p < 0.05 ) , but acc levels were decreased ( f3,27 = 6.045 , p < 0.01 ) .
. a : effects of intracerebroventricular ghrelin injection ( 5 g / rat ) , ex527 ( 1 g / rat ) , and ghrelin + ex527 on food intake after 6 h. hypothalamic protein levels of pampk , ampk1 , ampk2 , pacc , acc , fas ( b and c ) , pcreb , foxo1 ( d ) , and bsx , npy , and agrp ( e and f ) after 6 h of ghrelin and ex527 injection .
values were normalized to those of the internal control -actin , and the results are expressed as arbitrary units .
values are the mean sem . * p < 0.05 , * * p < 0.01 , * * * p < 0.001 . it is important to note that even though pampk levels were increased , pacc did not reach statistical significance , probably because of the different kinetics of phosphorylation of both enzymes ( 6 ) .
furthermore , the higher expression of the transcription factors foxo1 ( f3,27 = 2.509 , p < 0.05 ) , pcreb ( f3,26 = 3.668 , p < 0.05 ; fig .
2d ) , and bsx ( f3,26 = 3.526 , p < 0.05 ; fig .
2e and f ) and the neuropeptides npy ( f(3,26 ) = 4.362 , p < 0.05 ) and agrp ( f3,26 = 3.33 , p < 0.05 ; fig .
2e and f ) in the hypothalamic arcuate nucleus induced by ghrelin was also abolished when the sirt1 inhibitor was coadministered .
when we used sirtinol , another inhibitor of sirt1 activity , results were similar to those obtained with ex527 ( supplementary fig .
1 ) . tumor suppressor protein p53 is a substrate of sirt1 , and it is found hyperacetylated in sirt1 ko mice ( 30 ) . because a recent report showed that p53 is involved in energy metabolism and homeostasis ( 31 ) ,
for this purpose , we treated wt and p53 ko mice with intracerebroventricular ghrelin , following the same protocol as that described above .
the p53 ko mice did not show alterations in body weight , food intake , fat mass , or nonfat mass compared with wt littermates ( supplementary fig .
d ) . as expected , central ghrelin administration increased food intake in wt animals , whereas identical intracerebroventricular ghrelin treatment in p53 ko animals had no effect on food intake after 2 ( fig .
effects of intracerebroventricular ghrelin injection ( 5 g / mouse ) on food intake after 2 h ( a ) and 6 h ( b ) in wt and p53 ko mice .
hypothalamic protein levels of pampk , ampk1 , ampk2 , pacc , acc , and fas after 6 h of ghrelin injection ( c and d ) .
values were normalized with to those of the internal control -actin , and the results are expressed as arbitrary units .
values are the mean sem . * p < 0.05 , * * p < 0.01 .
no principal differences were found between wt and p53 ko mice regarding the expression of ampk1 , ampk2 , or fas ( fig .
it is noteworthy that we found that 6 h after its central injection , ghrelin increased pampk levels in wt mice ( f1,12 = 4.466 , p < 0.05 ) but failed to do so in p53 ko mice ( fig .
3c and d ) , suggesting that p53 is an essential mediator of ghrelin actions on ampk .
the levels of pampk and pacc are correlated in normal conditions ; however , we found that the hypothalamic levels of pacc are downregulated in p53 ko mice ( f1,12 = 8.576 , p < 0.01 ) but not in wt mice ( fig .
although we do not have a clear explanation for these results , it seems that ghrelin is able to activate acc when p53 is not present , suggesting that p53 might also regulate the actions of ghrelin on different key enzymes modulating fatty acid metabolism .
further studies analyzing not only protein levels but also enzymatic activity and lipolysis / lipogenesis will be necessary to address this issue .
furthermore , we detected that central ghrelin injection decreased acc levels in both wt ( f1,12 = 2.844 , p < 0.05 ) and p53 ko mice ( f1,12 = 6.699 , p < 0.01 ; fig .
3c and d ) , indicating that p53 is not essential for ghrelin - mediated acc regulation .
central injection of aicar , a potent activator of ampk activity , stimulates food intake in rodents ( 32 ) . to determine whether p53 is a crucial player for the orexigenic action of aicar
, we centrally treated p53 ko mice with aicar ( 3 g ) and found a stimulation in food intake after 6 h ( f1,12 = 3.542 , p < 0.05 ; fig .
hypothalamic pampk levels were also increased in p53 ko mice treated with aicar ( f1,12 = 4.479 ; fig .
therefore , our data indicate that p53 is not required for the orexigenic action of direct ampk activators .
a : effects of intracerebroventricular aicar injection ( 3 g / mouse ) on food intake after 6 h in p53 ko mice .
b and c : hypothalamic protein levels of pampk , pacc , ampk1 , ampk2 , acc , and fas after 6 h of aicar injection .
values were normalized to those of the internal control -actin , and the results are expressed as arbitrary units .
finally , we assessed whether the sirt1 pathway is mediating other neuroendocrine actions of ghrelin , namely gh secretion .
administration of ghrelin ( 27 ) led to the expected increase in plasma gh levels at 5 , 10 , and 15 min ( fig .
5a ) , whereas the central blockade of sirt1 did not alter that response ( fig .
ghrelin exhibited a similar stimulatory effect in both area under the curve and mean peak gh levels ( fig .
a : effects of intravenous ghrelin injection ( 12 nmol / kg ) , intracerebroventricular ex527 ( 1 g / rat ) , and ghrelin + ex527 on plasma gh levels in adult male freely moving rats .
area under the curve ( auc ) ( b ) and mean peak gh ( c ) levels .
rats fasted during 48 h exhibited a loss of body weight , whereas the refeeding during 24 h partially led to a substantial recovery ( fig .
acetyl - p53 levels , a marker of sirt1 activity in vivo ( 28 ) , were decreased in the hypothalamus of fasted rats ( f2,18 = 3.651 , p < 0.05 ) , whereas those levels were similar to baseline in rats after refeeding ( fig .
because ghrelin is a key player for increasing feeding behavior , we tested the hypothesis that central ghrelin administration might stimulate hypothalamic sirt1 activity
. as previously reported , ghrelin increased food intake after 2 h ( f1,13 = 24.161 , p < 0.001 ; fig .
1c ) and 6 h ( f1,13 = 36.14 , p < 0.001 ; fig .
1e ) ( 29 ) and decreased hypothalamic acetyl - p53 levels after 2 h ( f1,13 = 7.915 , p < 0.01 ; fig .
1d ) and 6 h ( f1,13 = 7.645 , p < 0.05 ; fig .
a : fasting for 48 h caused a significant ( p < 0.001 ) decrease in body weight , whereas refeeding during 24 h partially recovered the weight loss .
b : hypothalamic acetylated p53 levels decreased in fasted rats and recovered in refed rats .
effects of intracerebroventricular ghrelin injection ( 5 g / rat ) after 2 h on food intake ( c ) , and hypothalamic acetylated p53 levels ( d ) .
effects of intracerebroventricular ghrelin injection ( 5 g / rat ) after 6 h on food intake ( e ) , and hypothalamic acetylated p53 levels ( f ) .
values were normalized to those of the internal control -actin , and the results are expressed as arbitrary units .
* p < 0.05 , * * p < 0.01 , * * * p < 0.001 .
we next studied the functional relevance of these findings by assessing whether the pharmacologic blockade of sirt1 activity might regulate the orexigenic action of ghrelin .
first , we observed that the central injection of ex527 , a potent inhibitor of sirt1 activity , increased hypothalamic acetyl - p53 levels at different doses ( 1 , 5 , and 10 g ; supplementary fig .
we then centrally administered ghrelin , ex527 , and ex527 + ghrelin to the rats .
we found that ghrelin increased food intake at 2 h ( data not shown ) and 6 h ( f3,27 = 12.282 , p < 0.001 ; fig .
2a ) , but when the sirt1 inhibitor was administered 20 min before ghrelin , the orexigenic action of ghrelin was markedly blunted after 6 h ( fig .
because ghrelin increases food intake through its effects on hypothalamic fatty acid metabolism ( 5,6 ) , we next assessed the levels of several key enzymes for the synthesis of lipids .
we found that 6 h after an intracerebroventricular ghrelin injection , pampk levels were increased ( f3,28 = 2.455 , p < 0.05 ) , but acc levels were decreased ( f3,27 = 6.045 , p < 0.01 ) .
a : effects of intracerebroventricular ghrelin injection ( 5 g / rat ) , ex527 ( 1 g / rat ) , and ghrelin + ex527 on food intake after 6 h. hypothalamic protein levels of pampk , ampk1 , ampk2 , pacc , acc , fas ( b and c ) , pcreb , foxo1 ( d ) , and bsx , npy , and agrp ( e and f ) after 6 h of ghrelin and ex527 injection .
values were normalized to those of the internal control -actin , and the results are expressed as arbitrary units .
* p < 0.05 , * * p < 0.01 , * * * p < 0.001 . it is important to note that even though pampk levels were increased , pacc did not reach statistical significance , probably because of the different kinetics of phosphorylation of both enzymes ( 6 ) . furthermore , the higher expression of the transcription factors foxo1 ( f3,27 = 2.509 , p < 0.05 ) , pcreb ( f3,26 = 3.668 , p < 0.05 ; fig .
2d ) , and bsx ( f3,26 = 3.526 , p < 0.05 ; fig .
2e and f ) and the neuropeptides npy ( f(3,26 ) = 4.362 , p < 0.05 ) and agrp ( f3,26 = 3.33 , p < 0.05 ; fig .
2e and f ) in the hypothalamic arcuate nucleus induced by ghrelin was also abolished when the sirt1 inhibitor was coadministered .
when we used sirtinol , another inhibitor of sirt1 activity , results were similar to those obtained with ex527 ( supplementary fig .
tumor suppressor protein p53 is a substrate of sirt1 , and it is found hyperacetylated in sirt1 ko mice ( 30 ) . because a recent report showed that p53 is involved in energy metabolism and homeostasis ( 31 ) ,
for this purpose , we treated wt and p53 ko mice with intracerebroventricular ghrelin , following the same protocol as that described above .
the p53 ko mice did not show alterations in body weight , food intake , fat mass , or nonfat mass compared with wt littermates ( supplementary fig .
d ) . as expected , central ghrelin administration increased food intake in wt animals , whereas identical intracerebroventricular ghrelin treatment in p53 ko animals had no effect on food intake after 2 ( fig .
effects of intracerebroventricular ghrelin injection ( 5 g / mouse ) on food intake after 2 h ( a ) and 6 h ( b ) in wt and p53 ko mice .
hypothalamic protein levels of pampk , ampk1 , ampk2 , pacc , acc , and fas after 6 h of ghrelin injection ( c and d ) .
values were normalized with to those of the internal control -actin , and the results are expressed as arbitrary units .
values are the mean sem . * p < 0.05 , * * p < 0.01 .
no principal differences were found between wt and p53 ko mice regarding the expression of ampk1 , ampk2 , or fas ( fig .
it is noteworthy that we found that 6 h after its central injection , ghrelin increased pampk levels in wt mice ( f1,12 = 4.466 , p < 0.05 ) but failed to do so in p53 ko mice ( fig .
3c and d ) , suggesting that p53 is an essential mediator of ghrelin actions on ampk .
the levels of pampk and pacc are correlated in normal conditions ; however , we found that the hypothalamic levels of pacc are downregulated in p53 ko mice ( f1,12 = 8.576 , p < 0.01 ) but not in wt mice ( fig .
although we do not have a clear explanation for these results , it seems that ghrelin is able to activate acc when p53 is not present , suggesting that p53 might also regulate the actions of ghrelin on different key enzymes modulating fatty acid metabolism .
further studies analyzing not only protein levels but also enzymatic activity and lipolysis / lipogenesis will be necessary to address this issue .
furthermore , we detected that central ghrelin injection decreased acc levels in both wt ( f1,12 = 2.844 , p < 0.05 ) and p53 ko mice ( f1,12 = 6.699 , p < 0.01 ; fig .
3c and d ) , indicating that p53 is not essential for ghrelin - mediated acc regulation .
central injection of aicar , a potent activator of ampk activity , stimulates food intake in rodents ( 32 ) . to determine whether p53 is a crucial player for the orexigenic action of aicar
, we centrally treated p53 ko mice with aicar ( 3 g ) and found a stimulation in food intake after 6 h ( f1,12 = 3.542 , p < 0.05 ; fig .
hypothalamic pampk levels were also increased in p53 ko mice treated with aicar ( f1,12 = 4.479 ; fig .
therefore , our data indicate that p53 is not required for the orexigenic action of direct ampk activators
a : effects of intracerebroventricular aicar injection ( 3 g / mouse ) on food intake after 6 h in p53 ko mice .
b and c : hypothalamic protein levels of pampk , pacc , ampk1 , ampk2 , acc , and fas after 6 h of aicar injection .
values were normalized to those of the internal control -actin , and the results are expressed as arbitrary units .
finally , we assessed whether the sirt1 pathway is mediating other neuroendocrine actions of ghrelin , namely gh secretion .
administration of ghrelin ( 27 ) led to the expected increase in plasma gh levels at 5 , 10 , and 15 min ( fig .
5a ) , whereas the central blockade of sirt1 did not alter that response ( fig .
5a ) . ghrelin exhibited a similar stimulatory effect in both area under the curve and mean peak gh levels ( fig .
a : effects of intravenous ghrelin injection ( 12 nmol / kg ) , intracerebroventricular ex527 ( 1 g / rat ) , and ghrelin + ex527 on plasma gh levels in adult male freely moving rats .
area under the curve ( auc ) ( b ) and mean peak gh ( c ) levels .
our current data demonstrate that the hypothalamic sirt1/p53 pathway is crucial for the orexigenic effect of ghrelin .
pharmacologic inhibition of sirt1 or genetic depletion of p53 abolish the effects of ghrelin on ampk and thereby blunt ghrelin - induced effects on transcription factors , including pcreb , foxo1 , and bsx , and neuropeptides , such as npy and agrp , leading to a suppression of ghrelin - induced food intake .
it has been reported recently that sirt1 mrna is located in metabolically relevant areas of the mouse neuroaxis , such as pro - opiomelanocortin neurons , which are critical for energy and glucose homeostasis ( 11 ) .
it seems that sirt1 regulates the central melanocortin system ( 13 ) and that the specific lack of sirt1 in the brain abolishes the higher physical activity induced by calorie restriction ( 12 ) .
more specifically , the lack of sirt1 in pro - opiomelanocortin neurons causes hypersensitivity to diet - induced obesity because of reduced energy expenditure ( 17 ) .
concurring with those data , we observed that acetylation of p53 in the hypothalamus is decreased after food deprivation , indicating that sirt1 as a deacetylase increased its hypothalamic activity during starvation .
therefore , the regulation of hypothalamic sirt1 activity by nutritional status is similar to its regulation in several peripheral tissues ( 33 ) .
ghrelin is a stomach - derived hormone that rapidly increases food intake and body weight ( 1,29 ) .
its regulation by nutritional status was controversial because the assays detected both acyl - ghrelin and des - acyl ghrelin and thus were not specific .
studies using new technologies for separately detecting both isoforms indicate that circulating des - acyl ghrelin increases significantly with fasting , whereas blood acyl - ghrelin levels are not changed over the course of fasting ( 34,35 ) .
most of the effects of ghrelin are exerted through the gh secretagogue receptor 1a ( ghs - r1a ) ( 36 ) , which is expressed in agrp / npy neurons in the hypothalamic arcuate nucleus ( 37 ) .
the orexigenic effect of ghrelin is mediated by ampk , a key upstream master regulator of lipid metabolism ( 5,6 ) . however , the molecular events regulating ampk phosphorylation after the activation of the ghs - r1a are unknown . in the present work , we demonstrate that central ghrelin administration increases hypothalamic sirt1 activity , stimulating the deacetylation of p53 .
more interestingly and consistent with previous findings ( 14 ) , the blockade of central sirt1 activity abolished the potent orexigenic effect of ghrelin . at molecular level , the ghrelin - induced activation of ampk is prevented when sirt1 activity is blocked .
the interaction between sirt1 and ampk has been previously shown in vitro , indicating that resveratrol activates ampk in neurons ( 38 ) .
although pharmacologic experiments based on the administration of sirt1 inhibitors to animal models are providing important insight into principal effects , targets , and mechanisms of the sirt1 system , understanding the function of its endogenous role requires more sophisticated approaches , such as genetic disruption of sirt1 or its substrates .
we focused on p53 because this tumor - suppressor protein is a well - known target of sirt1 action , and there is growing evidence of its role on metabolism and energy balance in peripheral tissues ( 31 ) .
our results indicate that p53 is required for the ghrelin - induced food intake , because ghrelin failed to increase food intake in p53 ko mice . in accordance with pharmacologic findings
, ghrelin stimulated hypothalamic pampk levels in wt mice but failed to do so in p53 ko mice .
on the other hand , it has been shown that sirt1 is a target gene of p53 in some but not all of the tissues ( 31,39 ) , so it might be possible that p53 mediates the changes in sirt1 upon ghrelin treatment or calorie restriction .
however , the observed correlation between acetylated p53 and sirt1 activity in the hypothalamus on different experimental conditions indicate that p53 is an essential mediator of sirt1-dependent effects of ghrelin on ampk .
mice lacking p53 in specific hypothalamic areas will be essential to demonstrating which particular neuronal circuits are responsible for those actions .
however , the central sirt1/p53 pathway is not required by direct ampk activators , because aicar stimulated food intake in p53-deficient mice .
therefore , these findings corroborate that the central sirt1/p53 pathway is not associated with aicar - induced activation of ampk .
finally , our results indicate that ghrelin stimulated gh release as expected , but the blockade of central sirt1 did not modify gh levels .
therefore , it seems that the central sirt1/p53 pathway is specifically mediating the ghrelin orexigenic action and suggests that different neuronal pathways modulate ghrelin - induced food intake and gh secretion . in summary , we provide a combination of pharmacologic and genetic evidence to demonstrate that the central nervous system sirt1/p53 pathway is essential for the orexigenic response to ghrelin ( fig . 6 ) .
the molecular pathway mediating those effects involves alterations in ampk activation , which leads to changes in hypothalamic fatty acid metabolism , and finally , modifies feeding behavior .
schematic overview summarizing our proposed model for the molecular mechanisms initiated by the activation of the ghrelin receptor leading to ampk activation and finally to an increased feeding behavior .
ros , reactive oxygen species ; cpt , carnitine palmitoyltransferase ; ucp , uncoupling protein .
( a high - quality color representation of this figure is available in the online issue . )
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### Summary:
: objectiveghrelin is a stomach - derived peptide that increases food intake through the activation of hypothalamic amp - activated protein kinase ( ampk ) .
however , the molecular mechanisms initiated by the activation of the ghrelin receptor , which in turn lead to ampk activation , remain unclear .
sirtuin 1 ( sirt1 ) is a deacetylase activated in response to calorie restriction that acts through the tumor suppressor gene p53 .
we tested the hypothesis that the central sirt1/p53 pathway might be mediating the orexigenic action of ghrelin.research design and methodssirt1 inhibitors , such as ex527 and sirtinol , and ampk activators , such as aicar , were administered alongside ghrelin in the brain of rats and mice ( wild - type versus p53 knockout [ ko ] ) .
their hypothalamic effects on lipid metabolism and changes in transcription factors and neuropeptides were assessed by western blot and in situ hybridization.resultsthe central pretreatment with ex527 , a potent sirt1 inhibitor , blunted the ghrelin - induced food intake in rats .
mice lacking p53 , a target of sirt1 action , failed to respond to ghrelin in feeding behavior .
ghrelin failed to phosphorylate hypothalamic ampk when rats were pretreated with ex527 , as it did in p53 ko mice .
it is noteworthy that the hypothalamic sirt1/p53 pathway seems to be specific for mediating the orexigenic action of ghrelin , because central administration of aicar , a potent ampk activator , increased food intake in p53 ko mice .
finally , blockade of the central sirt1 pathway did not modify ghrelin - induced growth hormone secretion.conclusionsghrelin specifically triggers a central sirt1/p53 pathway that is essential for its orexigenic action , but not for the release of growth hormone .
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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 mechanisms behind the observed changes in selectivity were initially speculative , based on models of the wildtype structure with mutations introduced in silico.2 substitutions w106l and l109y were proposed to be responsible for the modified regioselectivity in the variant ( rc1b1 ) displaying the largest change from the parent enzyme .
the side chains of these residues are believed to interact with the substrate . in the wildtype enzyme
, w106 also has a catalytic role , in that its mainchain amide contributes to an oxyanion hole and stabilizes the tetrahedral intermediate formed during the hydrolytic halfreaction .
the residue at this position ( adjacent to the nucleophile ) has been shown to influence enzyme selectivity and activity in related epoxide hydrolases,6 thus further supporting involvement here .
a role for w106 in substrate recognition has also been suggested based on empirical valencebond calculations of ( wildtype ) steh1catalyzed hydrolysis of the related styrene oxide .
these calculations proposed that the residue stabilizes a certain binding mode through interactions between the indole and the substrate.7 this study also identified a possible link between the preferred binding mode of styrene oxide and the preferred point of epoxide ring opening , hence , to an extent , predicting the stereoconfiguration of the ultimate diol product .
the methylene carbon in 1 gives this compound fundamentally different dynamic properties from those of styrene oxide , in which the phenyl ring is directly bonded to one of the epoxide carbons .
the larger conformational flexibility severely increases the challenges involved in theoretical predictions of binding modes as well as the amount of sampling required to obtain convergent free energies in empirical valencebond or qm / mm free energy calculations .
therefore , resolving the structures of these invitroevolved enzymes would provide previously unavailable information about the structural causes of the observed changes in regioselectivity , and also about how an enzyme activesite structure can adapt to catalyze the transformation of a ( new ) reaction .
all variants were crystallized under similar , but not identical , conditions to those used for wildtype steh1;8 this resulted in crystals of the same space group and unit cell dimensions , containing two monomers per asymmetric unit .
pairwise superposition of all monomers yielded rmsds of 0.140.46 , with the largest deviations observed for residues 9396 of a solventexposed loop .
this deviation in loop structure is most likely associated with an unintentional additional mutation at position 94 ( p94l ) introduced during the course of the directed evolution ; this occurred first in rc1b1 and was inherited by its offspring rc1b1d33 and rc1b1d33e6 .
the p94l exchange is not expected to influence steh1 catalytic parameters because of its distance from the active site ( 25 ) .
the details of the rc1b1 structure have been described in detail elsewhere.7
a ) superposition of c carbons from the crystal structures of the wildtype enzyme and evolved variants .
figures were generated in pymol ( v. 1.81 ) from atomic coordinates in pdb ids : 2cjp 8 ( wild type ) , 4uhb ( rc1 ) , 4ufn 7 ( rc1b1 ) , 4ufp ( rc1b1d33 ) , and 4ufo ( rc1b1d33e6 ) .
all enzymes were expressed and purified as described.9 crystallization details and model refinements are in the supporting information .
v141 is located at the entrance to the active site , and is not expected to form direct contacts with the tested enantiomers of 1 .
the mutation to ( larger ) lysine could affect activesite accessibility by partially blocking the entrance , but the weakness or lack of electron density for all atoms beyond c indicates high mobility of this side chain and the lack of such an effect .
the side chain of i155 is close to h153 and the two catalytic tyrosines , y154 and y235 ( figure 1 b ) .
although the hydroxy group position of y235 differs by 1.2 between wildtype steh1 and rc1b1 ( figure 1 b ) and the distances between the hydroxyl groups of y235 and y154 range from 4.4 ( rc1b1 ) to 5.0 ( rc1b1d33 ) , there is little support for markedly increased flexibility from the crystallographic temperature factors ( figure s2 in the supporting information ) .
the differences are minor in extent and might be attributed to interactions with ligands bound to the active sites ( glycerol in the case of rc1 , and dioxane in rc1b1 ) . in rc1b1 and its offspring ,
surprisingly , the exchange of l109 with the considerably bulkier tyrosine causes no structural change in the active site .
the main difference between wildtype steh1 and rc1b1 is the formation of a hydrogen bond between the side chain of n241 and the hydroxyl group of y109 ( figure 1 b ) . as a consequence
, the y109 side chain is oriented away from the binding site , thus increasing its volume ( figure 2 , table s1 ) and weakening rather than strengthening the interactions with the bound substrate .
replacement of the bulky and aromatic hydrophobic side chain of w106 with the smaller leucine side chain also did not result in any significant structural changes in the active site .
the only discernible difference from wildtype steh1 is a slight movement ( 0.20.3 ) of the y235 phenol ring towards l109 in rc1 , probably as a consequence of structural relaxation of the protein in the absence of the w106 side chain .
a ) side view ( activesite entrance on right ) , b ) axial view , and c ) preferred docking poses of ( s)1 of wildtype and variants .
volumes in the crystal structures were calculated with caver12 ( v. 3.01;0.9 radius probe ) .
distances are in ngstrm , and are drawn between the closest epoxide carbon and d105 o. images were generated in pymol ( v. 1.8.1 ; www.pymol.org ) .
the l266 g replacement in rc1b1d33e6 potentially increases backbone flexibility , but no backbone shifts or changes in backbone dihedral angles were observed in the crystal structure ( representing the most highly evolved steh1 variant ) .
the sidechain deletion just increased the activesite volume , without causing conformational changes of the surrounding residues .
it should be noted that we were unsuccessful in all our attempts to crystallize any of these enzymes with relevant ligands bound to the active site , although a glycerol molecule from the crystallization solution was found in one of the rc1 monomers ( figure s1 ) .
this triol can be viewed as a product analogue of epoxide ( glycidol ) hydrolysis and does provide information regarding possible product binding . for further analysis of how the evolved structures acquired the changes in regioselectivity displayed by rc1b1 and rc1b1d33 , we pursued computational modeling approaches .
although the crystallographic data provide insight into how the enzyme structure adapted during laboratory evolution of steh1 activity , they do not provide insights into how this affects substrate binding in the active site ( something which we recently showed to be important for determining steh1 selectivity towards a different epoxide).7 hence , and given the success of related approaches on similar systems,10 we performed constrained molecular docking to explore the available binding modes in the steh1 active site ( table 1 ) .
both enantiomers of 1 were modeled into the active sites of the crystal structure as a starting point .
restraints were set for the enzyme substrate complexes to maintain hydrogenbonding distances between the epoxide ring oxygen and the catalytic tyrosine pair ( y154 and y235 ) .
the preferred binding mode(s ) and the distance between the nucleophile ( d105 ) and each of the epoxide carbons were noted and compared with the experimentally determined regioselectivities . in all but one of the cases
, we found poses of the docked substrate enantiomers that were in agreement with the observed regioselectivities ( tables 1 and table s2 ) , if assuming that the epoxide ringopening and alkylenzyme formation steers the stereoconfiguration of the final product with this epoxide substrate .
this variant showed a clear preference for ring opening at c2 , but the distances in the docking poses were similar between the nucleophile and either epoxide carbon ( table 1 ) .
earlier empirical valencebond studies on the same enzyme with both transstilbene oxide11 and styrene oxide7 suggested that this is not always the case ; an energetically favorable pathway leading to alkylenzyme formation might be ( kinetically ) trapped due to a comparably higher barrier for hydrolysis .
considering the complexity of the catalysis , our docking results should be viewed mainly as suggestions as to how regioselectivity towards ( s)1 altered during the trajectory of the laboratory evolution .
preferred binding modes after docking of ( r)1 and ( s)1 into the active sites of wildtype and evolved steh1 enzymes .
[ a ] experimental data from ref . 3 [ b ] calculated distance between d105 and c1/c2 of the epoxide ring of 1 .
[ c ] mode 1 involves interaction of the phenyl ring and h300 ; mode 2 directs the phenyl ring of the substrate towards w / l106 ; in mode 3 , the phenyl substituent is sandwiched between f189 and f33 ( figure 2 ) .
binding modes 3 ( wild type and rc1 ) , 1 ( rc1b1 ) , and 2 ( rc1b1d33 ) provide distances between the nucleophile and the epoxide carbons in line with experimentally determined product configurations . for calculations
see the supporting information ( all docking poses in table s2 ) . in the wildtype enzyme and variant rc1 , the preferred binding mode places the phenyl substituent of ( s)1 such that it is sandwiched between the rings of f189 and f33 ( figure 2 c ) .
this binding mode was not observed in earlier studies of monosubstituted epoxides modeled into the active site of steh1 , and is thus termed mode 3 . binding in mode 3 places the c2 carbon of the epoxide ( scheme 1 ) closest to the o of the d105 nucleophile .
the rc1b1d33e6 variant displays a similar binding pose , but its enlarged activesite cavity allows for many different binding configurations , and the relatively poor activity of this variant makes it harder to discern which binding mode is relevant . the rc1b1 variant displays a slightly different binding mode , which resembles ( but is different from ) that found for ( s)styrene oxide,7 where the epoxide phenyl substituent is directed towards h300 ( mode 1 in that report ) .
binding of the substrate in mode 1 shifts the position of the epoxide ring so that the asymmetric c1 is closer to the nucleophile
. rc1b1d33 displays a distinct binding mode , similar to that for styrene oxide binding in mode 2,7 where the phenyl substituent is directed towards w106 . in this variant w106
is substituted by leucine , but the concomitant l109y substitution provides aromatic edgeon interactions between the substrate and y109 . binding in mode 2 also places c1 closer to the nucleophilic carboxylate .
the crystal structure of rc1b1d33 was the lowestresolution structure ( 2.95 ) ; thus fewer water molecules could be modeled with maintained stringency .
this might have affected the docking results . with this in mind , the preferred binding mode of ( s)1 in this variant ( mode 2 ) places the phenyl ring of the substrate towards the mutationintroduced y109 , thus making an edgeon interaction .
the finding that rc1b1d33 also displays clear quenching of the tyrosine fluorescence when mixed with ( s)1 in stoppedflow experiments ( see the supporting information ) suggests that this interaction could be valid .
also in this binding mode , c1 of the epoxide comes closest to the d105 side chain , thus facilitating nucleophilic attack , again in agreement with experimental results of regiopreference in this enzyme .
when comparing the catalytic parameters for the evolved variants to those for wildtype steh1 , the k
m for both enantiomers of 1 increased but k
cat for ( s)1 decreased to a larger extent , thus resulting in lower overall catalytic efficiency with this enantiomer ( table s3 ) .
the relatively high k
m for the evolved enzymes probably resulted from the initial screening conditions , under which high epoxide concentrations were used , and thus did not select for low values of k
m. the activesite volumes of the variants also gradually grew , compared to the wildtype enzyme ( figure 2 , table s1 ) , thus further decreasing the possibility of tight binding of the substrate , and possibly contributing to the observed elevated k
m values .
we assume that the low binding affinity in the respective michaelis complexes is responsible for our inability to achieve stability in md simulations . however , combining the new structural data with the restrained docking results still provided important information about structural changes that lead to enrichment of ( r)2 during our laboratory evolution .
it is interesting that a new epoxidebinding mode ( mode 3 ) was preferred for most variants as well as the wild type .
this binding mode involves interactions between the epoxide phenyl ring and the side chains of f33 and f189 .
the involvement of f33 in substrate binding might explain the degree of conservation of this residue during the directed evolution ( only exchanges to tyrosine were observed).3 the docking also proposed previously neglected residues as putative targets for future mutagenesis studies ( including f191 and f158 interacting with ( r)1 and y183 and f301 interacting with ( s)1 ) . although we could rationalize the observed regioselectivity from simple docking of the different enantiomers of 1 into the respective active sites , it is important to keep in mind that selectivity is often more complicated than binding and productive orientation of the substrate in its ground state . in summary ,
we present the crystal structures of enzyme variants isolated after laboratory evolution ; these were selected for enrichment of a defined product enantiomer from a racemic substrate mixture . by combining crystallographic data and molecular simulation with previous experimental studies of this system
, we were able to rationalize possible structure function relationships that have evolved over the course of multiple rounds of mutagenesis and selection .
our work provides an atomiclevel insight into the ( engineered ) evolution of enantioconvergence in this highly biocatalytically important system .
as a service to our authors and readers , this journal provides supporting information supplied by the authors .
such materials are peer reviewed and may be reorganized for online delivery , but are not copyedited or typeset .
technical support issues arising from supporting information ( other than missing files ) should be addressed to the authors .
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### Summary:
: abstractengineered enzyme variants of potato epoxide hydrolase ( steh1 ) display varying degrees of enrichment of ( 2r)3phenylpropane1,2diol from racemic benzyloxirane .
curiously , the observed increase in the enantiomeric excess of the ( r)diol is not only a consequence of changes in enantioselectivity for the preferred epoxide enantiomer , but also to changes in the regioselectivity of the epoxide ring opening of ( s)benzyloxirane . in order to probe the structural origin of these differences in substrate selectivity and catalytic regiopreference
, we solved the crystal structures for the evolved steh1 variants .
we used these structures as a starting point for molecular docking studies of the epoxide enantiomers into the respective active sites .
interestingly , despite the simplicity of our docking analysis , the apparent preferred binding modes appear to rationalize the experimentally determined regioselectivities .
the analysis also identifies an active site residue ( f33 ) as a potentially important interaction partner , a role that could explain the high conservation of this residue during evolution .
overall , our experimental , structural , and computational studies provide snapshots into the evolution of enantioconvergence in steh1catalyzed epoxide hydrolysis .
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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:
: induction of general anaesthesia per se as also the use of 100% oxygen during induction of anaesthesia results in the development of atelectasis in dependent lung regions within minutes of anaesthetic induction .
application of continuous positive airway pressure ( cpap ) during pre - oxygenation and induction of anaesthesia helps to increase the duration of apnoea before the development of significant arterial desaturation by preventing atelectasis , increasing oxygen stores , and decreasing intrapulmonary shunt .
therefore , avoiding the formation of atelectasis during induction of general anaesthesia may increase the duration of non - hypoxic apnoea which in turn will increase the margin of safety .
the study was designed to assess the effect of application of a positive airway pressure of 5 cm h2o during pre - oxygenation and induction of anaesthesia on the period of apnoea before the occurrence of clinically significant desaturation that is , an arterial saturation of haemoglobin as measured by a pulse oximeter ( oxygen saturation [ spo2 ] ) of < 93% .
a written and informed consent was obtained from the patients to participate in the study .
a previous study by herriger et al . found that non - hypoxic apnoea duration was longer in the positive end - expiratory pressure ( peep ) group compared to zero end - expiratory pressure ( zeep ) group ( 599 135 s vs. 470 150 s ) . assuming 30% difference , at two - sided type 1 error of 0.05 and power of 90%
40 adult patients of either gender ( 20 in each group ) participated in the study .
patients belonged to the age group of 1870 years and underwent elective surgery requiring endotracheal anaesthesia for major surgical procedures which required an invasive blood pressure monitoring , during the period from december 2004 to march 2006 .
all of them belonged to physical status i or ii as outlined by the american society of anesthesiologists .
patients with an spo2 of < 97% while breathing room air , those who had been non - ambulant in hospital for > 24 h , patients with a body mass index ( bmi ) > 25
kg / m , patients with haemoglobin < 8 g% , those with medical conditions that preclude even a short period of arterial desaturation or rise in arterial partial pressure of carbon dioxide ( paco2 ) such as patients with coronary artery disease , cerebrovascular disease , intracranial hypertension , epilepsy or severe pulmonary disease , and patients in whom difficulty in maintaining airway or obtaining an effective mask fit was anticipated were excluded from the study .
patients were pre - medicated with oral diazepam ( 5 mg if they weighed < 50 kg ; 10 mg if they weighed > 50 kg ) on the night before and on the morning of surgery .
they were randomly allocated to one of the two groups using random number draws , group z ( zeep group ) ( control group ) and group p ( peep group ) ( study group ) . after shifting the patients into the operating room ,
the following monitoring was established : electrocardiography , non - invasive blood pressure , pulse oximetry ( spo2 ) ( in two locations ) .
the additional precaution of monitoring spo2 simultaneously at two sites was taken for reasons of patient safety .
, the welch allyn pic50 biphasic defibrillator monitor and the bci capnocheck pulse oximeter - with - capnograph .
an intravenous line was secured on the upper limb using an 18-gauge cannula . under strict aseptic precautions ,
the radial artery was cannulated after local infiltration with 2% lignocaine and the arterial line flushed with heparinised saline .
baseline values of heart rate , blood pressure and spo2 were recorded , and a sample of arterial blood gas ( abg1 ) was taken with the patient breathing room air .
application and maintenance of position of the facemask were done by the anaesthesia consultant in charge of the case ( observer 1 ) . in both the groups ,
patients were pre - oxygenated with 100% oxygen for 5 min using an oxygen flow of 5 lpm . in group p , pre - oxygenation was undertaken using a mapleson a circuit with a fixed peep device attached to the expiratory port that maintained a cpap of 5 cm h2o [ figure 1 ] . in group
fixed positive end expiratory pressure device attached to mapleson a circuit a sample of arterial blood was obtained after 5 min of pre - oxygenation ( abg2 ) and the spo2 recorded at this point .
anaesthesia was induced by observer 2 using fentanyl 2 g / kg ( rounded off to the nearest multiple of 25 g ) and propofol 2.5 mg / kg ( rounded off to the nearest multiple of 10 mg ) .
patients were paralysed with succinylcholine hydrochloride ( sch ) 2 mg / kg and tracheal intubation performed 60 s later by the anaesthesia consultant in charge of the case .
the correct position of the tracheal tube was confirmed by observer 1 using a modified oesophageal detector device [ figure 2 ] .
this would supplement the fact that tracheal intubation was performed under direct vision by observer 1 .
the correct position of the tracheal tube confirmation using a modified esophageal detector device patients were administered intravenous vecuronium bromide 0.08 mg / kg immediately after tracheal intubation to maintain muscle relaxation and anaesthesia maintained using an infusion of propofol at 50 g / kg / min .
following tracheal intubation , the cuvette of a mainstream capnograph was connected to the tracheal tube to detect any spontaneous breaths that could possibly negate study conditions .
the tracheal tube was left open to air at atmospheric pressure and the patient allowed to remain apnoeic until spo2 fell to 93% at either of the two sites of pulse oximetry monitoring or a period of 10 min had elapsed , whichever was earlier .
observer 2 who performed anaesthetic induction also observed capnograph ( for evidence of breathing ) , pulse oximeter ( for evidence of clinically significant desaturation as indicated by an spo2 <
93% , duration of apnoea ( in seconds ) measured as the time from the administration of sch to the time when spo2 fell to 93% or a period of 10 min had elapsed , whichever occurred earlier .
statistical analysis was performed using spss 16.0 ( statistical package for the social science for windows ; version 16.0 , spss inc . ,
chi - square test and for student 's t - test used comparing demographic variables , duration of apnoea and the haemodynamic variables between the two groups .
the pearson product - moment correlation coefficient was used for seeing any correlation between the duration of non - hypoxic apnoea with a partial pressure of arterial oxygen ( pao2 ) after pre - oxygenation , bmi , smoking , age and gender .
the age , gender , weight , height , bmi , and history of smoking of the 40 patients were noted .
the arterial spo2 dropped to 93% within the study period of 10 min in all 20 patients in the zeep group and only 16 out of 20 patients in the peep group .
the mean and standard deviation of the safe duration of apnoea was found to be significantly longer [ table 2 ] in patients receiving positive airway pressure of 5 cm h2o ( group p ; n = 16 ) compared to the group receiving no positive airway pressure ( group z ; n = 20 ) , that is , 472.50 71.46 s versus 249.20 64.82 s. this difference was statistically very highly significant .
comparison of duration of apnoea and time to return to baseline spo2 among the two groups the time taken for arterial spo2 to drop to 95% was also noted .
this event also occurred in all 20 patients in the zeep group and only 16 out of 20 patients in the peep group .
the mean and standard deviation of the time taken for the spo2 to drop to 95% was also significantly longer [ table 2 ] in patients receiving positive airway pressure of 5 cm h2o ( group p ; n = 16 ) compared to the group receiving no positive airway pressure ( group z ; n = 20 ) , that is , 472.50 71.46 s versus 249.20 64.82 s. this difference was statistically very highly significant .
the time taken to return to baseline spo2 was also less in the peep group [ table 2 ] , but this difference was not statistically significant .
the pao2 and paco2 at the start of pre - oxygenation were comparable in both the groups [ table 3 ] .
arterial blood gases at various time intervals of measurement the pao2 measured following pre - oxygenation was 355.65 96.55 mmhg in the zeep group and 433.44 75.11 mmhg in the peep group .
the haemoglobin spo2 in four patients in the peep group remained above 96% during the 10 min of apnoea that we had defined to be the end point of our study .
influence of demographic variables on the duration of non - hypoxic apnoea are depicted in table 4 .
no correlation was found between the duration of non - hypoxic apnoea with pao2 after pre - oxygenation , bmi , smoking , age or gender in both the zeep group and peep group .
correlation between demographic variables and duration of non - hypoxic apnoea the heart rate , systolic blood pressure , diastolic blood pressure , and mean arterial pressure were comparable in the zeep group and peep group at various time intervals , baseline , after 5 min of pre - oxygenation and at the point of desaturation ( at spo2 93% ) .
the principal stores of oxygen in an individual breathing air are in the lungs ( 450 ml ) , in blood ( 850 ml ) , dissolved in tissue fluids ( 50 ml ) and in combination with myoglobin ( 200 ml ) .
these stores are small while breathing air . very little of this small store of oxygen
can be released without an unacceptable reduction in pao2 . according to the oxygen dissociation curve
, blood will not release substantial quantities of oxygen until the pao2 falls below 40 mmhg .
myoglobin is even more reluctant to part with oxygen , and very little can be released above a pao2 of 20 mmhg . breathing 100% oxygen causes a nearly three - fold increase in oxygen stores to around 4250 ml .
most of this additional oxygen is accommodated in the alveolar gas where 80% can be withdrawn without causing the pao2 to fall below the normal value .
however , breathing 100% oxygen also results in near - complete denitrogenation of the alveoli . while breathing room air , the low solubility of nitrogen in the blood causes the unabsorbed nitrogen to act as a pneumatic splint and prevent atelectasis from developing . during general anaesthesia , up to 8590% of patients develop atelectasis in dependent lung regions within 5 min of anaesthetic induction .
this results in a decrease in functional residual capacity ( frc ) which in turn causes a reduction in the oxygen stores in the body .
in addition , it also increases the intrapulmonary shunt which will hasten desaturation to hypoxic levels .
positive end - expiratory pressure increases frc to or above a lung volume greater than closing capacity ( cc ) , thereby restoring a normal frc to cc relationship , so that no airways are closed at any time during the tidal respiration .
application of peep during induction of anaesthesia increases the duration of non - hypoxic apnoea by preventing atelectasis formation , increasing oxygen stores , and decreasing intrapulmonary shunt .
the development of atelectasis is a consistent finding with the use of 100% oxygen for pre - oxygenation before induction of anaesthesia .
the use of lower fractional concentration of inspired oxygen may increase this risk of hypoxaemia , especially when difficulty in airway management and/or ventilation is encountered .
some investigators have found that during routine induction of general anaesthesia , pre - oxygenation with 80% oxygen caused minimal atelectasis , but the time duration before desaturation occurred was significantly shortened compared to a situation when 100% oxygen was inhaled .
a clinical study found that atelectasis formation can be effectively prevented by the use of peep applied during induction of anaesthesia despite the use of 100% oxygen .
they noted that applying peep during the entire anaesthetic induction with 100% oxygen provided the clinical benefit of an increased duration of non - hypoxic apnoea .
in other studies , higher arterial oxygen tensions and longer duration of non - hypoxic apnoea ( > 2 min ) , was observed in patients who had received cpap or peep during anaesthetic induction as compared to those who had not received such manoeuvres .
however , as pointed out by the authors , the limitation of their study was the inability to distinguish between the effects of cpap applied during pre - oxygenation and peep applied during the initial phase of ventilation with mask prior to tracheal intubation . keeping this limitation in mind , we designed our study to specifically look at the effect of applying peep only during the period of pre - oxygenation . in our study , patients who received a peep of 5 cm h2o during pre - oxygenation had higher arterial oxygen tensions following pre - oxygenation than patients who did not receive such a manoeuvre ( 433.44 75.11 mmhg vs. 355.65 96.55 mmhg ) .
in addition , they also tolerated longer durations of apnoea ( 496.56 71.68 s vs. 273.00 69.31
s ) which was statistically very highly significant . as our patients did not receive any peep following muscle paralysis nor were any positive pressure breaths administered after tracheal intubation
, we can attribute the observed differences between the groups to be the result of application of cpap during the 5 min of pre - oxygenation .
our study was designed to avoid any manoeuvres that could cause alveolar recruitment and reinflate any atelectatic areas that might have occurred during anaesthetic induction . to this end
, we intentionally kept our patients apnoeic following neuromuscular blockade and also avoided positive pressure breaths following tracheal intubation .
we also closely watched the capnograph waveform as detected by a mainstream capnograph for evidence of spontaneous breathing which could also open up previously atelectatic areas of the lung .
earlier studies have used fibreoptic endoscopy to confirm correct tracheal tube position , which is not only the gold standard for such confirmation but also avoids alveolar recruitment .
the mainstream capnograph has also been used to detect the presence of carbon dioxide following the administration of one single small breath of 100% oxygen . as mentioned earlier
, such a manoeuvre could open up atelectatic areas of the lung and negate study conditions .
we therefore confirmed correct placement of the tracheal tube with the help of the modified oesophageal detector device as this technique does not rely on the use of positive pressure breaths for its performance .
hence , the differences observed in the peep group as compared to the zeep group could be directly attributed to the beneficial effects of peep .
this technique of application of positive airway pressure during pre - oxygenation and induction of anaesthesia may have advantages especially in those patients in whom difficulty in airway management is anticipated , those who are more at risk of desaturation such as morbidly obese patients and when assisted ventilation is not applied such as during rapid sequence induction .
the application of cpap or peep can have potentially deleterious effects on the cardiovascular system .
an earlier study using a cpap of 7.5 cm h2o has not reported any adverse effects on systolic and diastolic blood pressure . as we have used a peep of 5 cm h2o during pre - oxygenation ,
it is unlikely to have produced any significant effects on the heart rate and blood pressure .
we observed no changes in heart rate , systolic blood pressure , diastolic blood pressure or mean arterial pressure both in the peep group and in the zeep group .
we attempted to evaluate any correlation between the period of non - hypoxic apnoea and parameters such as arterial oxygen tension after pre - oxygenation , bmi , age , gender , and smoking .
there was no correlation between any of the above parameters and the duration of non - hypoxic apnoea .
this was in agreement with a previous study which also found that other than gender , the other parameters showed no correlation to the period of non - hypoxic apnoea . with regard to correlation with gender
the same study found that females had a tendency towards shorter duration of non - hypoxic apnoea as compared with males in the peep group , but this difference was not observed in the zeep group .
thus , in summary , our study showed that the use of 5 cm h2o cpap during pre - oxygenation with 100% oxygen for 5 min provided higher arterial oxygen tensions at the end of pre - oxygenation when compared to patients who breathed spontaneously at zeep .
in addition , these patients also had a significantly longer duration of apnoea before they developed arterial desaturation to a spo2 of < 93% .
this technique could afford some degree of protection against the development of hypoxia during tracheal intubation , especially when one is confronted with difficulty in airway management .
in comparison to pre - oxygenation at ambient pressures ( zero positive airway pressure ) , the application of cpap of 5 cm h2o using a mapleson a circuit with a fixed peep device during 5 min of pre - oxygenation with 100% oxygen prior to the induction of anaesthesia is a safe and simple technique , well - tolerated by patients , provides higher arterial oxygen tensions at the end of pre - oxygenation and a clearly longer duration of apnoea before clinically significant arterial desaturation .
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### Summary:
: background and aims : induction of general anaesthesia per se as also the use of 100% oxygen during induction of anaesthesia , results in the development of atelectasis in dependent lung regions within minutes of anaesthetic induction .
we aimed to assess the effect of application of a continuous positive airway pressure ( cpap ) of 5 cm h2o during pre - oxygenation and induction of anaesthesia on the period of apnoea before the occurrence of clinically significant desaturation.methods:in this prospective , randomised , and double - blind study , 40 patients posted for elective surgery were enrolled .
duration of apnoea was measured as the time from the administration of succinylcholine hydrochloride to the time when oxygen saturation fell to 93% .
student 's t - test was used for comparing the duration of apnoea.results:the safe duration of apnoea was found to be significantly longer in patients receiving cpap of 5 cm h2o ( group p ; n = 16 ) compared to the group receiving no cpap ( group z ; n = 20 ) , that is , 496.56 71.68 s versus 273.00 69.31 s ( p < 0.001).conclusion : the application of cpap of 5 cm h2o using a mapleson a circuit with a fixed positive end - expiratory pressure device during 5 min of pre - oxygenation with 100% oxygen prior to the induction of anaesthesia provides a clearly longer duration of apnoea before clinically significant arterial desaturation occurs .
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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:
: developmental dysplasia of the hip ( ddh ) is a major cause of osteoarthrosis in adolescent and adult patients .
currently , periacetabular osteotomy ( pao ) , a widely employed surgical treatment for ddh , is performed to provide ideal acetabular coverage of the femoral head .
however , it is estimated that the 10-year success rate of pao is 87% , and the 20-year rate is 61% , which are suboptimal results , considering the young age at which many patients undergo the pao procedure .
current thinking holds that several factors may potentially result in undesirable outcomes of pao , such as patient age , grade of osteoarthritis , and skill and experience of the surgeon .
recently , variability in the extent of acetabular cartilage development has received increasing research interest and has been investigated as a major cause .
. found that patients with acetabular dysplasia had a clearly decreased lunate surface size , decreased outer acetabular rim , and increased acetabular fossa .
concluded that dysplastic cartilages were related to global deficiency , not deficiency in just a single dimension .
categorized acetabular morphologic deficiencies as anterior deficiency , posterior deficiency , and lateral deficiency through three - dimensional ( 3d ) computed tomography ( ct ) .
based on these views , we retrospectively analyzed the imaging data of patients with poor post - pao outcomes .
interestingly , we found obviously irregular defects on the outer edge of the acetabular lunate in these patients , especially in the superior and anterosuperior regions ( figure 1 ) . with decreased size of the lunate surface ,
it is understandable that the weight - bearing area of the femoral head could not be completely covered by the articular cartilage , even though the pao can provide sufficient acetabular coverage .
recently , fea has been employed in the study of hip joint mechanical behavior and pre - clinical testing of ddh [ 6,1013 ] .
generated a series of fea models of dysplastic hips created through deforming the acetabular rim of a normal hip to investigate the effects of pao .
developed a 3d fea of pao generated from ct scans of 5 ddh hips to analyze contact area , pressure , and von mises stress in the femoral and acetabular cartilages .
however , there is no published research related to the variability of the abnormal shape among real dysplastic acetabula .
therefore , we developed fe simulation of ddh models with theoretical anterosuperior defect ( asd ) and superior defect ( sd ) of the acetabular lunate surface generated from imaging of normal hips , based on our previous work , to verify whether different configurations of cartilage deficiency affect the biomechanical environment pre- and post - pao
. this work may enable surgeons to provide patients with personalized preoperative planning of pao .
three ddh models ( asd , sd , and normal shape ) were developed from the model created in previous work .
the 3 models had the same ce angles , but differently shaped acetabular cartilage defects .
mimics 14.1 ( materialise , leuven , belgium ) and msc.marc/mentat2005r3 ( msc software , santa ana , ca , usa ) were used for the development and analysis of these models .
the patients involved in this study all provided informed consent and this study was approved by our institutional review board .
briefly , the normal model ( figure 2 ) was generated from a 24-year - old male ( with informed consent ) without clinical or radiological abnormalities .
the presupposed target center - edge ( ce ) angle and anterior center - edge ( ace ) angle in this model were both 25 degrees .
the main linear elastic and isotropic material properties of cortical bone , trabecular bone , cartilage , and acetabular labrum are shown in table 1 .
the 3 ddh models with decreased coverage of acetabular cartilage were generated by deforming the acetabular rim toward the posteromedial direction of the normal hip model .
the presupposed target ce angle and ace angle were both 10 degrees . compared to the normal hip ,
the ddh-1 model had the same acetabular cartilage shape but less contact area ( 1585.4 mm ) .
the shape of the acetabular cartilage of the 2 other models ddh-2 and ddh-3 were trimmed to the superior defect and anterosuperior defect , respectively . however , the 3 models had similar acetabular cartilage area through adding certain elements in the acetabular fossae .
the area of acetabular cartilage in the superior defect model ( ddh-2 ) was 1523.23 mm and in the anterosuperior defect model ( ddh-3 ) it was 1492.67 mm ( figure 1 ) .
first , pao were implemented in clinical settings by rotating the acetabular bone fragment around the femoral head anterolaterally until the target ce and vca angles were 25 degrees .
thus , the ddh-1 , ddh-2 , and ddh-3 models were rotated by 15 degrees in the anterolateral direction to create pao-1 , pao-2 , and pao-3 , respectively .
vertically , a load of 620 n ( body weight of 74 kg ) was placed on the center of the superior aspect of the sacral mount .
the simulated abductor force of the middle gluteal muscle was defined as 460 n ( figure 2 ) . the sacral mount was fixed on the transverse plane , and the distal femur was fixed in all directions . for nonlinear analysis , force control was used as the numerical procedure .
the newton - raphson method was applied as an iterative method , applying the load in 20 steps by an incremental loading method .
briefly , the normal model ( figure 2 ) was generated from a 24-year - old male ( with informed consent ) without clinical or radiological abnormalities .
the presupposed target center - edge ( ce ) angle and anterior center - edge ( ace ) angle in this model were both 25 degrees .
the main linear elastic and isotropic material properties of cortical bone , trabecular bone , cartilage , and acetabular labrum are shown in table 1 .
the 3 ddh models with decreased coverage of acetabular cartilage were generated by deforming the acetabular rim toward the posteromedial direction of the normal hip model .
the presupposed target ce angle and ace angle were both 10 degrees . compared to the normal hip ,
the ddh-1 model had the same acetabular cartilage shape but less contact area ( 1585.4 mm ) .
the shape of the acetabular cartilage of the 2 other models ddh-2 and ddh-3 were trimmed to the superior defect and anterosuperior defect , respectively . however , the 3 models had similar acetabular cartilage area through adding certain elements in the acetabular fossae .
the area of acetabular cartilage in the superior defect model ( ddh-2 ) was 1523.23 mm and in the anterosuperior defect model ( ddh-3 ) it was 1492.67 mm ( figure 1 ) .
first , pao were implemented in clinical settings by rotating the acetabular bone fragment around the femoral head anterolaterally until the target ce and vca angles were 25 degrees .
thus , the ddh-1 , ddh-2 , and ddh-3 models were rotated by 15 degrees in the anterolateral direction to create pao-1 , pao-2 , and pao-3 , respectively .
vertically , a load of 620 n ( body weight of 74 kg ) was placed on the center of the superior aspect of the sacral mount .
the simulated abductor force of the middle gluteal muscle was defined as 460 n ( figure 2 ) .
the sacral mount was fixed on the transverse plane , and the distal femur was fixed in all directions . for nonlinear analysis ,
the newton - raphson method was applied as an iterative method , applying the load in 20 steps by an incremental loading method .
stress distribution on the acetabular cortical bone ( figures 3 , 4 ) . in the normal hip ,
the von mises stress showed a uniform distribution pattern , mainly distributed in dispersed fashion on the superior region of the lunate surface , and mostly concentrated on the intermediate region .
however , the von mises stress in the 3 ddh models concentrated intensively on the edge of the acetabulum , which was higher than in the normal model .
the maximum value of von mises stress on the load - bearing area of the acetabulum decreased from 15.49 mpa pre - pao to 14.28 mpa post - pao in the ddh-1 model .
the maximum value in ddh-2 fell from 30.46 mpa pre - pao to 26.04 mpa post - pao .
the maximum value in ddh-3 decreased from 33.89 mpa pre - pao to 27.48 mpa post - pao .
although the 3 models were adjusted to the same angle , the stress on the anterosuperior edge of the acetabulum in ddh-1 became dispersed after surgery , while the stress in the ddh-2 and ddh-3 models remained concentrated on this region .
severe acetabular dysplasia has been proven to be prone to progression to hip osteoarthritis . in ddh patients ,
pao is widely applied in patients with ddh because the acetabular osteotomy fragment is rotated in the anterolateral direction to cover the femoral head load - bearing area through the preserved articular cartilage .
generally , pao can decrease the maximum stress on the load - bearing area and , subsequently , improve the biomechanical environment of the hip joint .
there are several potential factors that can lead to undesirable outcomes of pao in patients with ddh .
given the above , the present study aimed to verify whether different types of acetabular cartilage deficiency affect the overall hip joint biomechanical environment , both pre- and post - pao .
postoperatively , the maximum value of von mises stress on the load - bearing area of the acetabulum decreased from 15.49 mpa pre - pao to 14.28 mpa post - pao in the ddh-1 model , which was close to the normal value ( 13.06 mpa ) .
the stress concentration area also shifted from the lateral portion pre - pao to the medial portion post - pao , which showed satisfactory outcomes , as previously reported .
the von mises stress distribution on the acetabulum in the ddh-2 model ( superior defect ) decreased to some extent ( the maximum value fell from 30.46 mpa pre - pao to 26.04 mpa post - pao ) .
the stress concentration area was still distributed on the anterosuperior edge of the acetabulum , not as ideal as in the ddh-1 model , which could cause biomechanical environment disorder of the hip due to high contact stress ( figures 3 , 4 ) .
reported that the stress was reduced by 13.4% post - pao of a 15-degree - rotation in a patient with a ce angle of 10 degree .
moreover , the von mises stress on the acetabulum in the ddh-3 model ( anterosuperior defect ) barely improved ( the maximum value decreased from 33.89 mpa pre - pao to 27.48 mpa post - pao ) .
therefore , stress concentration might be a crucial reason for the development of osteoarthritis in some dhh patients post - pao .
reported that about 25 degrees would be the optimal ce angle for rotational osteotomy based on fea , which closely approximates the study results of armiger et al . and steppacher et al . .
in our ddh-1 model with normally shaped acetabular cartilage , the target ce angle post - pao was also 25 degrees .
because the ddh-2 and ddh-3 models originated from the ddh-1 model , these models had similar ce and ace angles , similar acetabular cartilage areas , the same pao surgery , and the same boundary and loading conditions .
post - pao , the outcome in models with different extents and locations of acetabular cartilage defect ( ddh-2 with superior defect and ddh-3 with anterosuperior defect ) was not as satisfactory as in the ddh-1 model ( normal shape of acetabular cartilage ) .
these findings showed that dysplastic hips ( superior or anterosuperior side ) , even treated with the optimal 25 degrees , still can cause long - term hip osteoarthritis due to the stress concentration on the outer edge .
this suggests a limitation in the application of pao for treating patients with severe defect of the outer rim of dysplastic cartilage .
acetabular reorientation is the most important and difficult step during pao . even with the ideal angle , the femoral weight - bearing area can not be completely covered by acetabular cartilage due to the decreased size of the lunate surface .
hence , the superior and anterior coverage should be simultaneously guaranteed during pao , according to the morphology of the lunate surface in hip dysplasia .
it appears that detailed 3d information about the acetabular weight - bearing surface , namely the lunate surface , is crucial for preoperative assessment for pao .
so far , the precise morphology of the lunate surface has only been discussed in the normal hip , not in the dysplastic hip . in the future ,
we plan to evaluate 3d morphology of the acetabular lunate surface in patients with ddh and to make possible real optimal preoperative planning of pao through fea and an intraoperative navigation system .
through these effects , optimum coverage of the weight - bearing area of the femoral head might be achieved with cartilaginous congruency .
the acetabular osteotomy bone fragments might then be effectively reoriented to diminish contact stress per unit area , contributing to more satisfactory postoperative prognoses .
first , the models used were only involved in rough superior and anterosuperior defects . due to deficiency of acetabular coverage
thus , it is necessary to ascertain accurate morphology of dysplastic acetabular cartilage and its matchability to the femoral head .
second , the ddh model deformities were derived from the normal hip model , which was not suited for revealing the abnormal anatomy of the femoral head and acetabulum in patients with dysplastic hips .
in conclusion , this study shows that different types of cartilage deficiency , such as anterosuperior or superior defects , affect the biomechanical environment both pre- and post - pao in 3d fe analysis .
it is crucial to acquire accurate and comprehensive 3d information on the size and shape of the acetabular cartilage in dysplastic hips to better inform surgeons who are making decisions regarding pao procedures .
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### Summary:
: backgrounddifferent extents and locations of acetabular cartilage defect have been supposed to be a major cause of undesirable outcomes of periacetabular osteotomy ( pao ) in patients with developmental dysplasia of the hip ( ddh ) .
this study aimed to verify whether different locations of cartilage deficiency affect the biomechanical environment in a three - dimensional model utilizing finite element analysis ( fea).material / methodswe developed 3 ddh models
ddh-1 ( normal shape ) , ddh-2 ( superior defect ) , and ddh-3 ( anterosuperior defect ) by deforming from a normal hip model .
we also developed 3 pao models
pao-1 , pao-2 , and pao-3 through rotating osteotomized fragments.resultsthe maximum von mises stress in the normal hip was 13.06 mpa . in the ddh-1 model ,
the maximum value on the load - bearing area decreased from 15.49 mpa pre - pao to 14.28 mpa post - pao , while stresses in the ddh-2 and ddh-3 models were higher than in the ddh-1 model , both pre - pao and post - pao ( 30.46 mpa to 26.04 mpa for ddh-2 ; 33.89 mpa to 27.48 mpa for ddh-3).conclusionsthis study shows that , both pre- and post - pao , different types of cartilage deficiency affect the biomechanical environment .
furthermore , in dysplastic hips , obtaining accurate three - dimensional information about the acetabular cartilage can contribute substantially to pao decision making .
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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:
: medicinal plants have been employed in various traditional medicines throughout the world since ancient time .
they have been a rich source of chemicals and thus many bioactive compounds have been isolated in their pure form .
flavonoids are a class of naturally occurring plant secondary metabolites imparting protection to the reservoir [ 1 , 2 ] .
they are compounds of low molecular weight and are chemically polyphenolic in nature presenting a common benzo--pyrone structure .
they have enormous biological and pharmacological activities conferring many health benefits to the human [ 1 , 2 ] .
they are the group of compounds which received considerable attention from the researchers as depicted from the scientific literature .
mostly they are present in plants as glycosides but can also be isolated in free aglycon form [ 4 , 5 ] .
dracocephalum heterophyllum benth . is a small perennial aromatic herb belonging to the family lamiaceae and has been of medicinal importance in chinese traditional medicine .
it is used in traditional way of treatment of tracheitis and cardiovascular disease in xinjiang and in tibet region of china [ 46 ] .
the plant used has been extensively used in amchi system of medicine in the ladakh region of the himalaya for a long period .
the decoction of dried flowers and leaves is used in cold , cough , and headache treatment .
the essential oil of the plants has been shown to possess antimicrobial and antioxidant activities and thus can be used in cosmetics , food , and pharmaceutical industries .
considering the importance of the phytochemicals responsible for the medical properties of dracocephalum heterophyllum benth . , the investigation was carried out for antioxidative , antidiabetic , and anticancer activity and the presence of phytochemicals with biological activity .
aerial part of dracocephalum heterophyllum is said to contain as many as 10 types of flavonoids , and among these are luteolin , kaempferol , diosmetin , and chrysosplenetin .
we have isolated 9 flavonoids from plant which were named chrysosplenetin , diosmetin , luteolin , acacetin 7-o - rutinoside , diosmetin 7-o - glucoside , rutinoside , kaempferol , kaempferol 3-o--d - glucoside , and quercetin [ 4 , 5 ] .
various methods have been employed for the determination of flavonoids based on the electrophoresis and chromatography [ 1 , 2 , 915 ] .
hplc is the method of choice among the chromatographic techniques for the analysis of flavonoids which needs no derivatization and thus reduces the time consumption in comparison to gc [ 1 , 2 , 10 ] .
moreover , it is safe for flavonoids as it can be operated even at room temperature thus avoiding the risk of decomposition of compounds like flavonoids at high temperature .
the present paper deals with the quantification of four flavonoids , namely , luteolin , kaempferol , diosmetin , and chrysosplenetin , which are available in free aglycon forms in the plant under study , using the hplc in a single run .
further , this is the first paper describing the quantification of these four flavonoids in the plant extract under study .
the aerial parts of dracocephalum heterophyllum were collected from atush in xinjiang , china , in august 2010 , respectively . after being air - dried in nature , the plant was ground with a laboratory mill and then passed through a 20-mesh sieve .
the standards of chrysosplenetin , diosmetin , kaempferol , and luteolin were isolated from d. heterophyllum in the pure form .
acetonitrile , hplc grade , was purchased from lichrosolv , merck , darmstadt , germany ; the methanol and formic acid ( lichrosolv , merck , darmstadt , germany ) were of analytical reagent grade .
extraction efficiency was determined based on the total extractive percent value using different compositions of aqueous ethanol as 50% , 70% , 80% , and 95% at room temperature for 48 hours .
afterwards , one hundred grams of above ground part of d. heterophyllum was weighed accurately and extracted with 400 ml of 80% aqueous ethanol for 48 hours at room temperature .
the extract was filtered , decolorized , and defatted by petroleum ether for several times .
the extract was reduced to dryness through rotary evaporator under reduced pressure yielding 20 mg dried extract .
the extract was reconstituted in 1 ml of pure methanol and injected 10 l into the column .
one g of plant material was extracted with 50 ml of methanol under reflux and the extract obtained was reduced to dryness .
the residue was reconstituted in 10 ml of methanol and this extract was used for the determination of total flavonoids contents .
briefly , 0.5 ml of plant extract / standard solution was mixed with 1.5 ml of methanol in a test tube .
0.1 ml of 10% aluminum chloride , 0.1 ml of 1 m potassium acetate , and 2.8 ml of distilled water were added to the test tube and mixed thoroughly after each addition .
it was allowed to react for flavonoid - aluminum complex formation for 30 minutes at room temperature .
afterwards , the absorbances of the reaction mixtures were measured at 415 nm using the uv - visible spectrophotometer .
quercetin was used as standard and six working standard solutions were prepared in the concentration range 0.01 mg / ml to 0.1 mg / ml for constructing the calibration curve .
the four flavonoid standards , that is , luteolin , kaempferol , diosmetin , and chrysosplenetin , were mixed and stock solution of standard flavonoids mixture was prepared in methanol having 1 mg / ml concentration of each standard . from this stock solution , four working standard solutions with a concentration range 0.00011 mg / ml were prepared .
hplc analysis was performed using a dionex ultimate 3000 hplc system ( thermo - fisher , usa ) equipped with autosampler and coupled to variable uv wavelength detector .
the chromatography was performed on sunfire c18 column from waters , usa , having the following specifications : internal diameter 4.6 mm , height 250 mm , and particle size 5 m .
the chromatographic column was protected by a sunfire c18 guard column of the following dimensions : internal diameter 4.6 mm , height 20 mm , and particle size 5 m obtained from waters , usa . the control of the instrument and the data analysis was performed by chromeleon version 7.2 software provided by the supplier .
chromatographic conditions were optimized in order to reach baseline separated peaks of the target analytes . for this purpose ,
different mobile phases with varying gradient elution were employed . the mobile phase consisting of a : methanol and b : 0.1% ( v / v ) formic acid in water with the gradient set up as mentioned below delivered good baseline separation of the targeted peaks .
the gradient used was as follows : zero time condition was 8% a and it was increased to 78% a in 50 minutes .
10 l of the sample extract and the standards were injected into the chromatographic column maintained at 35c .
the flow rate used was 1 ml / min and detection of the eluted peaks was performed at 254 nm .
the method of extraction by soaking the plant material in solvent was selected due to its simplicity and easy manageability .
ethanol in combination with water was used as extracting solvent because of its less toxicity and easy availability .
different combinations of ethanol with water as 50% , 70% , 80% , and 95% aqueous ethanol were evaluated in order to determine the extraction efficiency and to reach optimized solvent for extraction .
figure 1 shows the graphical comparison of the extraction yields of various compositions of aqueous ethanol .
80% ethanol delivered the highest extraction yield ( 3.76 mg / g ) among the tested solvents .
the extractive values for 50% , 70% , and 95% ethanol were 3 mg / g , 3.4 mg / g , and 2.35 mg / g , respectively , from dry d. heterophyllum plant .
total flavonoids contents were determined using the published method in the literature using alcl3 as complexation reagent forming a complex with flavonoids which has a maximum absorption at 415 nm .
total flavonoids contents were quantified as equivalent of quercetin and calibration curve was produced with an r
value 0.9971 .
the calibration curve was passed through zero and the contents of flavonoids were calculated using the regression equation obtained from the calibration curve .
the total flavonoids contents yielded in the aerial part of d. heterophyllum were 0.324 mg / ml of the final extract .
preliminary separation of the standard mixture and the extract was performed with mobile phase consisting acetonitrile and 0.1% ( v / v ) formic acid in water using the gradient mode of elution .
this mobile phase did not deliver good resolution as in figure 2 it is clear that at 48 min two target peaks of luteolin and quercetin and at 58 min two target peaks of diosmetin and kaempferol are coeluting and are merged .
therefore , quantification of these four flavonoids was not possible as baseline separated peaks are required for the quantitative determination . therefore , the mobile phase was changed to methanol and 0.1% ( v / v ) formic acid in water using the conditions as described in experimental section . with this optimum baseline separation of the target analytes
the peaks of target flavonoids luteolin , kaempferol , diosmetin , and chrysosplenetin eluted at retention times 38.8 min , 41.5 min , 42.3 min , and 45.8 min , respectively , in the sample extract . using the optimized chromatographic conditions calibration curves for the four flavonoids were established through analyzing working standard solutions in triplicate .
regression equations and r
values and percentage concentrations of the flavonoids in the plant extract obtained from these analyses are tabulated in table 1 .
contents of individual flavonoids were calculated as percentage of the dried extract using the regression equations .
contents of the diosmetin ( 0.28% ) and chrysosplenetin ( 0.79% ) were significant and luteolin yielded the lowest amount ( 0.08% ) in this study while the amount of kaempferol was 0.14% .
standard deviation and the % rsd are the results of the five replicate injections of the plant extracts .
lod and loq were calculated using microsoft excel sheet based on standard deviation ( table 1 ) .
reproducibility and accuracy of the method were tested by analyzing the sample extract five times and their standard deviation and % rsd were calculated based on retention times and area under the curve for each target analytes individually .
table 2 shows the data obtained from the five replicate injections of the sample extract . in no case , the % rsd was higher than 1 taking retention time as a factor while in the case of area under the curve maximum % rsd was noted in the case of diosmetin as 2.85 ( table 2 ) .
percent recovery of the optimized hplc method was determined through injecting the two concentrations ( 1 mg / ml and 0.1 mg / ml ) of each individual flavonoid standard under study .
this experiment resulted in the recovery percentage within the acceptable range of 95% to 105% according to the ich guidelines for validation of analytical methods . from our literature review regarding the plant species under study
, it appears that these flavonoids have not been quantified before and are reported for the first time in this paper .
the study proved the presence of biologically and pharmacologically important flavonoids in quantifiable amount making the plant dracocephalum heterophyllum b. beneficial for the preparation of phytopharmacon .
the results of the study can be used for developing the quality control profile by the pharmaceutical and phytopharmaceutical industries .
further , the method applied is reliable and reproducible and can be used for the determination of flavonoids in plant extracts .
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### Summary:
: quantification of the four flavonoids , namely , luteolin , kaempferol , diosmetin , and chrysosplenetin , has been performed for the first time in 80% ethanolic extract of dracocephalum heterophyllum b. through hplc coupled to uv detector after optimization of extracting solvent and chromatographic conditions .
total flavonoids quantified were 0.324 mg / ml of the extract .
hplc analysis delivered contents of the luteolin , kaempferol , diosmetin , and chrysosplenetin as 0.08% , 0.14% , 0.28% , and 0.79% of the dried extract , respectively .
lod ( % ) values calculated were 0.04 , 0.03 , 0.03 , and 0.08 and loq ( % ) values were 0.08 , 0.12 , 0.11 , and 0.28 for luteolin , kaempferol , diosmetin , and chrysosplenetin , respectively .
the recovery percentages for these flavonoids were within the acceptable range of 95% to 105% .
standard deviation and % rsd were calculated for each target analytes individually in extract for determining the reproducibility and accuracy of the method . in no case
the % rsd was higher than 1 taking retention time as a factor while in the case of area under the curve maximum % rsd was noted in the case of diosmetin as 2.85 . from our literature review regarding the plant species under study , it appears that these flavonoids have not been quantified before and are reported for the first time in this paper .
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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:
: cancer cells express many factors that enable them to overcome regulatory barriers towards uninterrupted growth and to survive in abnormal circumstances in which normal cells will not . among such factors , tyrosine kinases play pivotal roles .
eph ( erythropoietin producing hepatoma ) receptors comprise the largest family of tyrosine kinases and are divided into two classes of ephas and ephbs based on their sequence homology .
one distinguishing feature of this family is their ability to propagate bidirectional signals in cells expressing receptor and ligand ; in other words , both eph receptors and ephrin ligands are capable of inducing downstream signals in the form of forward and reverse signals . owing to such spatial orientation , eph receptors and ephrin ligands construct a communication system between cells expressing the receptor and ligand , which allows them to be involved in many physiological processes such as proliferation , morphology and movement , normal organ out - growth during neuronal path finding , and angiogenesis [ 47 ] .
unlike other tyrosine kinases which are mostly oncogenic , dual functions of tumor promotion and suppression have been reported for this family .
ephb4 expressed on cancer cells interacts with ephrinb2 present on endothelial cells and induces angiogenesis .
consistently , soluble ephb4 receptors which are incapable of stimulating endothelial ephrinb2 ligands have been shown to possess therapeutic potential in decreasing tumor growth through inhibition of angiogenesis [ 10 , 11 ] .
moreover , ephb4 overexpression has been shown to be correlated with increased tumor grade and stage and overexpressing ephb4 receptor in nonmalignant breast and prostate cells leads to their transformation and manifestation of malignant behavior .
accordingly , downregulation of ephb4 decreases breast cancer cells ' viability indicating that ephb4 expression serves as a survival factor .
besides ephb4 overexpression in cancer cells , receptor phosphorylation in tumor cells is very low , and it has been shown that ephrinb2 , the preferred ligand for ephb4 , is downregulated as the receptor is overexpressed .
this has led to a hypothesis that ephrinb2 mediated ephb4 activation and a balanced expression of receptor and ligand lead to tumor suppression .
, in which they reported activation of a tumor suppressor signaling pathway , abl - crk , downstream of ephrinb2/ephb4 signaling in breast cancer cells . besides novel studies to date dedicated to characterize functions of eph receptors in cancer , the complexities associated with their role necessitates more elaborate understanding of their contribution to tumor biology in order to properly target and fully exploit their tumor suppressive behavior in cancer treatment .
we believe that fatal effects of ephrinb2 treatment on breast cancer cells may also be time and dose - dependent .
herein , we examine the effect of short- and long - term treatment of various ephrinb2-fc concentrations on growth of mda - mb-231 breast cancer cells in different states of confluence , and we test the effects of such treatments on aggressive behavior of cancer cells in a three - dimensional culture with matrigel .
cells were maintained in dmem supplemented with 10% fbs plus 1% penicillin / streptomycin and were kept in humidified 5% co2 incubator with medium renewal every 2 - 3 days .
alamar - blue is a commercially available solution of resazurin salt developed to measure viability and proliferation of various cultured cells . unlike tetrazolium salts ( such as mtt ) , alamar - blue dye is water soluble which obviates further crystal solubilization by addition of dmso .
moreover , alamar - blue is not toxic to cells and allows repeated measurements of cell viability over a long period of time making kinetic studies possible .
alamar - blue is converted to a reduced form by mitochondrial enzymes , and the process is accompanied by a change in color from indigo blue to pink , which can be measured by colorimetric or fluorometric reading . due to the difference in metabolic capacity of cells in reducing alamar - blue dye , optimum length of incubation and number of cells for plating
are two critical variables to be determined before performing viability / cell proliferation assay for each cell line used .
cells growing in the log phase of growth were harvested by trypsin - edta , and an initial concentration of 1 10 and further dilutions were made and seeded into wells of a 96-well plate ( 200 l for each well ) .
the medium without cells was used as negative control , and the plate was incubated for 4 h to allow cell attachment .
the absorbance was measured immediately and every 2 hours at 570 and 600 nm for the first 6 hours using powerwavexs plate reader .
the plate was also incubated for the following 24 hours to measure the maximum dye reduction .
ph was strictly controlled at 77.4 by keeping the plate in a co2 incubator during the test .
percentage reduction of alamar - blue is typically calculated using equation ( 1 )
( 1)percent reduction of alamar - blue = ( 117216a1)(80586a2)100(155677n2)(14652n1)a1 and a2 are recorded absorbance of test wells at 570 and 600 nm , respectively , and n1 and n2 are observed absorbance of negative control . alternatively , an online calculator suggested by providing company was used for measuring percentage reduction ( http://www.abdserotec.com/ ) .
dimerization of ephrinb2-fc ligand is necessary in order to fully activate ephb4 receptor ; hence ephrinb2-fc and fc were preclustered with goat antihuman igg at 1 : 3 concentration for 1 hour at room temperature prior to experiments .
cells at 2.5 10 concentration were seeded into each well of a 24-well plate .
twenty four hours later , cells were incubated with medium containing 1 , 3 or 10 g / ml pre - clustered ephrinb2-fc or control fc .
cell viability was measured on days 3 and 6 , when cells were in sub- and postconfluent state , respectively .
alamar - blue was added to each well containing fresh medium with 10% fbs in an amount equal to 10% of volume in each well and was incubated for 3 hours .
aliquots of 200 l were dispensed in 96-well plates and absorbance was measured at 570 and 600 nm using a plate reader .
cells plus alamar - blue containing no test agent were used as positive growth control .
difference between percentage reduction of ephrinb2-fc and fc treated groups were then calculated based on equation ( 2 ) or online calculator .
( 2)percent difference of dye reduction = ( 117216a1)(80586a2)100(117216p1)(117216p2)a1 and a2 are observed absorbance of test wells at 570 and 600 nm , while p1 and p2 are observed absorbance of positive growth control , which consisted of cells plus alamar - blue but no test agent .
matrigel was thawed on ice and 100 l solution was evenly added to each well of ice cold 24-well plate and was kept in incubator for 30 minutes .
a suspension of 10 cells plus solutions of 3 and 10 g / ml preclustered ephrinb2-fc or pbs as negative control were added to each well in a total volume of 400 l , and plate was incubated for 24 hours .
analysis of variance followed by post - hoc test was performed to compare survival between various doses .
data are represented as average s.e.m and p < 0.05 was considered as significant .
percentage reduction of alamar - blue after incubation with mda - mb-231 cell line was measured at different cell densities and incubation periods , and data was plotted against various cell concentrations for each time point .
the curve was linear between 5 10 and 2 10 cell / ml ( figure 1 ) . based on these results and a pilot test to determine optimal cell density for seeding cells in 24-well plates , 2.5 10 cell / ml concentration
incubation time of 3 hours with alamar - blue was found to be optimal for calculation of percentage reduction .
analysis of receptor phosphorylation following stimulation via clustered ephrinb2 showed that ephb4 receptor was active in mda - mb-231 breast cancer cell line ( data not shown ) . to determine the effect of receptor activation on cell viability and growth
, cells were exposed to various doses of clustered ephrinb2-fc at different time points as discussed earlier .
no significant reduction in cell viability was observed when cells were incubated with ephrinb2-fc or fc control for 3 days , neither when cells were about 60% confluent and were growing in monolayer state ( figure 2(a ) ) .
a significant decrease was detected after 6 days of incubation when cells had reached confluence and were continued to grow as a second layer ; reduction in cell viability was more prominent in higher doses ( figure 2(b ) ) .
these results indicate that inhibition of cell growth mediated by ephb4 stimulation via ephrinb2 occurs only after longer incubation times .
matrigel is a commercial mixture of collagen and laminin which are the main constituents of extracellular matrix .
transformed and nontransformed cells display different morphologies on matrigel and this property that can be exploited to study the effect of antitumor agents on reversing the transform cell behavior .
normal cells such as mcf-10a form spherical bodies on matrigel , while transformed and invasive cells such as mda - md-231 breast cancer cell line invade matrigel and form tubular networks .
we tested if ephrinb2-fc treatment can inhibit tubular network formation of mda - mb-231 on matrigel .
cells were incubated on matrigel for 24 hours in the presence of preclustered ephrinb2-fc ( examining 3 g / ml and 10 g / ml concentrations ) .
ephrinb2 , at any of tested doses ; did not alter invasive behavior of cells as shown in figure 3 .
if ephrinb2 treatment was to affect invasive behavior on matrigel , the tube formation was expected to be abrogated totally , and aggregated colonies were to be seen instead of tubules , as shown by carles - kinch et al . .
these results indicate that the observed decrease in cell viability mediated via ephb4 stimulation after 6 days is not likely due to specific inhibition of multi layer growth stage named anchorage independent growth .
eph family of receptors are interesting targets for molecular cancer therapy since they are mostly overexpressed in tumors and seem to be involved in tumor cell survival and proliferation , invasion , metastasis , and angiogenesis .
thus , designing agents to properly target them can induce tumor growth arrest by multiple mechanisms .
however , rational drug design to thoroughly exploit their ability to inhibit tumor growth requires more accurate understanding of mechanisms underlying eph / ephrin system signaling in cancer cells and their microenvironment . in this study
, we showed that long term incubation of mda - mb-231 breast cancer cells with ephrinb2-fc inhibited their growth when cells were growing in postconfluent state , and growth inhibition was more prominent in higher doses .
a similar study by carles - kinch et al . revealed that use of activating antibodies against epha2 , another member of eph family overexpressed in mda - mb-231 cell line , led to inhibition of cell growth after reaching confluence as well as inhibiting tubular formation on matrigel .
inhibition of cell growth after 6 days might be due to receptor downregulation and deletion from cell surface rather than inhibition of anchorage independent growth .
in which they showed that long term treatment of mcf-7 cells with ephrinb2 led to receptor downregulation and growth inhibition , similar to results from knock down of ephb4 . on the other hand , with the conditions used in this study , ephrinb2-fc treatment did not reduce formation of tubules and invasion .
it is thus speculated that ephrinb2-fc is more likely an inhibitor of tumor cell viability and reduction of tumor invasion may require higher doses or in vivo conditions where inhibition of angiogenesis leads to suppression of invasion and metastasis .
recent studies have uncovered interesting aspects of eph receptors in breast cancer yet exact roles of eph / ephrin in promotion or suppression of tumors remains unclear .
dual roles of tumor promotion and suppression ( figure 4 ) have been assigned to this family , possibly based on presence or absence of their cognate ligand .
therefore , ephb4 may serve as a survival factor for breast cancer cells possibly due to constitutive activation or crosstalk with other oncogenic growth factor receptors such as egfr family .
in contrast , ephb4 activation by its ligand , ephrinb2 , in breast cancer cells has been shown to inhibit tumor promotion and invasion through activation of abl - crk pathway that was consistant with our results . yet the scenario seems to be much more complicated to describe the opposing effects of ephb4 stimulation solely by presence or absence of ephrinb2 . in this
regard , cell context also seems to play a pivotal role in determining effects on tumor promotion or suppression as well .
in which they demonstrated that ephrinb2-fc treatment leads to growth inhibition in huvec cell , while the same stimulation leads to growth promotion in mcf-7 cells .
paradoxes about the role of ephb4 receptor in breast cancer go even further and are evident in signaling mechanisms assigned for them as well .
have previously shown that ephb4 stimulation via ephrinb2 leads to activation of pi3 k / akt pathway- and a 4-day treatment of mcf-7 cells with the ligand led to cell death due to receptor down - regulation .
on the other hand , xiao et al . reported an increase in growth of mcf-7 cells following ephrinb2 treatment due to activation of ras / erk pathway after 6 days .
such discrepancies in the same context may be due to variations in experimental conditions such as ligand dose and timing of receptor stimulation which was shown to be effective in our study as well and the extent of ligand clustering with anti - fc antibody or sensitivity of viability assays used .
dependence of response from growth inhibition to promotion upon different stimulation conditions further sophisticates smart drug design for targeting ephb4 in breast cancer and therefore necessitates further studies to more accurately address the advantage of ephb4 activation over ephb4 inhibition in various cancers .
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### Summary:
: background .
ephb4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors .
dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand . to elucidate such discrepancy , we aimed to determine the effect of time- and dose - dependent stimulation of ephb4 on viability and invasion of breast cancer cells via recombinant ephrinb2-fc . methods .
cells were seeded into multiwell plates and were stimulated by various concentrations of preclustered ephrinb2-fc .
cell viability was measured on days 3 and 6 following treatment using alamar - blue when cells were in different states of confluence .
results .
stimulation of cells with ephrinb2 did not pose any significant effect on cell viability before reaching confluence , while inhibition of cell growth was detected after 6 days when cells were in postconfluent state following a dose - dependent manner .
ephrinb2 treatment did not affect tubular formation and invasion on matrigel .
conclusion .
this study showed that ephb4 can differentially inhibit cells at post confluent state and that presence of ligand manifests growth - inhibitory properties of ephb4 receptor .
it is concluded that growth inhibition has occurred possibly due to long treatment with ligand , a process which leads to receptor downregulation .
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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:
: isolated deficiency of a single anterior pituitary hormone is by now accepted as a clinical entity , even if uncommon , although this entity may be heterogenous .
idiopathic isolated adrenal corticotropic hormone ( acth ) or tsh deficiency is generally discovered in subjects over 40 years of age ( 1 ) . in such patients , it is difficult to deduce if the defect is a developmental or genetic one .
reported here is a case regarded as being compatible to an acquired defect of tsh secretion in the pituitary itself without an ascertainable cause .
a woman , 76 years old , was admitted to our hospital for fatigability , puffy face and leg edema in august , 1992 . in 1985
the tc and i thyroid scintigraphy indicated large functioning thyroid nodule in right thyroid lobe [ i uptake : 37.6% ( 3h ) , 40.6% ( 6h ) ( normal range 6h .
in the following year , she got an operation of the thyroid gland for functioning follicular adenoma of the right lobe and nodular hyperplasia ( adenomatous goiter ) of the left one .
the right lobe of the thyroid had been totally resected and only half of the left lobe remamed . before and after the operation , free t4 and tsh levels were below normal range and desiccated thyroid was administered .
the thyroid evaluation , performed after three months following the operation , was hypothyroid state as follows ; t3 ( 66ng / dl ) , t4 ( 5.3g / dl ) , f - t4 ( 0.29g / dl ) and tsh ( 32.3 u / ml ) ( table 1 ) . the dosage of desiccated thyroid was increased to 60 mg and serum tsh level became low level .
in may , 1991 , thyroid function test showed normal serum total thyroid hormone , suppressed tsh and low free t4 levels .
thereafter her compliance of taking drugs was insufficient . on admission , ( in august , 1992 ) , she appeared clinically to be myxoedematous because of puffy face and non - pitting leg edema . on physical examination ,
the body temperature was 36.5c , pulse rate 72 beats per minute and regular , and blood pressure 132/70mmhg .
urinalysis , hemogram , levels of electrolytes , blood urea nitrogen , blood glucose , uric acid , cholesterol and liver function were within normal limits .
tsh was still suppressed despite low level of t4 ( 1.6g / dl ) , t3(15ng / dl ) , free t4(0.15ng / dl ) and free t3 ( below 0.4 ) .
serum tbg level was 20.5g / ml and anti - thyroglobulin , microsome antibodies , tsh receptor antibody and anti - tsh antibody were negative .
as shown in table 2 , a significant increase in serum tsh levels did not occur after drip infusion ( 2 mg ) of trh for 30 minutes .
after repeated injection of trh ( 2mg / day ) for 4 consecutive days , serum tsh levels were still suppressed ( maximum level : 1.45u / ml in 120 minutes of final injection day ) . with the final trh injection , combined
pituitary stimulation test by intravenous injection of 0.1 units / kg reglar insulin , 0.1 mg lh - rh was performed .
growth hormone ( gh ) , lh , fsh , prolactin ( prl ) and cortisol kept almost normal responses ( table 2 ) .
isolated tsh deficiency was first reported in 1953 by shuman . since then , more than 30 patients with isolated tsh deficiency have been reported .
these patients were diagnosed by exogenous trh administration test and the direct determination of tsh in serum .
recently , the advance of endocrinology and radiology is explaining the pathogenesis of isolated tsh deficiency , which is classified as disorders of pituitary lesion associated with central hypothyroidism .
the pituitary causes can be broadly divided into mass lesions , infiltrative diseases , pituitary atrophy due to necrosis or autoimmune destruction and idiopathic tsh deficiency .
the diagnostic criteria of idiopathic tsh deficiency are to satisfy 1 ) low serum levels of thyroid hormones , 2 ) low or undetectable tsh levels , 3 ) no tsh response to exogenous trh , 4 ) no evidence of other pituitary hormone deficiencies , 5 ) no abnormalities on radiographic studies .
our case first occurred undetectable tsh and low ft4 before the operation of functioning adenoma , and abruptly became hypothyroidism with transient rise of tsh .
when the dose of desiccated thyroid was increased , serum t4 and t3 normalized , in spite of low free t4 and suppressed tsh level .
it is assumed that isolated tsh deficiency in adult populations shows commonly absent or mild symptoms of hypothyoidism . finally , she had various symptoms of hypothyroidism such as fatigability , puffy face , leg edema and cardiomegaly because of insufficiently taking drugs .
the tsh values were measured many times by means of immunoradiometric assay ( irma ) and the results were almost the same .
the characteristic finding of hypothalamic hypothyroidism is that a significant secretion of tsh occurs following repeated injection of trh . in hypothalamic hypothyroidism
, normal responsiveness of tsh to trh usually persists despite of many years continuing pituitary hypofunction .
high basal level of growth hormone in our case may be due to her poor nutrition . the responsiveness of pituitary hormones , except of rtsh , were intact and the brain mri showed no abnormality .
though the etiology of isolated tsh deficiency was speculated as genetic origin , it is not true in our case as she had no family history and had once experienced the tsh elevation in 1990 .
thus , we diagnosed our patient as acquired and idiopathic isolated tsh deficiency based on these findings .
the relationship between thyroid functioning adenoma and pituitary hypothyroidism is unknown and the cause of the disease remains obscure , though arteriosclerotic cerebrovascular disease and autoimmune damage to the anterior pituitary may be suggested as possible causes .
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### Summary:
: the first case of idiopathic thyrotropin ( tsh ) deficiency in an old woman with thyroid functioning adenoma was reported .
she got subtotal thyroidectomy before about four years of her admission to our hospital because of fatigability , puffy face and leg edema . at that time , she had low tsh and free t4 levels despite replacement therapy with desiccated thyroid .
no response of only serum tsh after adminstration of combined stimulant containing trh and repeated trh suggested the failure of tsh secretion .
ct mri did not show any abnormality .
these results indicated that her hypothyroidism was due to acquired idiopathic tsh deficiency .
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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:
: acetylsalicylic acid ( asa ) is one of the most commonly used drugs in the world due to its anti - inflammatory , analgesic , and antipyretic properties .
this review aims to describe the relationship between acetylsalicylic acid and age - related macular degeneration ( amd ) a chronic disease that causes deterioration of visual acuity and is one of the most common ophthalmological diseases these days .
data presented in this review were collected from both research and review articles concerning ophthalmology and pharmacology .
the results of the studies analyzed in this review are not unambiguous . moreover , the studies are not homogenous .
they differed from one another in terms of the number of patients , the age criteria , the asa dose , and the duration of control period .
the reviewed studies revealed that asa therapy , which is applied as a protection in cardiovascular diseases in patients with early forms of amd and geographic atrophy , should not be discontinued .
on the basis of the present studies , it can not be unequivocally said whether asa influences people s vision and if people endangered with amd progression or who are diagnosed with amd should use this drug .
it may increase the risk of amd , but it can also reduce the risk of life - threatening conditions .
the authors suggest that in order to avoid possible risks of amd development , people who frequently take asa should have their vision checked regularly .
acetylsalicylic acid ( asa ) is one of the most commonly used drugs1 in the world , due to its anti - inflammatory , analgesic , and antipyretic properties , as well as properties of inhibition of platelet aggregation.2 moreover , it has been proven that a relationship exists between asa consumption and a lower risk of cancer and that asa has positive therapeutic applications in the adjuvant therapy of cancer ( malignant tumors).3 it is estimated that 100 billion asa pills are consumed worldwide per annum.1 for short - term treatment of problems such as aches and fever , a typical daily dose of asa ranges from 0.5 g to 1.0 g to a maximum of 4.0 g in divided doses . in the case of rheumatic fever ,
the daily dose may even amount to 8.0 g. however , in the prevention and the treatment of cardiovascular diseases , the daily dosage generally amounts to 75150 mg ( in some cases , up to 325 mg / d).4 the basic mechanism of the asa effect is nonenzymatic protein modification acetylation which results in cyclooxygenase ( cox ) blocking .
as a consequence , inhibition appears in the formation of prostaglandins , which participate in inflammation , fever , and conduction of painful stimuli .
the asa effect is irreversible , and in cox-1 , it leads to strong and long - term antiplatelet action , whereas in cox-2 , it is favorable for the formation of antiphlogistic lipoxins.5 cox presents two distinct activities , the activities of cox and of peroxidase , and it appears in two isoforms ( cox-1 and cox-2 ) .
asa is more prominent in cox-1 , which is produced on a continuous basis as a constitutive enzyme ( mainly in gastric mucosa , platelets , vascular endothelium , and kidney ) , than in cox-2 an inducible enzyme ( in which synthesis appears mainly under the influence of proinflammatory factors in macrophages , monocytes , smooth muscles , epithelial cells , and neurons ) .
cox is the main enzyme of the arachidonic acid pathway , and it participates in the transformation into at least five compounds belonging to the group of prostanoids proinflammatory prostaglandin d2 , prostaglandin e2 ( pge2 ) , prostaglandin f2 alpha , thromboxane a2 ( txa2 ) , and prostacyclin .
pge2 , prostaglandin a2 , and pgi1 ( prostacyclin ) reduce blood pressure through spasmolytic effects on the smooth muscles of small arteries . on the other hand , txa2 influences the shrinking effects of these arteries and therefore increases blood pressure .
leukotrienes and their precursors are classified as mediators of inflammation processes , primarily allergic ones .
they are ascribed with the ability to slow the shrinkage of smooth muscles of the airway and alimentary canals , as well as having the ability to increase the permeability of capillaries , which is favorable for inflammatory edema appearance.68 using asa causes many side effects , such as nausea , vomiting , stomachache , mucosa erosion , alimentary canal bleeding , and in people with hypersensitivity , allergic reactions in the form of lung function perturbations ( dyspnea).2
recently , there have been many controversial reports on the influence of asa on one of the most common ophthalmological diseases these days age - related macular degeneration ( amd ) .
currently , it is believed that the occurrence of this disease entity is influenced by a number of modifiable and nonmodifiable factors .
nonmodifiable determinants embrace genetic factors , advanced age , sex , race , and iris color .
modifiable determinants , in turn , embrace cardiovascular diseases ( hypertension , atherosclerosis ) , systemic diseases ( for instance , diabetes ) , obesity , and smoking .
all monozygotic twins ( 100% ) are diagnosed with amd if the first sibling suffers from amd .
a study performed by klaver et al9 revealed that 23% of patients with late amd have inherited predispositions to disease occurrence .
variants at chromosome 1q32 ( in the region of complement factor h [ cfh ] ) and 10q26 ( loc387715/arms2 ) have very important and scientifically certified influence on the development of amd . in recent years ,
it has been proven that excessive activation of the complement system participates in amd progression .
the relationship between the development of amd and gene encoding factors h , i , and b of the complement and also components 2 and 3 of the complement has been found.10,11 the first discovery was made during a study by francis et al in a small case
control sample.12 there exists strong association between y402h variant in the cfh gene and increased risk of amd .
a meta - analysis connecting outcomes from multiple association studies of cfh and amd shows that heterozygote carriers of the risk allele have a 2.5-fold increase in developing amd and homozygous carriers have a sixfold increase in developing amd compared to the nonrisk allele.13 the most recent trials show not only genetic variants of amd pathogenesis but also the very important role of gene gene and gene environment factor interactions for this disease appearance .
the strongest candidate , according to studies , among all genes is apolipoprotein e gene ( apoe ) , because it exhibits a strong association with macular degeneration .
apoe is responsible for the transport and metabolism of lipids and cholesterol and in response to neuronal injury ; thus , it shows us that it could be an important connector with environmental factors our lifestyle and diet , for example.14
apoe has three common alleles : 2 , 3 , and 4 .
initially , two studies reported a reduction in the frequency of the 4 allele in patients with amd compared to controls , suggesting a protective effect .
further scientific studies about interactions between environmental factors and genetic variants will be necessary to solve the problems concerning the reason of amd development .
amd is a result of a number of processes that occur within the outer layer of the retina ; lipofuscin genesis
gathering of lipofuscin lodgments within the retinal pigment epithelium ( rpe ) ; drusen genesis creation of insoluble drusen ( extracellular collection of glycoproteins , lipids , and cellular debris deposits ) , which gathers between the layer of the rpe and the bruch s membrane ; and chronic local inflammatory process and neovascularization as a result of proangiogenic factors ( vascular endothelial growth factor [ vegf ] ) domination over antiangiogenic factors ( pigment epithelium - derived factor).15,16 two forms of amd have been distinguished : 1 ) dry form of amd is the most common , which occurs in 90% of cases and is characterized by the appearance of drusen and/or hyperpigmentation / hypopigmentation of pigment epithelium .
drusen that occurred earlier may disappear ( the so - called geographic atrophy [ ga ] ) ; it appears in the advanced stage of dry amd .
2 ) wet ( neovascular ) amd is the second type , which leads to significant impairment of vision . in case of neovascular form of amd , there is formation of abnormal vessels in the macular region .
moreover , they lead to retinal or subretinal hemorrhage.17 its main symptoms are choroidal neovascularization ( cnv ) and pigment epithelial detachment .
it is possible for the dry form to develop into the wet form.18 the authors of the blue mountains eye study ( bmes ) studied the relationship between the regular intake of asa over a 15-year period and the occurrence of amd , particularly its wet form .
bmes is a cohort population study of eye diseases , which was conducted on a group of 2,389 australians living in urban regions , aged older than 49 years .
the research showed that regular intake of asa doubles the risk of neovascular amd , regardless of medical history ( cardiovascular diseases , smoking ) .
the use of asa was not related either to the occurrence of ga or to incidents of early amd .
regular use of asa was defined in this study as taking the drug at least once a week . in the majority of cases ,
according to bmes , increased risk of development of cnv was observed in patients who used the drug for 15 years , which suggests that in pathogenesis , the accumulated dose is crucial.1 a european research study
european eye study was conducted in seven centers on a group of 4,691 participants aged older than 65 years . in the group under examination
, the patients took asa with varied frequencies : one dose a month and one dose a week .
it was proven that the intake of asa was connected with significantly more frequent ( double ) occurrence of both the early and late forms of amd , regardless of the risk factors .
moreover , in the research , it was noted that people who take asa every day are at a greater risk of hemorrhage ( 3.75 times more often ) .
the bleeding was three times as much as in people who did not take the drug.19 an american study beaver dam eye study was conducted on 6,243 people aged between 43 years and 86 years ( at the beginning of the research ) .
the frequencies of both the early and late forms of amd were estimated with reference to the frequency , period , and dose of asa intake .
it was proven that a 5-year period of asa consumption does not increase the risk of development of either the early or late form of amd . a 10-year period of asa intake , in turn , statistically has a significant influence on the development of wet amd , in comparison to the group of people who do not use asa .
there was no stated relationship between the dose of asa and the frequency of occurrence of early and late forms of amd , regardless of the period of its intake.20 in these three major studies , a substantially larger risk of wet amd development was observed in people who take asa . on the other hand ,
the relationship between asa consumption and the appearance of ga was not observed.1,19,20 another large randomized piece of research project,21 which was conducted in the us on women working in the health service , aimed to investigate whether the consumption of low doses of asa every second day has an influence on the frequency of amd .
the study embraced 39,876 healthy women aged at least 45 years , who were divided into two groups : one group of women who took 100 mg of asa every second day and a second group of women who took a placebo . throughout a 10-year observation period ,
it was evaluated and confirmed by ophthalmological examination whether any cases of amd occurred in which visual acuity deteriorated to the degree of 20/30 or worse .
after 10 years of observation , 111 cases of amd were observed in the first group and 134 cases in the group of patients taking the placebo .
it was proven that the use of low doses of asa by women does not influence the risk of amd development . in the san
francisco veterans affairs hospital eye clinic , a retrospective research22 was conducted that aimed to determine whether the frequency of cnv development increased in patients with recognized amd who took asa and statins .
the examination embraced 326 patients with amd and aimed to compare the progression of diseases in patients who took and did not take asa and statins over at least 6 months .
the research revealed that in patients treated with asa and statins , the risk of cnv development was lower .
researchers from the department of ophthalmology of maria sklodowska - curie memorial hospital in zgierz and department of internal diseases and cardiac rehabilitation of the medical university of lodz , poland , studied the impact of asa on amd development .
the researchers state that patients with drusen and cnv used asa more often , but the acid is not an independent risk factor of amd development .
the researchers found that the major risk factor of amd is the occurrence of macular diseases in family members.23 meta - analysis conducted by li et al24 shows that there is a slight but significant correlation between asa intake and the risk of amd development , especially in very advanced stages of amd .
another important research project was presented by aronow et al.25 the research investigated the association between asa use and the progression of amd .
age - related eye disease study 2 was a multicenter , randomized , controlled clinical trial .
participants aged 5085 years with no ga and neovascularization were divided into two groups :
asa users ( those patients who took asa five times a week ) andnon - asa users .
asa users ( those patients who took asa five times a week ) and progression of amd was defined as the development of either ga or neovascularization during the study period ( 20062012 ) .
the observations from this study suggest that the use of asa has no statistically significant association with amd progression .
scientists state that patients with amd can use asa , if taking it is necessary .
completely contrary reports were presented by kahawita and casson.26 the aim of this review was to evaluate the impact of asa on early stage of amd .
the review presented four studies involving 10,292 individuals and examining the correlation between asa and amd .
the conclusion arising from this review shows that there is a small but statistically significant association between asa use and amd progression .
asa inhibition of cox-1 and prostaglandin - endoperoxide synthase 2 causes the decrease in the synthesis of prostacyclin ( pgi2 ) , which shows vasodilation effects . as a result ,
retina hypoxia occurs , which is one of the causes of neovascularization and the development of wet amd .
eventually , a hypoxia - induced factor 1 occurs , which stimulates the formation of proangiogenic factors.27 it was also indicated that an influence of asa on endothelial progenitor cells ( epcs ) exists , which fulfils , primarily , angiogenic functions through the production of growth cytokines such as vegf and stromal cell - derived factor 1 and which takes part in the formation of endothelial cells .
it was proven that patients with increased cardiovascular risk and with risk factors of atherosclerosis have a smaller number of circulating progenitor cells , which is a cause of reduced immunity to thrombosis and inflammation in the vessels.28 the study conducted in 2010 examined patients who chronically took a 325 mg dose of asa in order to determine whether the asa influences circulating epcs . in patients who had not been previously treated with asa but then started to take the drug , the number of epcs decreased .
it is assumed that this phenomenon is caused by the inhibitory effect of asa on the cox - dependent pathway , especially cox-2 .
it turns out that pge-2 is indispensable for the production and the correct operation of progenitor cells .
the blocking of cox-2 leads to the blockage of angiogenesis and apoptosis of cells.29 additionally , asa reduces blood viscosity , thus decreasing critical speed in vessels . in some circumstances
studies indicate that laminar flow of fluids becomes the so - called turbulent flow after exceeding the critical speed , which depends on the type of fluid and the type ( diameter ) of vessel.30 during turbulent flow , fluid fractions do not move in a direction parallel to the vessel s conductor axis . instead
, they perform chaotic movements with different directions of velocity . such movements are accompanied by the formation of whirls.31 it was proven that asa has influence on the lipids reaction of lipid oxidation particularly , low - density lipoproteins ( ldls).19 in a study that was conducted on ten healthy , nonsmoking men , the influence of asa on ldl oxidation was evaluated .
it was determined that sensitivity to plasma ldl oxidation increased after asa consumption.32 it is believed that salicylates may support ldl oxidation caused by the myeloperoxidase enzyme ( the enzyme that participates in the initiation and formation of some cardiovascular diseases , for example , through an increase in ldl oxidation and acceleration of atherogenesis).33 moreover , salicylates , as monophenyl compounds , in some pro - oxidant cases may create phenoxy radicals , which cause oxidative damage . however , it turns out that radical effects are effectively slowed down through asa s metabolite
gentisic acid.34 it is possible that plasma concentration of gentisic acid , salicylate metabolite , which weakens ldl oxidation , was not high after the intake of a daily dose of 75 mg , which was applied in the aforementioned study .
they also have prothrombotic and proinflammatory effects.32 oxidized ldls are responsible for the development of atherosclerotic plaque and its destabilization .
endothelial damage makes it easier for inflammatory cells and ldls to move on , and they intensify platelet adhesion
. moreover , changed ldls activate macrophages , which produce more chemotactic substances , inflammatory substances , growth factors , and free radicals of prothrombotic tissue factor and proteolytic enzymes ( metalloproteinases ) .
the appearance of oxidized ldl , that is , abnormal ldl in the inner membrane is a signal for monocytes circulating in the blood ( or monocytes that occur in the walls of vessels macrophages ) to destroy the abnormal ldl through phagocytosis .
macrophages that are filled with cholesterol ( foam cells ) and are gathered under the endothelium constitute the early phase of atherosclerotic changes .
then , foam cell atrophy and its lipid content gather extracellularly , thus creating the lipid nucleus of atherosclerotic plaque.35 as a result of retina microenvironment damage , the progression of degenerative changes related to age occurs .
it was proven that meclofenamic acid and other nonsteroidal anti - inflammatory drugs , including asa , irreversibly block gap junctions between rpe cells.36 these junctions allow for direct communication with adjacent cells and enable inorganic ions and small hydrosoluble particles ( up to 1,000 da molecular weight ) to move from one cell cytoplasm to another .
this provides an electric and metabolic connection among cells.37 this kind of intercellular communication is indispensable for the proliferation , differentiation , and correct functioning of rpe .
scientists from the institutional review board of the university of chicago conducted research that involved 195 patients , and it was carried out over 73 months .
the research revealed that anticoagulant and antiplatelet treatments , including therapy with asa , are independent factors of intraocular hemorrhage development .
the destruction of retina photoreceptors occurs due to a clot retraction , the toxic effects of iron , and the blockage of nutritious diffusion . in the end
, a scar formation process occurs that causes permanent loss of vision.38 as the authors pointed out earlier , reports on the protective influence of asa on the development of amd also appear . in another research trial
, researchers also studied the association between antiplatelet and anticoagulant drugs as well as retinal or subretinal hemorrhages in patients with amd .
scientists stated that daily antiplatelet and anticoagulant therapy was not a statistical risk factor of occurrence of retinal hemorrhages , but this therapy was a risk factor in participants with hypertension.39 in the physicians health study published in 2001 , which was conducted in a group of 22,071 american male physicians aged between 40 years and 84 years , researchers asked themselves whether the doses of asa ( 325 mg ) and beta - carotene ( 50 mg ) , which are consumed every second day as part of cardiovascular diseases and tumor prophylaxis , influence amd development .
the research was a randomized double - blind trial with the control group receiving a placebo .
the statistics were enlarged with new cases of amd , confirmed by ophthalmological examination , which appeared during the study , with visual acuity worsening to the degree of $ 20/30 . throughout 60.2 months of observation ,
117 new cases of amd manifested themselves within the group , in which 51 patients took asa and 66 patients placebo .
it turned out that in the group of patients who were consuming asa , there were fewer cases of amd occurrence .
, however , is that the study exposed , statistically , extreme reduction ( 44% ) in the risk of myocardial infarct appearance , and therefore , the study was stopped earlier than was originally planned .
the conclusions from this research precluded the stimulating influence of asa consumption in small doses within 5 years on the risk of earlier development of amd.40 the results of other studies41,42 revealed that in people with amd , blood flow in choroidal vessels were reduced , which may suggest that primary vascular disease has some influence on amd pathogenesis . taking into account that cardiovascular diseases , as well as the presence of risk factors of their progression ( for instance , lipid disorders ) , increase the risk of amd development,4346 the prevention of these diseases , through both improving systemic circulation and decreasing the risk of vascular incidents , may benefit in preventing amd development .
along with age , it comes down to the damage of rpe cells , which leads to the influx of dendritic cells dc1 presenting the antigen .
this is one of drusen s components.47 in drusen s components , plasma proteins and proteins connected with the activity of the complement system are also found .
drusen s composition also includes substances that cause activation of local complement system.48 it suggests that amd progression is influenced by local inflammation in the subretinal space.49 this local inflammation , which begins subretinally , turns into chronic cytomegalovirus retinitis with the activation of the complement system and the migration of macrophages , t - lymphocytes , and mast cells into the retina.16 as a consequence , chronic cytomegalovirus retinitis leads to the death of the rpe and their dependent photoreceptors , thus leading to the development of ga . therefore , the anti - inflammatory effects of asa may be favorable for the inhibition of amd progression , especially in its early form , and for preventing the progression of advanced dry amd .
asa , through paths independent of platelets inhibition , may have positive effects in preventing amd progression .
it was proven that asa initiates the production of 15-epi - lipoxin 4a in the endothelial vessel cells , which has local inflammatory effects.50 asa may protect endothelial cells through antioxidizing activity,51 and it prevents peroxidation of lipids.52 the fundamental function of asa is an easy chemical reaction
products of this reaction show that asa has twofold effect :
provides acetylic group andprovides salicylate.53 provides acetylic group and provides salicylate.53 asa influence on human organisms is an example of nonenzymatic protein modification .
the function of asa in our body is pleiotropic , but the pharmacological area of this function is addicted to possibility of getting through to the protein in certain places.53 we can not ignore significant asa influence on human short - lived cells , eg , on endothelial cells that includes the endothelial cells located in the human eye .
asa directly increases production of nitric oxide ( no ) by endothelium causing 15-epi - lipoxin a4 creation ( a mediator responsible for nos activation).50,54 no has the following influences on the cells :
cytoprotective due to its activation of guanylate cyclase51 andanti - inflammatory due to its inhibition of leukocytes and interaction of endothelial cells.55 cytoprotective due to its activation of guanylate cyclase51 and anti - inflammatory due to its inhibition of leukocytes and interaction of endothelial cells.55 these mechanisms prevent hypoxia and pathological angiogenesis .
it is proved that asa may decrease endothelial proliferation through the influence on dna synthesis , which is addicted to p53 protein expression .
there is a strong correlation between these mechanisms and a lower secretion of vegf , and due to this , the creation of new vessels is reduced .
scientists are trying to find a new derivative of asa that will be more specific and thereby will cause reduction in side effects.54
in light of often contradictory reports on the influence of asa on the development of early and late forms of amd , it is difficult to give an unambiguous answer on whether patients with amd should use this drug . taking into account these reports and the fact that among people endangered with amd progression or diagnosed with amd there is a large group of patients who consume asa
, we all should ask ourselves the following questions :
is amd progression directly connected to the consumption of asa?may asa delay amd progression through its anti - inflammatory and antioxidant effects or quite the opposite?how does asa influence the development of early and late stages of amd?at what stage of amd progression do the aspects of asa use , which are unfavorable for maintaining visual acuity , begin to outweigh the undoubted systemic benefits derived from its usage ? is amd progression directly connected to the consumption of asa ?
may asa delay amd progression through its anti - inflammatory and antioxidant effects or quite the opposite ?
how does asa influence the development of early and late stages of amd ? at what stage of amd progression do the aspects of asa use , which are unfavorable for maintaining visual acuity , begin to outweigh the undoubted systemic benefits derived from its usage ?
if we want to answer the question does the use of asa have any influence on our vision ? , we have to take into account all the research presented in this review .
we can not ignore the fact that it is difficult to determine unequivocally what is the exact impact of asa on the human eye .
three of many studies ( bmes , europe an eye study , beaver dam eye study ) show that asa increases the risk of amd development , particularly its wet phenotype.1,19,20 furthermore , this research demonstrated that the dose of asa , the frequency of administration , and the period of intake have a very important influence on amd development .
the higher and the more frequent the dose and the longer period of dosage , the higher the risk.19,20 scientists have proved stronger correlation of asa with cnv than with the dry form.20 however , in this review , we can notice some evidence that denies the destructive influence of asa on macula lutea , what is more , a favorable influence on it , for example by blocking cox2
it stops angiogenesis.29 asa decreases ldl oxidation and prevents blinding disease.35 a significant study proves that those who take asa with statins are less exposed to the risk of amd.22 asa , due to its anti - inflammatory specificity , decreases the possibility of disease occurrence if we take into account inflammatory pathogenesis of amd.10,11 regarding all the research , including risk for amd and benefits of reducing risk for cardiovascular events , we can be sure that asa is really beneficial . it may increase the risk of amd insignificantly , but it can really reduce the risk of life - threatening conditions .
one thing is clear , if we do take asa frequently for its other health benefits , it is very important to have our vision checked regularly .
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### Summary:
: purposeacetylsalicylic acid ( asa ) is one of the most commonly used drugs in the world due to its anti - inflammatory , analgesic , and antipyretic properties .
this review aims to describe the relationship between acetylsalicylic acid and age - related macular degeneration ( amd ) a chronic disease that causes deterioration of visual acuity and is one of the most common ophthalmological diseases these days.methodsdata presented in this review were collected from both research and review articles concerning ophthalmology and pharmacology.resultsthe results of the studies analyzed in this review are not unambiguous .
moreover , the studies are not homogenous .
they differed from one another in terms of the number of patients , the age criteria , the asa dose , and the duration of control period .
the reviewed studies revealed that asa therapy , which is applied as a protection in cardiovascular diseases in patients with early forms of amd and geographic atrophy , should not be discontinued.conclusionon the basis of the present studies , it can not be unequivocally said whether asa influences people s vision and if people endangered with amd progression or who are diagnosed with amd should use this drug .
it may increase the risk of amd , but it can also reduce the risk of life - threatening conditions .
the authors suggest that in order to avoid possible risks of amd development , people who frequently take asa should have their vision checked regularly .
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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 population genetics and conservation the big question is genetic drift instead of natural selection .
definitely both processes determine evolution , but genetic drift operates randomly and depends on effective population size while natural selection proceeds nonrandomly and relies on environmental variables . the evolution towards hereditary adaptations to the current environment
is determined by natural selection and has a direction ; genetic drift instead is governed solely by chance .
consequently , drift acts on alleles , which generally have no phenotypic effect ; instead selection favours certain alleles that increase fitness , reduce the unfavourable alleles frequencies , and ignore neutral alleles .
knowing what the main microevolutionary force is is very relevant for rational genetic management of threatened species , especially for species with geographical distribution severely fragmented .
approaches to addressing adaptive variation have been incorporated into the definition of evolutionary significant units [ 3 , 4 ] .
new technologies like next generation sequencing ( ngs ) and fine - scale gis , coupled with advances in computer hardware and software in the field of genomics [ 57 ] , have allowed the development of new methods for comprehensive evaluation of adaptive diversity [ 8 , 9 ] .
the discovery and genotyping of massive genetic markers are now enabled by modern genomic tools at very low cost .
this makes the study of adaptive genetic loci possible on a wide range of species , which can facilitate the identification of key biodiversity areas .
kirk and freeland reviewed some of the applications of neutral versus adaptive markers in molecular ecology , discussed some of the advantages that can be obtained by supplementing studies of molecular ecology with data from nonneutral molecular markers , and summarized new methods that allow generating data from loci under selection .
population genomic analyses require multilocus datasets from multiple populations and identification of nonneutral or adaptive loci by contrasting patterns of population divergence among genetic regions .
studies in nonmodel organisms have shown relatively broad candidate genomic regions that are under selection , but it remains difficult to identify the genes ( or the mutations ) that are affected by selection .
increasing the density of markers in genome scans is paramount to overcome this problem , and validating signals of selection from particular genes using multiple methods should also help .
one of the most exciting developments in population genomics is the development of various reduced - representation protocols , collectively referred to as genotyping - by - sequencing ( gbs ) , which allow sequencing of a subset of the genome through selective amplification of restriction fragments .
( nothofagaceae ) is an endemic tree species occurring both in chile and in argentina temperate forests with a remarkably broad altitudinal and latitudinal distribution , across many different ecological gradients in the former .
the evergreen tree n. dombeyi is a pioneer species and constitutes an important element in the dynamics of south american forest .
its postglacial history has been studied with chloroplast dna and evolutionary forces shaping genetic variation patterns have been analysed with isozymes [ 12 , 13 ] .
however , genome - wide scan methods using thousands of markers to study a representative portion of the genome are needed . in this work ,
we assess gbs in the nonmodel woody species n. dombeyi to develop high quantity of informative markers such as single nucleotide polymorphisms ( snp ) .
our aim is to determine the contribution of selection and molecular adaptation to shaping genome - wide variation .
we expect higher genetic population differentiation ( for ecological separated localities ) for adaptive snp than neutral snp if natural selection is the principal source of differentiation . alternatively
, if other sources of differentiation ( mutation , genetic drift , and migration ) are relevant , they will equally affect both types of snp .
knowing the contribution of selection effect to shaping genome variation patterns will have many applications for biodiversity conservation , especially in endangered species , because neutral and adaptive genetic diversity will likely have different impacts on long - term survival .
in fact , in most cases , only adaptive diversity will allow a population to adapt to changing environmental conditions .
to consider the remarkably broad altitudinal and latitudinal distribution of this species , across many different ecological gradients , we used the method proposed by alarcn and cavieres to niche modelling of nothofagus dombeyi in chile using biomod .
eight variables were selected from the worldclim global climate database corresponding to the present climate conditions with a 30-arc - second grid resolution , with the least correlation among them for the studied species range area .
four variables were related to energy constraints : ( a ) bio2 : mean diurnal temperature range ; ( b ) bio4 : temperature seasonality ; ( c ) bio5 : maximum temperature in the warmest month ; and ( d ) bio6 : minimum temperature in the coldest month .
other four variables were related to water availability : ( e ) bio12 : annual precipitation ; ( f ) bio15 : precipitation seasonality ; ( g ) bio18 : precipitation in the warmest quarter ; and ( h ) bio19 : precipitation in the coldest quarter .
then , we projected the current and future distribution ( year 2050 ) considering a conservative future climate projection csiro b2a 2050 by using the tools of biomod software .
further , we identified geographical areas with potential habitat loss , which should be identified as high priority in genetic conservation programs .
relatively homogeneous units in ecological terms ( strata ) were defined from natural populations of the species associated with the geographical areas projected in its ecological niche modelling .
the calinski - harabasz criterion , which is a pseudo - f statistic as in anova , was used to assess the best number of strata identified by k - means partitioning .
adult trees with a diameter higher than 50 cm were sampled during the growing season of 2013 - 2014 from twenty - one sites covering almost the entire range of the species n. dombeyi in chile .
one to four sites were assigned to each stratum according to its superficies and 2 to 9 samples per site were taken ( table 1 ; supplementary figure 1 in supplementary material available online at http://dx.doi.org/10.1155/2016/3654093 ) .
lyophilized leaf tissue ( 20 mg ) was ground in a precellys24 ( precellys , usa ) homogenizer with two 1/4 ceramic spheres ( mp biomedicals , usa ) and ap1 buffer .
dna extraction protocol was done following the manufacturer instructions but elution was done with 30 l ( instead of 100 l ) to increase the final dna concentration in the eluate ( > 100 ng/l ) .
the integrity of genomic dna was evaluated by agarose gel and quantified using a qubit fluorometer ( invitrogen , usa ) .
library preparation and high - throughput sequencing were performed at university of wisconsin biotechnology center ( dna sequencing facility ) .
the gbs genomic library preparation was done following the protocol detailed by elshire et al . with the methylation - sensitive restriction enzyme apeki and 96 custom barcodes .
illumina high - throughput sequencing was conducted on an illumina hiseq 2000 ( illumina , usa ) using 100 bp single - end sequencing runs .
sequence results were analysed and snp genotypes were assigned using the uneak ( universal network enabled analysis kit ) gbs pipeline , which is part of the tassel 3.0 bioinformatic analysis package .
this pipeline does not depend on a reference sequence , which is the actual case for n. dombeyi .
snp discovery is performed directly within pairs of matched sequence tags ( unique sequence representing a group of reads ) and filtered through network analysis .
the network filter trimmed reads to 64 bp to reduce the effects of error sequencing and enabled efficient storage of data in bit format .
briefly , tags differing by a single nucleotide were retained as snp and those with a minor allele frequency 0.05 were removed to minimize the impact of sequencing errors .
we used a minimum call rate of 0 and additional filters were applied in next steps .
given that we are trying to find snp for population genetic analysis , we applied some filters to remove loci and individuals that contain very low levels of information prior to further analysis .
we applied two functions of tassel 5.2 that removed all snp ( rows ) and then samples ( columns ) containing 90% or more
these ns represent individuals where the allele can not be called from the sequence reads .
this is because either no read is available at this site ( for this individual ) or the sequence quality is too low to be called . in order to cope with missing data ,
genotype imputation was used to fill in the missing data and improve the power of downstream analyses .
we used linkimpute implemented in tassel 5.2 , a software package based on a k - nearest neighbour genotype imputation method , ld - knni .
this imputation method was designed specifically for nonmodel organisms in which genomic resources are poorly developed and marker order is unreliable or unknown . to identify adaptive snp ( putative loci under selection ) , we used lositan
we used 50,000 simulations , 0.99 for confidence interval , false discovery rate of 0.05 , mutation model infinite alleles , and the options
neutral mean fst and force mean fst , which iteratively identify and remove fst outliers when calculating the global distribution of fst .
our interest is in patterns of adaptation driven by environmental gradients ; therefore we focused on outlier patterns indicating divergent selection ( fst significantly higher than neutral expectations ) .
lositan analyses were complemented with bayescan 2.1 for estimating the posterior probability that a given locus is affected by selection .
briefly , prior odds of 100 were used for identifying the top candidates of the selected loci and a total of 50,000 reversible - jump markov chain monte carlo chains were run with a thinning interval of 10 , following 20 pilot runs of 5,000 iterations each , and a burn - in length of 50,000 .
loci were considered outliers with an fdr of 0.05 . to confirm the adaptive snp detected by previous methods , the spatial analysis method ( sam ) implemented in the program samada
samada uses logistic regressions to model the probability of presence of an allelic variant in a polymorphic marker given the environmental conditions of the sampling locations .
eight environmental variables previously described in section 2.1.1 were used ( temperature related bio2 , bio4 , bio5 , and bio6 ; precipitation related bio12 , bio15 , bio18 , and bio19 ) . regarding genotypes ,
each of the states of a given snp is considered independently as binary presence / absence in each sample .
our biallelic snp were recoded as three distinct genotypes ( aa , ab , and bb ) . a maximum likelihood approach is used to fit the models using univariate analyses .
each model for a given genotype is compared to a constant model , where the probability of presence of the genotype is the same at each location .
significance was assessed with log likelihood ratio ( g ) tests selecting loci / allele that tested higher than the 99th percentile of the g score distribution .
we made all estimations in parallel with neutral snp ( 10,109 ) and adaptive snp .
all the results were obtained using the adegenet [ 26 , 27 ] and hierfstat r packages .
basic statistics were estimated including observed heterozygosity ( ho ) and genetic diversity ( hs ) within population . also , overall gene diversity ( ht ) and corrected ht ( htp ) , gene diversity among samples ( dst ) , and corrected dst ( dstp ) were estimated .
fst and corrected fst ( fstp ) were assessed as well as fis following nei per overall loci .
dest , a measure of population differentiation as defined by jost , was also calculated .
the degree of genetic differentiation among populations is expected to be low for neutral snp but highly divergent in snp subject to directional selection . to describe the genetic biodiversity of a species , more important than diversity among individuals is the diversity between groups of individuals .
first we analysed individual data to identify populations , or more large genetic clusters , and then we described these clusters by adegenet r package . to get a simplified picture of the genetic diversity observed among individuals or populations we used principal component analysis ( pca ) .
discriminant analysis of principal components ( dapc ) function was used to describe the relationships between these clusters .
for each pair of strata , we computed pairwise fst values with hierfstat r package .
principal coordinates analysis ( pcoa ) on fst values was performed to detect major genetic clusters ( k ) at individual level . in dapc ,
loadings of these variables are generally uninformative , since pcs themselves do not all have straightforward interpretations .
however , we can also compute contributions of the alleles , which can turn out to be very informative . in general
, there are many alleles and their contribution is best plotted for a single discriminant function at a time using adegenet r package .
modelled area of n. dombeyi presence under present climate conditions is 88,174 km and in the future ( year 2050 ) under dispersal constraints is 72,928 km . although it is not qualified with a status of threatened species , we estimated a decrease of almost 20% of its habitat area in a relatively short time , particularly in the northern populations , associated with mediterranean - influenced climate , which is at least worrisome considering we used the most conservative future climate scenario .
the k - means analyses , applied to four best least correlated variables of worldclim ( bio2 , bio4 , bio12 , and bio15 ) , identified seven strata groups of n. dombeyi in chile at very broad spatial scales ( figure 1 ) .
the strata named septentrional ( # 1 ) , alto biobo ( # 2 ) , los lagos andes ( # 7 ) , and patagonia ( # 3 ) form the latitudinal gradient across andes mountain range including higher altitudes , while the strata nahuelbuta ( # 4 ) , araucana y los ros ( # 5 ) , and los lagos costa ( # 6 ) present some oceanic influence at a gradient located in coastal mountain range and central valley of the central distribution of n. dombeyi at lower elevation .
the strata were coherently identified as the bioclimatic transition from temperate biome with some mediterranean influence , especially in the northern portion of the septentrional stratum and then the typical temperate bioclimatic classification across the rest of the distribution of the species .
we obtained more than 17 gb out of 172,171,356 reads , from which 85.82% keep a score q 30 . from the 96 barcoded samples in our study , an average of 1.5 million ( sd 1.7 million ) sequence reads per sample
were obtained ( range from 278 to 8.2 millions ) ( see supplementary figure 2 ) .
after removal of snp with a minor allele frequency 0.05 and removing samples and snp with more than 90% nn
( unassigned ) genotypes , the dataset consisted of 73 individuals with 10,109 binary snp from seven strata .
this dataset was subjected to the impute step and finally total numbers of nn genotypes were 19,067 ( 0.03% ) missing data . using the lositan approach , 124 adaptive snp ( 1.2% ) were identified ( directionally selected ) at the false discovery rate ( fdr ) threshold of 0.1 ( table 2 ; supplementary table 1 ) .
we detected 99 adaptive snp in bayescan and there were 48 overlap cases between the loci reported by each method ( see supplementary table 1 ) .
the adaptive snp detected by both approaches were limited ( 39% ) , possibly reflecting discrepancies in their methodologies . however , all the 124 snp identified by lositan had fst values 0.30 ( estimated across the 73 n. dombeyi individuals and 10,109 loci ) , which may be considered as strongly differentiated . using samada we detected 2,406 significant genotypes associated with a given environmental variable .
they represent 884 snp ( 8.7% of total snp assessed ) and only 3% correspond to heterozygous genotypes . from the 124 outlier snp identified by lositan ,
genotypes in 121 snp were identified as associated with environmental variables by samada ( see supplementary table 1 ) . genetic differentiation associated with both temperature and precipitation gradients was detected .
using neutral plus outlier snp ( 10,109 ) , different basic statistics of genetic variation of n. dombeyi in chile show low to medium genetic diversity level and low level of strata differentiation ( figure 2 ) .
the low genetic structure found indicates relatively high gene flow , which is consistent with the fact that n. dombeyi has a distribution more or less continuous and is wind pollinated .
this result is similar to other results obtained with the same and other species of nothofagus gender [ 33 , 34 ] . with outlier snp ,
overall average pairwise fst values among populations , calculated over the set of the 10,109 snp , show medium population structuring across the distribution of n. dombeyi in chile ( table 3 ) .
the average pairwise fst values ranged from 0.062 between two very close strata ( 4 and 5 ) in the coastal mountains to 0.258 between strata 1 and 3 , both in andean mountains but in the extremes of distribution ( table 1 ) .
the principal coordinates analysis ( pcoa ) plot revealed a geographically ordered pattern ( see supplementary figure 3 ) .
the first pc suggests the existence of two clades in the data , while the second one shows groups of closely related isolates arranged along a cline of genetic differentiation .
premoli found continuous clinal genetic variation in populations of n. pumilio along the altitudinal gradient , as a result of adaptive responses to ecological gradients and/or restrictions for gene flow .
the same pattern is shown by neutral snp and adaptive snp but with a more clear delimitation in the latter case .
this structure was confirmed by a neighbour - joining ( nj ) tree ( supplementary figure 4 ) .
as expected , both approaches give congruent results , but both are complementary ; nj shows bunches of related individuals , but the cline of genetic differentiation is much clearer in pca .
visualisation of broad - scale population structure using a dapc ( figure 3 and table 4 ) with 124 outlier snp revealed two distinct genetic groups .
one group included individuals sampled in all strata corresponding to clusters 1 , 2 , 3 , and 5 ( table 4 ) , and the other group comprised only ten individuals of stratum 3 plus one individual of stratum 2 forming cluster 4 ( represented almost exclusively by individuals of patagonia stratum ) .
also the actual proximities between clusters show the great genetic distance of cluster 4 with the rest .
this result is consistent with a north south phylogenetic divergence at c. 43s found within subgenus nothofagus in southern south america , including n. dombeyi [ 12 , 36 ] .
clearly , when examining patterns of n. dombeyi population differentiation at neutral versus adaptive snp , we have detected several distinct differences .
primarily stochastic processes drive differentiation of neutral snp , whereas both selective and stochastic processes drive that of adaptive snp , for example , [ 3739 ] .
this result supports the hypothesis that putative under selection snp are being affected by adaptation , which is not affecting the neutral snp .
the next step is to characterize the phenotypic outcomes of alternative genotypes to confirm if the mechanism is genetic drift or selection , similar to previous studies in nothofagus pumilio [ 40 , 41 ] .
ideally , phenotype - genotype association studies should be followed by the profiling of gene expression , functional tests , and selection tests to determine that a gene or genes are involved in shaping an adaptive trait . over 24% of the adaptive snp detected by lositan had a high loading ( here defined as 0.02 ) in one or two of the three pc in a pca with more than 10 k loci of the chilean population of n. dombeyi ( supplementary figures 5 , 6 , and 7 ) , thus confirming its contribution to population structure .
adaptive snp i d 4 , 14 , 42 , 50 , and 91 are five of the most discriminating loci and their allele frequencies over seven strata show a high or even dominant allele frequency in stratum 3 ( figure 4 ) .
this is the southernmost stratum ( # 3 patagonia ) and this may justify the differences in allele frequencies .
irrespective of the mechanism underlying these changes ( drift or selection ) , this illustrates that , in the natural distribution of n. dombeyi in chile , specific nucleotides can undergo drastic changes within only a hundred kilometres of distance .
our results exhibited spatial patterns differentiating one stratum in loci which could occur in genomic regions or genes for important functions of n. dombeyi across their habitat .
for example , the gbs sequence tags of adaptive snp i d 43 ( tp30852 ) show a high identity with a heat shock protein or adaptive snp i d 44 ( tp32296 ) with histone acetyltransferase enzyme ( data not shown ) .
the first is fundamental for heat or other environmental stresses and the second can be involved in drought sensing or another response to environmental factors .
we therefore suggest that these two snp may be interesting candidates for future functional studies that might facilitate other studies , for example , focused on the development of genomic resources for nothofagus species .
however , improvements in study design and analyses of replicated studies will be needed before this very promising approach can be brought to application for managing genetic resources .
development of 10,109 genome - wide snp for n. dombeyi using gbs made evaluation of genomic diversity and fine - scale population structure possible for the first time in this species in chile .
results showed that genome - wide patterns of genetic diversity and differentiation varied widely across the genome .
we have also provided strong evidence of substantial genetic differentiation associated with both temperature and precipitation gradients , suggesting local adaptation .
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### Summary:
: within a woody plant species , environmental heterogeneity has the potential to influence the distribution of genetic variation among populations through several evolutionary processes . in some species ,
a relationship between environmental characteristics and the distribution of genotypes can be detected , showing the importance of natural selection as the main source of differentiation .
nothofagus dombeyi ( mirb . ) oerst .
( nothofagaceae ) is an endemic tree species occurring both in chile and in argentina temperate forests .
postglacial history has been studied with chloroplast dna and evolutionary forces shaping genetic variation patterns have been analysed with isozymes but fine - scale genetic diversity studies are needed .
the study of demographic and selection histories in nothofagus dombeyi requires more informative markers such as single nucleotide polymorphisms ( snp ) . genotyping - by -
sequencing tools now allow studying thousands of snp markers at reasonable prices in nonmodel species .
we investigated more than 10 k snp loci for signatures of local adaptation and showed that interrogation of genomic resources can identify shifts in genetic diversity and putative adaptive signals in this nonmodel woody species .
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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 their desirable shape memory properties , nickel - titanium ( niti ) wires are increasingly used during the first stage of a comprehensive treatment in orthodontics that is , mainly for the alignment of teeth by correcting crowding and rotations .
these favorable characteristics include high spring back , flexibility , and ability to apply light and constant forces , as well as superelasticity , which are based on a martensitic phase transformation allowing the niti alloys to return to a previously defined shape when strained up to 8% .
suboptimal oral health and biofilm formation are common issues in orthodontic treatment which can cause demineralization and caries and for solving such problems , orthodontists may prescribe fluoride producs for their patients . in the acidic products , such as prophylactic agents
, the titanium protective film reacts with hydrofluoric acid to form sodium titanium fluoride and the breakdown of the film reduces corrosion resistance because titanium indicates an intrinsically high activity .
kaneko et al . , showed degradation in performance of four major orthodontic alloys ( niti , -titanium , stainless steel , cobalt chromium ) caused by hydrogen absorption during short - term immersion ( 1 h ) in 2.0% acidulated phosphate fluoride . walker et al . also found that mechanical properties and surface characterization of orthodontic archwire decreased during short - term immersion ( 1.5 h ) in topical fluoride treatment with either an acidulated fluoride agent or a neutral fluoride agent compared with distilled water ( as a control group ) .
investigated mechanical properties of -titanium orthodontic wires in the presence of four sodium fluoride solutions ( 0.05% ph = 6 , 0.05% ph = 4 , 0.2% ph = 6 ,
he found that the tensile strength of the immersed wires was significantly reduced compared to as received one , and ion released had much increased for higher sodium fluoride ( naf ) concentration and lower ph .
walker et al . immersed stainless steel and -titanium orthodontic archwires in either an acidulated fluoride agent , a neutral fluoride agent or distilled water ( control ) for 1.5 h and found that unloading mechanical properties
kaneko et al . examined hydrogen embrittlement of -titanium orthodontic wires in acidic and neutral aqueous solutions and concluded that the immersion in fluoride solutions led to the degradation of the mechanical properties and fracture of beta titanium alloy associated with hydrogen absorption .
similarly , they stated that when immersion in acidic fluoride solutions was carried out , ni - ti superelastic alloy underwent general corrosion and absorbed substantial amounts of hydrogen . in another investigation , after the tensile test ( after immersion ) and hydrogen thermal desorption analysis of of ni - ti superelastic alloy , they hypothesized that one reason that ti and its alloys fractured in the oral cavity is because hydrogen was absorbed in a fluoride solution , such as prophylactic agents .
evaluated the effects of fluoride - containing solutions on the commercially pure titanium ( cpti ) using three solutions as follows : distilled water , 0.05% naf , 0.2% naf during different times and concluded that fluoride containing solutions ( ph = 7 ) used as mouthwashes did not damage the surface of cpti and could be used in patients with titanium - based restorations .
determined the in vivo effect of fluoride agents on the mechanical properties of niti and copper niti archwires .
the second group used fluoride mouthrinse and the third group used fluoride gel . then arch wires were examined and it was concluded that unloading properties of orthodontic wires fell significantly in gel group . apparently , topical fluoride agents altered the mechanical properties of niti wire and
hence could prolong orthodontic treatment . the widespread use of niti wires in orthodontics and the importance of mechanical properties of orthodontic wires in the treatment efficiency as well as the probable effect of fluoride mouthwashes resulting from the presence of hydrogen and fluoride ions on the orthodontic wires , demand further research on the possible interaction between fluoride use and niti archwire properties .
the aim of this in vitro study was to assess the effect of daily fluoride mouthwashes on the mechanical characteristics of orthodontic niti orthodontic archwires .
for the present in vitro study , 36 niti wires ( 3 cm length ) with the dimensions of 0.016 0.022 inches ( sent 1622 ,
the samples were divided into three groups of 12 each as follows :
g1 , the ph = 4 group , samples were immersed in the normal saline solution for 30 days , and were immersed in the 0.05% fluoride solution ( ph = 4 ) twice a day for 90 s ; subsequently , they were returned into normal saline.g2 , the ph = 6.6 group , samples were immersed in the normal saline solution for 30 days , but were immersed in the 0.05% commercial fluoride mouthwash ( advantage mouth rinse , oral b , south boston , uk ) with the ph = 6.6 twice a day for 90 s ; subsequently they were returned they were returned into normal saline solution.g3 , the normal saline group ; samples were only immersed in normal saline solution ( ph = 7 ) for 30 days .
g1 , the ph = 4 group , samples were immersed in the normal saline solution for 30 days , and were immersed in the 0.05% fluoride solution ( ph = 4 ) twice a day for 90 s ; subsequently , they were returned into normal saline .
g2 , the ph = 6.6 group , samples were immersed in the normal saline solution for 30 days , but were immersed in the 0.05% commercial fluoride mouthwash ( advantage mouth rinse , oral b , south boston , uk ) with the ph = 6.6 twice a day for 90 s ; subsequently they were returned they were returned into normal saline solution .
g3 , the normal saline group ; samples were only immersed in normal saline solution ( ph = 7 ) for 30 days .
after 30 days , the wires were removed from the solutions and universal testometric machine ( testometric co , rochdale , uk ) measured the load - deflection characteristics of the samples in the 37c water bath using a setup made for this purpose . in order to produce the load - deflection curves , three copper cylinders with a length of 3 cm and a rectangular cube bar with dimensions of 10 cm 12 cm
1 cm with completely smooth surfaces were prepared , two copper cylinders with the central distance of 14 mm were screwed , and the third cylinder was connected to the crosshead of the instrument . on each of the three cylinders , a stainless steel maxillary canine bracket was placed ( equilibrium 2 , dentarum , inspringen , germany ) with the slot size of 0.018 inches , and fixed with the cianoacrylate glue . the wire was subsequently placed passively in the slot of the brackets so that the wire maintained the straight form ; subsequently wires were placed in the bracket slots and tied by elastomeric ligatures ( safe - t - tie silver , ortho organizer , carisbad , ca , usa ) and the three bracket bending test was performed on each sample . the instrument began to move with a speed of 0.5 mm / min with the range of 2.4 mm ; the loading and unloading forces were registered , and the load - deflection curves plotted .
loading forces at 2.4 - 0.2 mm deflection ( l2.4 to l0.2 ) and unloading forces at 2.2 - 0.2 mm deflection with 0.2 mm deflection intervals ( l2.2 to l0.2 ) were recorded .
further , the unloading ( between ul0.6 and ul1.6 ) and loading plateau means ( between l 0.6 and l 1.6 ) and the difference between them ( hysteresis ) was estimated for each sample .
data were analyzed using spss 15 for windows ( spss inc , chicago , iii ) .
the repeated measurement of anova and tukey 's post - hoc tests were used for statistical analysis .
after 30 days , the wires were removed from the solutions and universal testometric machine ( testometric co , rochdale , uk ) measured the load - deflection characteristics of the samples in the 37c water bath using a setup made for this purpose . in order to produce the load - deflection curves , three copper cylinders with a length of 3 cm and a rectangular cube bar with dimensions of 10 cm 12 cm
1 cm with completely smooth surfaces were prepared , two copper cylinders with the central distance of 14 mm were screwed , and the third cylinder was connected to the crosshead of the instrument . on each of the three cylinders , a stainless steel maxillary canine bracket was placed ( equilibrium 2 , dentarum , inspringen , germany ) with the slot size of 0.018 inches , and fixed with the cianoacrylate glue . the wire was subsequently placed passively in the slot of the brackets so that the wire maintained the straight form ; subsequently wires were placed in the bracket slots and tied by elastomeric ligatures ( safe - t - tie silver , ortho organizer , carisbad , ca , usa ) and the three bracket bending test was performed on each sample .
the instrument began to move with a speed of 0.5 mm / min with the range of 2.4 mm ; the loading and unloading forces were registered , and the load - deflection curves plotted .
loading forces at 2.4 - 0.2 mm deflection ( l2.4 to l0.2 ) and unloading forces at 2.2 - 0.2 mm deflection with 0.2 mm deflection intervals ( l2.2 to l0.2 ) were recorded .
further , the unloading ( between ul0.6 and ul1.6 ) and loading plateau means ( between l 0.6 and l 1.6 ) and the difference between them ( hysteresis ) was estimated for each sample .
data were analyzed using spss 15 for windows ( spss inc , chicago , iii ) .
the repeated measurement of anova and tukey 's post - hoc tests were used for statistical analysis .
the measured force values ( mean and standard deviation ) for loading and unloading of all groups are shown in table 1 .
the loading and unloading plateau means and the hysteresis relevant to three groups are shown in table 2 and figure 1 .
mean ( sd ) of measured force values during the loading / unloading in three groups mean ( sd ) of force values related to loading plateau , unloading plateau , and hys of three groups load - deflection diagram related to three groups during the loading phase , there was a significant difference between the deflections ( p < 0.001 ) .
there was also no interaction effect ( p = 0.191 ) ; the changes occurred in three groups at various deflections were similar .
overall , there was no significant difference among three groups ( p = 0.268 ) . in the unloading phase ,
firstly , there was a significant difference between the deflections ( p < 0.001 ) .
secondly , there was an interaction effect ( p = 0.008 ) , that is , the changes occurred in three groups at various deflections were not similar .
it became clear that this difference was related to the unloading phase between the g1 and g3 groups ( p = 0.037 ) and at ul0.2 , ul0.4 , ul1.4 , ul1.6 , ul1.8 , ul2 , ul2.2 ( p < 0.05 ) .
there was not any significant differences between the mean values of unloading plateau ( p = 0.324 ) , loading plateau ( p = 0.464 ) and hysteresis ( p = 0.566 ) for three groups .
the present in - vitro study demonstrated that the fluoride and hydrogen ions could affect the load - deflection characteristics of niti wires , particularly , the hydrogen embrittlement effect , which has been discussed previously . despite the presence of a protective film , metal ions such as titanium and nickel
could leak out of the alloy and presenting with relatively lower corrosion resistance and higher amount of ion release , which can be cytotoxic .
although the released titanium is not cytotoxic , the lower ph can result in higher release of nickel ions .
it is possible to examine surface roughness and topographic characteristics of the wires with scanning electronic microscope reported by other researches and these studies had shown that the immersed wires as compared with the control group also showed a difference in this regard .
overall , a protective layer is formed on niti and the titanium surface when these contact with the aqueous environment .
for the titanium surface the protective film is constituted by titanium oxide ( tio2 ) , but on niti the passive film has also smaller amounts of nickel oxide or metallic ni , making it more susceptible to chemical attack .
further , issues associated with poor corrosion resistance can affect the treatment effectiveness as well as toxic and allergic reactions due to nickel release , creating biocompatibility issues for of niti alloys .
the present study , however , did not assess the corrosive characteristics of the niti wires .
change in mechanical characteristics of wires immersed in the acidic electrolytes could be related to different factors such as the concentration of fluoride ions present in the solution , the ph of the solution , the manufacturing characteristics of the wires , and the duration of immersion , that had been referred to in the previous studies . in this study , three bracket bending test was used , which is the alternative to the three point bending test , and the most precise design for examining mechanical properties of orthodontic wires .
as brackets were used in this procedure , a relatively comprehensive simulation was obtained in terms of the inter bracket distance , wire length , bracket type , and the friction between the wire and bracket .
the central distance between two brackets , which were installed on the fixed cylinders , was selected to be 14 mm , that is , the inter - bracket distance was 7 mm , which was more consistent with the bracket distance in the patient 's mouth .
the speed of the middle cylinder connected to the crosshead of the machine was 0.5 mm / min with a range of 2.4 mm , which lies within the scope of previous studies . in this study , incubation and three bracket bending test was performed in the humid environment at 37c , which simulated the mouth condition .
there were controversies in various studies regarding the effects of the acidity rate on the performance and characteristics of orthodontic alloys .
reported that through increasing the acidity ( reducing ) ph , elements released from the alloy had been increased . while according to harris et al .
, the acidity of the environment did not have any effect on the properties of the alloy .
the niti wires were used due to their increasing use in clinical practice and their desirable properties .
in addition , regarding the crucial importance of the mechanical characteristics of the wires in efficiency and duration of orthodontic treatment , it was decided to use this kind of wire in the present study .
the reason for using 0.05% fluoride was that this concentration is present in the commercial fluoride mouthwashes , which are used daily as part of home health care .
moreover , using various ph values allowed us to examine the effect of acidity on the properties of niti wires . in most studies on the mechanical characteristics , yield strength and modulus of elasticity and tensile strength
report in that the mechanical characteristics of niti wires during unloading was dropped using professional fluoride gel , but did not change with mouthwash .
walker et al . found that the acidity caused the unloading of the mechanical characteristics of niti alloy to be reduced .
this finding verified our research but regarding the effect of fluoride ions on the niti alloys , they reported a reduction in mechanical characteristics while we did not observe such an effect statistically .
moreover , one probable reason can be that they have used high fluoride concentration of 1.1% in their research .
findings suggested that fluoride ion in the concentrations of 0.05% daily did not damage the surface of the titanium alloys .
findings of kao and huang indicated that niti alloy corroded in the artificial saliva with ph = 4 more than naf solution , this may explain the results of present study concerning the effect of acidity .
stated that acidic fluoride solutions adversely affected the properties of superelastic alloys that show some similarity with our findings .
the niti mechanical characteristics were affected in the acidic solutionscompared to neutral fluoride solution , a fluoride mouthwash with more acidic ph of 4 affected the niti wires mechanical characteristics adversely during unloading phase .
the niti mechanical characteristics were affected in the acidic solutions compared to neutral fluoride solution , a fluoride mouthwash with more acidic ph of 4 affected the niti wires mechanical characteristics adversely during unloading phase .
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### Summary:
: objectives : the aim was to evaluate the in vitro effects of fluoride solutions with different acidities on load - deflection characteristics of nickel - titanium ( niti ) orthodontic wires.materials and methods : in this study , which lasted 30 days , 36 ( 3 cm long , 0.016 0.022 inches , sent 1622 , g & h wire company , greenwood , indiana , usa ) niti wires , were divided into three experimental groups of 12 each .
two groups were subjected to 0.05 topical fluoride mouthwash with different acidities ( g1 , ph 4 ; g2 , ph 6.6 ) for 90 s , twice a day , and kept in normal saline after that .
the third group ( g3 , the control group ) was kept in normal saline only .
load and unload forces were measured with three bracket bending test in a universal testing machine ( testometric co , rochdale , uk ) .
loading and unloading plateaus and hysteresis were also recorded .
data were then analyzed using analysis of variance and honestly significant difference tukey at p < 0.05.results:during the loading phase , there was a significant difference between deflections ( p < 0.001 ) ; but there was no interaction effect ( p = 0.191 ) and no significant difference among three groups ( p = 0.268 ) . in the unloading phase , there was a significant difference between deflections ( p < 0.001 ) and an interaction effect was also observed ( p = 0.008 ) .
further , significant differences noted among three groups ( p = 0.037 ) . only in the unloading phase , at deflections of 2.2 through 0.2 mm , significant differences between the mean force values of the g1 and g3 groups were observed ( p = 0.037).conclusion : based on this in - vitro study , compared to neutral fluoride solution , daily mouthwash with a fluoride solution with more acidic ph of 4 affected the niti wires load - deflection characteristics during the unloading phase .
this finding may have clinical implications and can be further validated by in - vivo studies .
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: aortic stenosis is the most frequent type of valvular heart disease in the western countries and presents mostly in an advanced age as a calcific form .
surgical valve replacement is the established standard management , which alleviates symptoms and improves survival .
valvuloplasty of the stenosed valve has been over many years a palliative option for the short term for highly selected , inoperable patients .
recently , catheter - based valve implantations have become an alternative for selected , particularly elderly patients .
smaller , randomized studies confirmed acceptable outcomes in high risk and inoperable patients for the transvascular ( tv ) as well as the transapical ( ta ) approach when compared with conservative or surgical management .
there are , however , no larger series available comparing conventional surgery with the novel techniques . in germany ,
catheter - based aortic valve implantations have rapidly been accepted at many centres and are performed at increasing numbers . the german aortic valve registry ( gary )
is a joint project of the german cardiac society ( dgk ) and the german society for thoracic and cardiovascular surgery ( dgthg ) with the aim to collect complete data on aortic valve interventions for aortic stenosis across germany .
this is the first report on the acute in - hospital outcome in patients recruited in 2011 .
patients undergoing invasive treatment for acquired aortic valve stenosis [ aortic valve surgery as conventional aortic valve replacement ( avr ) or ross and david procedures , trancatheter aortic valve intervention ( avi ) , or aortic valvuloplasty ] in participating centres have consecutively been enrolled in the registry .
transcatheter avi was divided in the retrograde tv techniques ( transfemoral , direct aortic , and transsubclavian access ) and the antegrade transapical access ( ta ) .
the study period started on 1 july 2010 and patient recruitment is scheduled up to the end of 2015 .
the protocol requests a follow - up at 30 days , 1 , 3 , and 5 years after the index aortic valve procedure .
briefly , data from different data sets ( baseline , procedural , and outcome data ) have been combined in an electronic case report form .
data completeness has been verified by an electronic tool on the basis of the hospitals ' reimbursement requests while data accuracy has been monitored by a multistage plausibility check combined with an on - site data verification on a randomly selected 5% of the participating hospitals ( audit ) .
data management and statistical analysis has been performed by the bqs institute for quality and patient safety ( www.bqs-institut.de ) . in germany
, it is mandatory for reimbursement to deliver a data set of specific cardiac interventions to the independent institute for quality assurance ( aqua , institut fr angewandte qualittsfrderung und forschung i m gesundheitswesen , gttingen , germany ) .
the data and results are published annually in a quality report and allow the evaluation of the enrolment completeness of gary .
in addition , all sites were asked to confirm in writing that the reported data are consistent with the patients reported to aqua excluding patients refusing to give informed consent for the registry ( 35% ) .
the present analysis comprises the in - hospital outcome of all patients who underwent conventional aortic valve replacement ( avr ) without ( n = 6523 ) or with ( n = 3462 ) concomitant coronary bypass surgery and patients who were treated with tv avi ( n = 2694 ) or ta avi ( n = 1181 ) in the year 2011 .
patients treated with other surgical procedures of the aortic valve ( e.g. ross , david ; n = 354 ) or balloon valvuloplasty alone ( n = 48 ) are not included in this analysis .
the descriptive analysis includes surgical avr without coronary artery bypass grafting ( cabg ) , surgical avr with cabg , tv avi , and ta avi .
wallis rest ( any differences ) or mann whitney u test ( pairwise ) for continuous variables .
expected values of the euroscore and the german av - score were used to analyse risk - stratified observed in - hospital mortality .
it is well known that the euroscore overestimates the operative risk , but it is still widely used .
the recently published german av - score focuses specifically on aortic valves and has been developed to better reflect the real - world care .
it is calculated from 15 variables including age ( five risk classes ) , gender , body mass index ( two risk classes ) , new york heart association class ( nyha ) , myocardial infarction within 3 weeks , critical pre - operative status , pulmonary hypertension , rhythm , left ventricular ejection fraction ( two risk classes ) , redo procedure , endocarditis , peripheral arterial disease , chronic obstructive lung disease ( two risk classes ) , renal failure , and emergency procedure .
the responsible body of the registry is a non - profit organization named deutsches aortenklappenregister ggmbh founded by the dgk and dgthg .
the responsible societies and the bqs institute are by the virtue of their constitutions independent organizations in both legal and scientific views .
the registry receives financial support in the format of unrestricted grants by medical device companies ( edwards lifesciences , jenavalve technology , medtronic , sorin , st jude medical , symetis sa ) , which however have neither access to data nor influence on their publication .
the descriptive analysis includes surgical avr without coronary artery bypass grafting ( cabg ) , surgical avr with cabg , tv avi , and ta avi .
wallis rest ( any differences ) or mann whitney u test ( pairwise ) for continuous variables .
expected values of the euroscore and the german av - score were used to analyse risk - stratified observed in - hospital mortality .
it is well known that the euroscore overestimates the operative risk , but it is still widely used .
the recently published german av - score focuses specifically on aortic valves and has been developed to better reflect the real - world care .
it is calculated from 15 variables including age ( five risk classes ) , gender , body mass index ( two risk classes ) , new york heart association class ( nyha ) , myocardial infarction within 3 weeks , critical pre - operative status , pulmonary hypertension , rhythm , left ventricular ejection fraction ( two risk classes ) , redo procedure , endocarditis , peripheral arterial disease , chronic obstructive lung disease ( two risk classes ) , renal failure , and emergency procedure .
the responsible body of the registry is a non - profit organization named deutsches aortenklappenregister ggmbh founded by the dgk and dgthg .
the responsible societies and the bqs institute are by the virtue of their constitutions independent organizations in both legal and scientific views . the registry receives financial support in the format of unrestricted grants by medical device companies ( edwards lifesciences , jenavalve technology , medtronic , sorin , st jude medical , symetis sa ) , which however have neither access to data nor influence on their publication
the following analysis is based on 13 860 consecutive patients who underwent aortic valve interventions from january 1 to 31 december 2011 covering 55% of all aortic interventions in germany during this period .
the data are derived from 78 sites ( out of 96 in germany ) , of which 62 sites contributed data from the beginning of the year .
since several centres joined only in the course of the year 2011 , the number of patients analysed in this manuscript does not match with the number of all aortic procedures performed in germany . here
, we summarize the results of 6537 conventional aortic valve replacements without and 3464 with concomitant coronary bypass surgery .
the decision for a transcatheter avi was made in most cases by a heart team ( tv 86.1 , ta 90.4% ) , but in some patients either a cardiologist ( tv 8.7 .
reasons for choosing a transcatheter valve implantation over a conventional avr were high patient age ( tv 69 , ta 72% ) , frailty ( tv 44 , ta 48% ) , overall high - operative risk defined as log .
euroscore > 20% or sts - score > 10% ( tv 64 , ta 65% ) , porcelain aorta ( tv 5 , ta 11% ) , or concomitant diseases limiting life expectancy ( tv 8 , ta 11% ) .
the patients ' wish played a minor role as an additional factor ( tv 29 , ta 15% ) .
patients undergoing either conventional avr or transcatheter avi differed markedly in baseline characteristics and risk profile .
most transcatheter aortic valve intervention ( tavi ) patients ( tv 86.3 , ta 84.0% ) were older than 75 years , whereas this was only the case for a minority of patients undergoing conventional avr ( 33.3% without cabg/44.9% with cabg , figure 1 ) .
the mean logistic euroscore was significantly higher in the tavi groups ( tv 25.9 ; ta 24.5% ) in comparison with patients who underwent conventional avr without ( 8.8% ) or with concomitant cabg ( 11.0% ) .
this is concordant with the fact that the tavi cohort had more cardiovascular risk factors ( table 1 ) .
table 1baseline characteristicsconventional avrtavip - value of global hypothesisp - values of pairwise comparisons [ alpha level has to be corrected by the bonferoni holm shaffer method for multiple comparisons ( 6 - 3 - 3 - 3 - 2 - 1-rule)]without cabgwith cabgtransvasculartransapicalh0 : no differences between any proceduresh0 : avr = avr + cabgh0 : avr = tv tavih0 : avr = ta tavih0 : avr + cabg = tv tavih0 : avr + cabg = ta tavih0 : tv tavi = ta tavin6523346226941181mean age ( years)68.3 11.372.5 8.081.1 6.280.3 6.1<0.001<0.001<0.001<0.001<0.001<0.001<0.001female2543 ( 39.0%)984 ( 28.4%)1583 ( 58.8%)588 ( 49.8%)<0.001<0.001<0.001<0.001<0.001<0.001<0.001mean bmi ( kg / m)28.1 4.928.2 4.427.0 4.927.2 5.0<0.0010.011<0.001<0.001<0.001<0.0010.123new york heart association ( % ) class i489 ( 7.5)197 ( 5.7)92 ( 3.4)40 ( 3.4)<0.0010.001<0.001<0.001<0.0010.0021.000 class ii1977 ( 30.3)874 ( 25.2)297 ( 11.0)129 ( 10.9)<0.001<0.001<0.001<0.001<0.001<0.0010.956 class iii3726 ( 57.1)2168 ( 62.6)1968 ( 73.1)883 ( 74.8)<0.001<0.001<0.001<0.001<0.001<0.0010.268 class iv331 ( 5.1)223 ( 6.4)337 ( 12.5)129 ( 10.9)<0.0010.005<0.001<0.001<0.001<0.0010.180cad1213 ( 18.6)3362 ( 97.1)1444 ( 53.6)663 ( 56.1)<0.001<0.001<0.001<0.001<0.001<0.0010.151myocardial infarction ( % ) within 21 days49 ( 0.8)171 ( 4.9)91 ( 3.4)22 ( 1.9)<0.001<0.001<0.0010.0010.003<0.0010.009 2290 days46 ( 0.7)89 ( 2.6)74 ( 2.7)38 ( 3.2)<0.001<0.001<0.001<0.0010.6900.2560.407 more than 90 days224 ( 3.4)290 ( 8.4)266 ( 9.9)153 ( 13.0)<0.001<0.001<0.001<0.0010.044<0.0010.005previous pci ( % ) 522 ( 8.0)599 ( 17.3)780 ( 29.0)348 ( 29.5)<0.001<0.001<0.001<0.001<0.001<0.0010.759previous cardiac surgery ( % ) 612 ( 9.4)220 ( 6.4)475 ( 17.7)348 ( 29.6)<0.001<0.001<0.001<0.001<0.001<0.001<0.001pulmonary hypertension ( % ) 697 ( 10.8)380 ( 11.1)1063 ( 39.8)273 ( 23.4)<0.0010.635<0.001<0.001<0.001<0.001<0.001insulin - dependent dm ( % ) 532 ( 8.2)448 ( 12.9)359 ( 13.3)206 ( 17.5)<0.001<0.001<0.001<0.0010.675<0.0010.001arterial hypertension ( % ) 5148 ( 79.5)2968 ( 86.1)2321 ( 86.4)1058 ( 90.0)<0.001<0.001<0.001<0.0010.7370.0010.002atrial fibrillation ( % ) 1039 ( 15.9)521 ( 15.0)779 ( 28.9)348 ( 29.5)<0.0010.259<0.001<0.001<0.001<0.0010.730obstructive lung disease ( % ) on medication407 ( 6.2)243 ( 7.0)406 ( 15.1)166 ( 14.1)<0.0010.136<0.001<0.001<0.001<0.0010.431 without medication248 ( 3.8)179 ( 5.2)126 ( 4.7)75 ( 6.4)<0.0010.0020.055<0.0010.4070.1200.033lvef ( % ) < 30199 ( 3.1)176 ( 5.1)250 ( 9.3)88 ( 7.5)<0.001<0.001<0.001<0.001<0.0010.0040.064 30501381 ( 21.2)972 ( 28.1)817 ( 30.3)418 ( 35.4)<0.001<0.001<0.001<0.0010.054<0.0010.002decompensated heart failure ( % ) within 12 months1047 ( 16.5)711 ( 21.2)1159 ( 44.9449 ( 39.5)<0.001<0.001<0.001<0.001<0.001<0.0010.002dialysis ( % ) acute94 ( 1.4)55 ( 1.6)43 ( 1.6)39 ( 3.3)<0.0010.6030.571<0.0011.0000.0010.001 chronic79 ( 1.2)52 ( 1.5)83 ( 3.1)54 ( 4.6)<0.0010.230<0.001<0.001<0.001<0.0010.023active endocarditis ( % ) 216 ( 3.3)51 ( 1.5)2 ( 0.11 ( 0.1)<0.001<0.001<0.001<0.001<0.001<0.0011.000cardiogenic shock ( % ) within 48 h64 ( 1.0)53 ( 1.5)104 ( 3.922 ( 1.9<0.0010.019<0.0010.015<0.0010.4230.001cardiopulmonary resuscitation ( % ) within 48 h4 ( 0.1)9 ( 0.3)5 ( 0.2)1 ( 0.1)0.0500.0160.1340.5640.6010.4680.674patient on mechanical ventilation ( % ) 38 ( 0.6)17 ( 0.5)72 ( 2.7)8 ( 0.7)<0.0010.670<0.0010.681<0.0010.490<0.001neurologicaldysfunction ( % ) 489 ( 7.5)304 ( 8.8)352 ( 13.1)174 ( 14.7)<0.0010.027<0.001<0.001<0.001<0.0010.169preop inotropic support ( % ) 71 ( 1.1)52 ( 1.5)158 ( 5.9)18 ( 1.5)<0.0010.086<0.0010.234<0.0011.000<0.001preop iabp ( % ) 11 ( 0.2)17 ( 0.5)2 ( 0.1)0 ( 0.0)0.0010.0050.3690.3910.0040.0101.000atherosclerotic disease ( % ) 1310 ( 20.1)951 ( 27.5)735 ( 27.3)505 ( 42.8)<0.001<0.001<0.001<0.0010.863<0.001<0.001 peripheral ( extremities)298 ( 4.6)402 ( 11.6)442 ( 16.4)335 ( 28.4)<0.001<0.001<0.001<0.001<0.001<0.001<0.001 carotid disease358 ( 5.5)457 ( 13.2)302 ( 11.2)209 ( 17.7)<0.001<0.001<0.001<0.0010.019<0.001<0.001 aortic aneurism636 ( 9.8)225 ( 6.5)90 ( 3.3)67 ( 5.7)<0.001<0.001<0.001<0.001<0.0010.3320.001 other216 ( 3.3)133 ( 3.9)132 ( 4.9)101 ( 8.6)<0.0010.169<0.001<0.0010.050<0.001<0.001intervention ( % ) elective5554 ( 85.1)2750 ( 79.4)2088 ( 77.5)1009 ( 85.4)<0.001<0.001<0.0010.8240.069<0.001<0.001 urgent891 ( 13.7)643 ( 18.6)567 ( 21.0)167 ( 14.1)<0.001<0.001<0.0010.6460.017<0.001<0.001 emergent78 ( 1.2)69 ( 2.0)39 ( 1.45 ( 0.4)<0.0010.0020.3570.0140.117<0.0010.005bmi , body mass index ; cad , coronary artery disease ; pci , percutaneous coronary intervention ; dm , diabetes mellitus ; iabp , intra - aortic balloon pump .
baseline characteristics bmi , body mass index ; cad , coronary artery disease ; pci , percutaneous coronary intervention ; dm , diabetes mellitus ; iabp , intra - aortic balloon pump . age ( a ) and risk ( b ) distribution .
the comparison between the tv and ta tavi patients revealed a significantly higher rate of pulmonary hypertension in the tv group and more patients with pre - operative acute and chronic renal failure with dialysis .
the ta patients more often suffered from both peripheral artery disease ( 28.4 vs. 16.4% ) and carotid disease ( 17.7 vs. 11.2% ) . in the tv group a considerable number of patients was treated < 48 h after or still in cardiogenic shock ( 3.9 vs. 1.9% ta - avi ) and/or still under inotropic support ( 5.9 vs. 1.5% ta - avi ) . no difference among all groups
however , the valve area was somewhat lower in both tavi groups ( table 2 ) .
likewise , the rate of mild - to - moderate concomitant mitral valve regurgitation was higher in the tavi - treated patients .
table 2valve - related baseline characteristicsconventional avrtavip - value of global hypothesisp - values of pairwise comparisons [ alpha level has to be corrected by the bonferoni holm shaffer method for multiple comparisons ( 6 - 3 - 3 - 3 - 2 - 1-rule)]without cabgwith cabgtransvasculartransapicalh0 : no differences between any proceduresh0 : avr = avr + cabgh0 : avr = tv tavih0 : avr = ta tavih0 : avr + cabg = tv tavih0 : avr + cabg = ta tavih0 : tv tavi = ta taviaortic valve orifice ( echo ; cm)0.86 0.660.85 0.500.68
0.250.68 0.20<0.001<0.001<0.001<0.001<0.001<0.0010.416delta pmean ( mmhg)44.2 19.541.1 17.646.1 17.643.7 16.3<0.001<0.0010.1180.014<0.0010.002<0.001delta pmax ( mmhg)70.1 29.865.7 26.773.4 26.771.4 25.0<0.001<0.0010.0120.760<0.001<0.0010.052degree of calcification ( % ) low7.57.15.63.7<0.0010.5350.002<0.0010.025<0.0010.018 average24.124.928.823.5<0.0010.422<0.0010.6680.0010.3660.001 heavy57.362.063.965.9<0.001<0.001<0.001<0.0010.1490.0230.263concomitant mitral regurgitation ( % ) none40.035.911.617.4<0.001<0.001<0.001<0.001<0.001<0.001<0.001 grade i44.748.257.854.4<0.0010.001<0.001<0.001<0.001<0.0010.055 grade ii10.912.926.626.0<0.0010.005<0.001<0.001<0.001<0.0010.719 grade iii3.72.73.92.00.0010.0090.7150.0030.0120.1930.002 grade iv0.70.30.10.2<0.0010.011<0.0010.0560.1260.7390.590 valve - related baseline characteristics the procedure times were significantly longer for conventional operations ( avr : 183 69 min , avr + cabg : 242 79 min ) as opposed to the tavi ( tv : 92 51 min , ta : 100 65 min ) . following the trend of the past years
a biological prosthesis was implanted in most patients undergoing conventional valve replacement ( 83.8% in patients without concomitant cabg , 92.2% in patients with cabg ) . in the tv group
the corevalve revalving system ( medtronic , minneapolis , mn , usa ) was used in > 60% of the cases , whereas the sapien valve ( edwards lifesciences , irvine usa ) was almost exclusively used for the ta route .
overall , tavi patients were treated with prostheses from edwards lifesciences ( n = 2061 ) or medtronic corevalve ( n = 1614 ) . only a minority was treated with second generation prostheses from symetis sa ( n = 53 ) or jenavalve ( n = 53 ) . the remaining patients ( n = 94 ) received either devices under clinical evaluation or no device due to different reasons . in the majority of patients , the native aortic valve was treated . within the tavi group , however ,
81 patients ( 2.1% ) received a valve - in - valve due to deterioration of a previously implanted surgical bioprosthesis .
most ta patients ( 95% ) were operated under general anaesthesia , whereas this was only the case in 44% of the tv patients . a small proportion of tavi patients underwent the procedure electively with under support of a heart lung machine ( 0.5% ) .
a true heart team approach with at least one cardiologist and one cardiac surgeon performing the procedure together was present in 40.3% of the tv and 69.4% of the ta cases .
the mean fluoroscopy time was lower in the ta ( 9 19 min ) than in the tv group ( 18 11 min ) .
conversion to sternotomy was necessary in 2.0% of the ta and 1.4% of the tv cases .
unplanned cardiopulmonary bypass was necessary in 2.1% of the ta cases and 0.7% of the tv cases .
vascular complications ( intra- and post - operative ) were expectedly highest in the tv avi patients ( 15.9% ) .
table 3procedural dataconventional avrtaviwithout cabgwith cabgtransvascular ( % ) transapical ( % ) heart team approach78 ( 1.3%)57 ( 1.8%)1.085 ( 40.3)820 ( 69.4)general anaesthesia1.179 ( 43.7)1.121 ( 94.9)procedure duration ( min)183 69242 7992 51100 65mean radiation time ( min)18 119 19balloon predilatation2.332 ( 86.5)1.112 ( 94.2)rapid pacing during implantation1.546 ( 57.4)1.046 ( 88.5)complications ( % ) coronary occlusion6 ( 0.1)6 ( 0.2)7 ( 0.3)0 ( 0.0 ) pericardial tamponade3 ( 0.05)0 ( 0.0)38 ( 1.4)2 ( 0.2 ) device embolization0 ( 0.0)0 ( 0.0)16 ( 0.6)4 ( 0.3 ) left ventricular decompensation12 ( 0.2)28 ( 0.8)24 ( 0.9)28 ( 2.4 ) vascular complications117 ( 1.8)78 ( 2.3)427 ( 15.9)48 ( 4.1 ) conversion to sternotomyn / an / a38 ( 1.4)24 ( 2.0)lv decompensation is defined as ( i ) need for prolonged ( > 24 h ) high - dose inotropic support and/or ( ii ) need for implantation of an intra - aortic balloon pump or extracorporeal membrane oxygenation and/or ( iii ) pulmonary oedema .
lv decompensation is defined as ( i ) need for prolonged ( > 24 h ) high - dose inotropic support and/or ( ii ) need for implantation of an intra - aortic balloon pump or extracorporeal membrane oxygenation and/or ( iii ) pulmonary oedema .
the different pre - operative risk profiles led to differences in the unadjusted post - operative outcome parameters .
in - hospital mortality for all patients ( including emergent procedures , endocarditis , and similar high - risk patients ) was 2.1% in the surgical group for avr alone and 4.5% for patients with avr plus cabg . in the tv group ,
the in - hospital mortality was 5.1% ( corevalve 4.3% , sapien 5.8% , n.s . ) and in - patients who underwent ta avi 7.7% ( figure 2 ) .
the in - hospital stroke rate was low in all groups with 1.3% ( avr ) , 1.9% ( avr + cabg ) , 1.7% ( tv tavi ) , and 2.3% ( ta tavi ) .
table 4unadjusted outcomeconventional avrtaviwithout cabgwith cabgtransvasculartransapicaln6523346226941181in - hospital mortality ( % ) 139 ( 2.1)155/(4.5)138 ( 5.1)91 ( 7.7)cerebrovascular event ( % ) 80 ( 1.3)61 ( 1.9)43 ( 1.7)25 ( 2.2)(redo-)thoracotomy ( % ) 453 ( 6.9)262 ( 7.6)25 ( 0.9)52 ( 4.4)valve - related redo intervention ( % ) 22 ( 0.3)6 ( 0.2)11 ( 0.4)3 ( 0.3)duration of mechanical ventilation ( h)32 11147 15629 10837 124post - operative need for haemodialysis ( % ) acute203 ( 3.2)165 ( 4.9)75 ( 2.9)73 ( 6.7 ) chronic16 ( 0.3)10 ( 0.3)2 ( 0.1)8 ( 0.7 ) new pacemaker236 ( 4.6)108 ( 3.9)390 ( 23.7)71 ( 9.9)transfusions ( % ) 02 units4.579 ( 70.6)1.993 ( 58.0)2.336 ( 88.5)875 ( 74.6 > 2 units1.908 ( 29.4)1.445 ( 42.0)305 ( 11.5)298 ( 25.4)residual aortic regurgitation ( % ) none990 ( 37.2)653 ( 57.3 ) grade i1.474 ( 55.5)440 ( 38.6 ) grade ii185 ( 7.0)39 ( 3.4 ) grade
iii / iv9 ( 0.3)7 ( 0.6)redo thoracotomy is defined as post - procedural re - exploration for any reason
redo thoracotomy is defined as post - procedural re - exploration for any reason .
the incidence of post - interventional atrioventriclar block requiring pacemaker implantation was highest in tv - treated patients ( 25.0% ) when compared with the ta group ( 11.3% ) and conventionally treated patients ( 5.2% without ; 4.5% with cabg ) .
the gary registry found very good results in both catheter - treated groups with either no regurgitation ( tv 37.2 , ta 57.3% ) or non - valve academic research consortium - relevant regurgitation grade i ( tv 55.5 , ta 38.6% ) .
grade ii - regurgitation occurred more often in the tv group ( 7.3% ) when compared with the ta group ( 4.0% ; table 4 ) .
the duration of post - intervention mechanical ventilation was shorter in the tv group in comparison with ta ( 29 108 vs. 37 124 h ) ( figure 3 ) .
the euroscore grossly overestimated the real mortality in the gary registry for all groups ( each euroscore vs. observed mortality : conventional surgery without cabg 8.8 vs. 2.1% ; conventional surgery with cabg 11.0 vs. 4.5% ; tv - avi 25.9 vs. 5.1% ;
the german av - score demonstrated reliable risk discrimination for the low - to - intermediate risk patients in all groups . in the tv - avi group and in conventionally operated patients without bypass surgery ,
the observed mortality for high - risk patients was significantly lower than expected from the german av - score ( figure 4 ) .
figure 4observed ( bars ) vs. predicted ( lines ) in - hospital mortality by the german av - score .
the risk was lower in the high - risk groups undergoing aortic valve replacement without cabg and transvascular tavi .
observed ( bars ) vs. predicted ( lines ) in - hospital mortality by the german av - score .
the risk was lower in the high - risk groups undergoing aortic valve replacement without cabg and transvascular tavi .
the following analysis is based on 13 860 consecutive patients who underwent aortic valve interventions from january 1 to 31 december 2011 covering 55% of all aortic interventions in germany during this period .
the data are derived from 78 sites ( out of 96 in germany ) , of which 62 sites contributed data from the beginning of the year .
since several centres joined only in the course of the year 2011 , the number of patients analysed in this manuscript does not match with the number of all aortic procedures performed in germany . here
, we summarize the results of 6537 conventional aortic valve replacements without and 3464 with concomitant coronary bypass surgery .
the decision for a transcatheter avi was made in most cases by a heart team ( tv 86.1 , ta 90.4% ) , but in some patients either a cardiologist ( tv 8.7 .
reasons for choosing a transcatheter valve implantation over a conventional avr were high patient age ( tv 69 , ta 72% ) , frailty ( tv 44 , ta 48% ) , overall high - operative risk defined as log .
euroscore > 20% or sts - score > 10% ( tv 64 , ta 65% ) , porcelain aorta ( tv 5 , ta 11% ) , or concomitant diseases limiting life expectancy ( tv 8 , ta 11% ) .
the patients ' wish played a minor role as an additional factor ( tv 29 , ta 15% ) .
patients undergoing either conventional avr or transcatheter avi differed markedly in baseline characteristics and risk profile . most transcatheter aortic valve intervention ( tavi ) patients
( tv 86.3 , ta 84.0% ) were older than 75 years , whereas this was only the case for a minority of patients undergoing conventional avr ( 33.3% without cabg/44.9% with cabg , figure 1 ) .
the mean logistic euroscore was significantly higher in the tavi groups ( tv 25.9 ; ta 24.5% ) in comparison with patients who underwent conventional avr without ( 8.8% ) or with concomitant cabg ( 11.0% ) .
this is concordant with the fact that the tavi cohort had more cardiovascular risk factors ( table 1 ) .
table 1baseline characteristicsconventional avrtavip - value of global hypothesisp - values of pairwise comparisons [ alpha level has to be corrected by the bonferoni holm shaffer method for multiple comparisons ( 6 - 3 - 3 - 3 - 2 - 1-rule)]without cabgwith cabgtransvasculartransapicalh0 : no differences between any proceduresh0 : avr = avr + cabgh0 : avr = tv tavih0 : avr = ta tavih0 : avr + cabg = tv tavih0 : avr + cabg = ta tavih0 : tv tavi = ta tavin6523346226941181mean age ( years)68.3 11.372.5 8.081.1 6.280.3 6.1<0.001<0.001<0.001<0.001<0.001<0.001<0.001female2543 ( 39.0%)984 ( 28.4%)1583 ( 58.8%)588 ( 49.8%)<0.001<0.001<0.001<0.001<0.001<0.001<0.001mean bmi ( kg / m)28.1 4.928.2 4.427.0 4.927.2 5.0<0.0010.011<0.001<0.001<0.001<0.0010.123new york heart association ( % ) class i489 ( 7.5)197 ( 5.7)92 ( 3.4)40 ( 3.4)<0.0010.001<0.001<0.001<0.0010.0021.000 class ii1977 ( 30.3)874 ( 25.2)297 ( 11.0)129 ( 10.9)<0.001<0.001<0.001<0.001<0.001<0.0010.956 class iii3726 ( 57.1)2168 ( 62.6)1968 ( 73.1)883 ( 74.8)<0.001<0.001<0.001<0.001<0.001<0.0010.268 class iv331 ( 5.1)223 ( 6.4)337 ( 12.5)129 ( 10.9)<0.0010.005<0.001<0.001<0.001<0.0010.180cad1213 ( 18.6)3362 ( 97.1)1444 ( 53.6)663 ( 56.1)<0.001<0.001<0.001<0.001<0.001<0.0010.151myocardial infarction ( % ) within 21 days49 ( 0.8)171 ( 4.9)91 ( 3.4)22 ( 1.9)<0.001<0.001<0.0010.0010.003<0.0010.009 2290 days46 ( 0.7)89 ( 2.6)74 ( 2.7)38 ( 3.2)<0.001<0.001<0.001<0.0010.6900.2560.407 more than 90 days224 ( 3.4)290 ( 8.4)266 ( 9.9)153 ( 13.0)<0.001<0.001<0.001<0.0010.044<0.0010.005previous pci ( % ) 522 ( 8.0)599 ( 17.3)780 ( 29.0)348 ( 29.5)<0.001<0.001<0.001<0.001<0.001<0.0010.759previous cardiac surgery ( % ) 612 ( 9.4)220 ( 6.4)475 ( 17.7)348 ( 29.6)<0.001<0.001<0.001<0.001<0.001<0.001<0.001pulmonary hypertension ( % ) 697 ( 10.8)380 ( 11.1)1063 ( 39.8)273 ( 23.4)<0.0010.635<0.001<0.001<0.001<0.001<0.001insulin - dependent dm ( % ) 532 ( 8.2)448 ( 12.9)359 ( 13.3)206 ( 17.5)<0.001<0.001<0.001<0.0010.675<0.0010.001arterial hypertension ( % ) 5148 ( 79.5)2968 ( 86.1)2321 ( 86.4)1058 ( 90.0)<0.001<0.001<0.001<0.0010.7370.0010.002atrial fibrillation ( % ) 1039 ( 15.9)521 ( 15.0)779 ( 28.9)348 ( 29.5)<0.0010.259<0.001<0.001<0.001<0.0010.730obstructive lung disease ( % ) on medication407 ( 6.2)243 ( 7.0)406 ( 15.1)166 ( 14.1)<0.0010.136<0.001<0.001<0.001<0.0010.431 without medication248 ( 3.8)179 ( 5.2)126 ( 4.7)75 ( 6.4)<0.0010.0020.055<0.0010.4070.1200.033lvef ( % ) < 30199 ( 3.1)176 ( 5.1)250 ( 9.3)88 ( 7.5)<0.001<0.001<0.001<0.001<0.0010.0040.064 30501381 ( 21.2)972 ( 28.1)817 ( 30.3)418 ( 35.4)<0.001<0.001<0.001<0.0010.054<0.0010.002decompensated heart failure ( % ) within 12 months1047 ( 16.5)711 ( 21.2)1159 ( 44.9449 ( 39.5)<0.001<0.001<0.001<0.001<0.001<0.0010.002dialysis ( % ) acute94 ( 1.4)55 ( 1.6)43 ( 1.6)39 ( 3.3)<0.0010.6030.571<0.0011.0000.0010.001 chronic79 ( 1.2)52 ( 1.5)83 ( 3.1)54 ( 4.6)<0.0010.230<0.001<0.001<0.001<0.0010.023active endocarditis ( % ) 216 ( 3.3)51 ( 1.5)2 ( 0.11 ( 0.1)<0.001<0.001<0.001<0.001<0.001<0.0011.000cardiogenic shock ( % ) within 48 h64 ( 1.0)53 ( 1.5)104 ( 3.922 ( 1.9<0.0010.019<0.0010.015<0.0010.4230.001cardiopulmonary resuscitation ( % ) within 48 h4 ( 0.1)9 ( 0.3)5 ( 0.2)1 ( 0.1)0.0500.0160.1340.5640.6010.4680.674patient on mechanical ventilation ( % ) 38 ( 0.6)17 ( 0.5)72 ( 2.7)8 ( 0.7)<0.0010.670<0.0010.681<0.0010.490<0.001neurologicaldysfunction ( % ) 489 ( 7.5)304 ( 8.8)352 ( 13.1)174 ( 14.7)<0.0010.027<0.001<0.001<0.001<0.0010.169preop inotropic support ( % ) 71 ( 1.1)52 ( 1.5)158 ( 5.9)18 ( 1.5)<0.0010.086<0.0010.234<0.0011.000<0.001preop iabp ( % ) 11 ( 0.2)17 ( 0.5)2 ( 0.1)0 ( 0.0)0.0010.0050.3690.3910.0040.0101.000atherosclerotic disease ( % ) 1310 ( 20.1)951 ( 27.5)735 ( 27.3)505 ( 42.8)<0.001<0.001<0.001<0.0010.863<0.001<0.001 peripheral ( extremities)298 ( 4.6)402 ( 11.6)442 ( 16.4)335 ( 28.4)<0.001<0.001<0.001<0.001<0.001<0.001<0.001 carotid disease358 ( 5.5)457 ( 13.2)302 ( 11.2)209 ( 17.7)<0.001<0.001<0.001<0.0010.019<0.001<0.001 aortic aneurism636 ( 9.8)225 ( 6.5)90 ( 3.3)67 ( 5.7)<0.001<0.001<0.001<0.001<0.0010.3320.001 other216 ( 3.3)133 ( 3.9)132 ( 4.9)101 ( 8.6)<0.0010.169<0.001<0.0010.050<0.001<0.001intervention ( % ) elective5554 ( 85.1)2750 ( 79.4)2088 ( 77.5)1009 ( 85.4)<0.001<0.001<0.0010.8240.069<0.001<0.001 urgent891 ( 13.7)643 ( 18.6)567 ( 21.0)167 ( 14.1)<0.001<0.001<0.0010.6460.017<0.001<0.001 emergent78 ( 1.2)69 ( 2.0)39 ( 1.45 ( 0.4)<0.0010.0020.3570.0140.117<0.0010.005bmi , body mass index ; cad , coronary artery disease ; pci , percutaneous coronary intervention ; dm , diabetes mellitus ; iabp , intra - aortic balloon pump .
figure 1age ( a ) and risk ( b ) distribution .
baseline characteristics bmi , body mass index ; cad , coronary artery disease ; pci , percutaneous coronary intervention ; dm , diabetes mellitus ; iabp , intra - aortic balloon pump . age
the comparison between the tv and ta tavi patients revealed a significantly higher rate of pulmonary hypertension in the tv group and more patients with pre - operative acute and chronic renal failure with dialysis .
the ta patients more often suffered from both peripheral artery disease ( 28.4 vs. 16.4% ) and carotid disease ( 17.7 vs. 11.2% ) . in the tv group a considerable number of patients was treated < 48 h after or still in cardiogenic shock ( 3.9 vs. 1.9% ta - avi ) and/or still under inotropic support ( 5.9 vs. 1.5% ta - avi ) . no difference among all groups
however , the valve area was somewhat lower in both tavi groups ( table 2 ) .
likewise , the rate of mild - to - moderate concomitant mitral valve regurgitation was higher in the tavi - treated patients .
table 2valve - related baseline characteristicsconventional avrtavip - value of global hypothesisp - values of pairwise comparisons [ alpha level has to be corrected by the bonferoni holm shaffer method for multiple comparisons ( 6 - 3 - 3 - 3 - 2 - 1-rule)]without cabgwith cabgtransvasculartransapicalh0 : no differences between any proceduresh0 : avr = avr + cabgh0 : avr = tv tavih0 : avr = ta tavih0 : avr + cabg = tv tavih0 : avr + cabg = ta tavih0 : tv tavi = ta taviaortic valve orifice ( echo ; cm)0.86 0.660.85 0.500.68 0.250.68 0.20<0.001<0.001<0.001<0.001<0.001<0.0010.416delta pmean ( mmhg)44.2 19.541.1 17.646.1
17.643.7 16.3<0.001<0.0010.1180.014<0.0010.002<0.001delta pmax ( mmhg)70.1 29.865.7 26.773.4 26.771.4 25.0<0.001<0.0010.0120.760<0.001<0.0010.052degree of calcification ( % ) low7.57.15.63.7<0.0010.5350.002<0.0010.025<0.0010.018 average24.124.928.823.5<0.0010.422<0.0010.6680.0010.3660.001 heavy57.362.063.965.9<0.001<0.001<0.001<0.0010.1490.0230.263concomitant mitral regurgitation ( % ) none40.035.911.617.4<0.001<0.001<0.001<0.001<0.001<0.001<0.001 grade i44.748.257.854.4<0.0010.001<0.001<0.001<0.001<0.0010.055 grade ii10.912.926.626.0<0.0010.005<0.001<0.001<0.001<0.0010.719 grade iii3.72.73.92.00.0010.0090.7150.0030.0120.1930.002 grade iv0.70.30.10.2<0.0010.011<0.0010.0560.1260.7390.590 valve - related baseline characteristics
the procedure times were significantly longer for conventional operations ( avr : 183 69 min , avr + cabg : 242 79 min ) as opposed to the tavi ( tv : 92 51 min , ta : 100 65 min ) . following the trend of the past years
a biological prosthesis was implanted in most patients undergoing conventional valve replacement ( 83.8% in patients without concomitant cabg , 92.2% in patients with cabg ) . in the tv group
the corevalve revalving system ( medtronic , minneapolis , mn , usa ) was used in > 60% of the cases , whereas the sapien valve ( edwards lifesciences , irvine usa ) was almost exclusively used for the ta route .
overall , tavi patients were treated with prostheses from edwards lifesciences ( n = 2061 ) or medtronic corevalve ( n = 1614 ) . only a minority was treated with second generation prostheses from symetis sa ( n = 53 ) or jenavalve ( n = 53 ) . the remaining patients ( n = 94 ) received either devices under clinical evaluation or no device due to different reasons . in the majority of patients , the native aortic valve was treated . within the tavi group , however ,
81 patients ( 2.1% ) received a valve - in - valve due to deterioration of a previously implanted surgical bioprosthesis .
most ta patients ( 95% ) were operated under general anaesthesia , whereas this was only the case in 44% of the tv patients .
a small proportion of tavi patients underwent the procedure electively with under support of a heart lung machine ( 0.5% ) .
a true heart team approach with at least one cardiologist and one cardiac surgeon performing the procedure together was present in 40.3% of the tv and 69.4% of the ta cases .
the mean fluoroscopy time was lower in the ta ( 9 19 min ) than in the tv group ( 18 11 min ) .
conversion to sternotomy was necessary in 2.0% of the ta and 1.4% of the tv cases .
unplanned cardiopulmonary bypass was necessary in 2.1% of the ta cases and 0.7% of the tv cases .
vascular complications ( intra- and post - operative ) were expectedly highest in the tv avi patients ( 15.9% ) .
table 3procedural dataconventional avrtaviwithout cabgwith cabgtransvascular ( % ) transapical ( % ) heart team approach78 ( 1.3%)57 ( 1.8%)1.085 ( 40.3)820 ( 69.4)general anaesthesia1.179 ( 43.7)1.121 ( 94.9)procedure duration ( min)183 69242 7992 51100 65mean radiation time ( min)18 119 19balloon predilatation2.332 ( 86.5)1.112 ( 94.2)rapid pacing during implantation1.546 ( 57.4)1.046 ( 88.5)complications ( % ) coronary occlusion6 ( 0.1)6 ( 0.2)7 ( 0.3)0 ( 0.0 ) pericardial tamponade3 ( 0.05)0 ( 0.0)38 ( 1.4)2 ( 0.2 ) device embolization0 ( 0.0)0 ( 0.0)16 ( 0.6)4 ( 0.3 ) left ventricular decompensation12 ( 0.2)28 ( 0.8)24 ( 0.9)28 ( 2.4 ) vascular complications117 ( 1.8)78 ( 2.3)427 ( 15.9)48 ( 4.1 ) conversion to sternotomyn / an / a38 ( 1.4)24 ( 2.0)lv decompensation is defined as ( i ) need for prolonged ( > 24 h ) high - dose inotropic support and/or ( ii ) need for implantation of an intra - aortic balloon pump or extracorporeal membrane oxygenation and/or ( iii ) pulmonary oedema .
lv decompensation is defined as ( i ) need for prolonged ( > 24 h ) high - dose inotropic support and/or ( ii ) need for implantation of an intra - aortic balloon pump or extracorporeal membrane oxygenation and/or ( iii ) pulmonary oedema .
the different pre - operative risk profiles led to differences in the unadjusted post - operative outcome parameters .
in - hospital mortality for all patients ( including emergent procedures , endocarditis , and similar high - risk patients ) was 2.1% in the surgical group for avr alone and 4.5% for patients with avr plus cabg . in the tv group ,
the in - hospital mortality was 5.1% ( corevalve 4.3% , sapien 5.8% , n.s . ) and in - patients who underwent ta avi 7.7% ( figure 2 ) .
the in - hospital stroke rate was low in all groups with 1.3% ( avr ) , 1.9% ( avr + cabg ) , 1.7% ( tv tavi ) , and 2.3% ( ta tavi ) .
table 4unadjusted outcomeconventional avrtaviwithout cabgwith cabgtransvasculartransapicaln6523346226941181in - hospital mortality ( % ) 139 ( 2.1)155/(4.5)138 ( 5.1)91 ( 7.7)cerebrovascular event ( % ) 80 ( 1.3)61 ( 1.9)43 ( 1.7)25 ( 2.2)(redo-)thoracotomy ( % ) 453 ( 6.9)262 ( 7.6)25 ( 0.9)52 ( 4.4)valve - related redo intervention ( % ) 22 ( 0.3)6 ( 0.2)11 ( 0.4)3 ( 0.3)duration of mechanical ventilation ( h)32 11147 15629 10837 124post - operative need for haemodialysis ( % ) acute203 ( 3.2)165 ( 4.9)75 ( 2.9)73 ( 6.7 ) chronic16 ( 0.3)10 ( 0.3)2 ( 0.1)8 ( 0.7 ) new pacemaker236 ( 4.6)108 ( 3.9)390 ( 23.7)71 ( 9.9)transfusions ( % ) 02 units4.579 ( 70.6)1.993 ( 58.0)2.336 ( 88.5)875 ( 74.6 > 2 units1.908 ( 29.4)1.445 ( 42.0)305 ( 11.5)298 ( 25.4)residual aortic regurgitation ( % ) none990 ( 37.2)653 ( 57.3 ) grade i1.474 ( 55.5)440 ( 38.6 ) grade ii185 ( 7.0)39 ( 3.4 ) grade
iii / iv9 ( 0.3)7 ( 0.6)redo thoracotomy is defined as post - procedural re - exploration for any reason .
redo thoracotomy is defined as post - procedural re - exploration for any reason .
the incidence of post - interventional atrioventriclar block requiring pacemaker implantation was highest in tv - treated patients ( 25.0% ) when compared with the ta group ( 11.3% ) and conventionally treated patients ( 5.2% without ; 4.5% with cabg ) .
the gary registry found very good results in both catheter - treated groups with either no regurgitation ( tv 37.2 , ta 57.3% ) or non - valve academic research consortium - relevant regurgitation grade i ( tv 55.5 , ta 38.6% ) .
grade ii - regurgitation occurred more often in the tv group ( 7.3% ) when compared with the ta group ( 4.0% ; table 4 ) .
the duration of post - intervention mechanical ventilation was shorter in the tv group in comparison with ta ( 29 108 vs. 37 124 h ) ( figure 3 ) .
the euroscore grossly overestimated the real mortality in the gary registry for all groups ( each euroscore vs. observed mortality : conventional surgery without cabg 8.8 vs. 2.1% ; conventional surgery with cabg 11.0 vs. 4.5% ; tv - avi 25.9 vs. 5.1% ; ta - avi 24.5 vs. 7.7% ) .
the german av - score demonstrated reliable risk discrimination for the low - to - intermediate risk patients in all groups . in the tv - avi group and in conventionally operated patients without bypass surgery ,
the observed mortality for high - risk patients was significantly lower than expected from the german av - score ( figure 4 ) .
figure 4observed ( bars ) vs. predicted ( lines ) in - hospital mortality by the german av - score .
the risk was lower in the high - risk groups undergoing aortic valve replacement without cabg and transvascular tavi .
observed ( bars ) vs. predicted ( lines ) in - hospital mortality by the german av - score .
the risk was lower in the high - risk groups undergoing aortic valve replacement without cabg and transvascular tavi .
the presented data pools for the first time a large number of patients who received either conventional or catheter - based aortic valve replacement .
conventional surgery was associated in all risk groups with an excellent outcome , which is in concordance with or even better than recent publications .
furthermore , the data support the favourable results of catheter - based aortic valve replacements from previous randomized studies and registries in an all comer real - world patient population .
the direct comparison with conventional surgical procedures allows to better define the role of this new technique in the future .
overall , we could confirm that the vast majority of patients treated by this new technology were at very high risk or elderly as shown in figure 1 .
the mean euroscore was more than two - fold higher in the tavi patients , accordingly .
this finding as well as the increasing total number of aortic valve interventions in germany ( + 7.3% ) suggests that this new technique was used regularly in patients who previously were not considered for valve surgery .
accordingly , the baseline characteristics in the treatment arms are considerably different , which thereby precludes reasonable risk adjustments . similarly , the use of the euroscore as comparator considerably overestimates the true risk in this patient population . for a better comparison ,
the german av - score was calculated which is derived from a 2007 data set of patients undergoing only aortic valve surgery .
this score better represents this patient population , as proven in the low - risk groups , but overestimated the risk in high - risk groups . this may be explained by the fact that tavi was done only at a very low rate in 2008 and some particular high - risk patients not captured by the av score have shifted over the time to tavi .
this obviously holds especially true for elderly patients , since most patients beyond the age of 85 were treated with a percutaneous approach .
it is reassuring that tavi in this high - risk subset resulted in lower mortality at least as predicted by the score .
vice versa , patients with a high av - score undergoing conventional surgery also had a lower risk as predicted in the pre - tavi era . when tavi was not routinely performed in 2009
the mortality of conventional avr with concomitant cabg was 36% higher , without concomitant cabg even 45% higher .
accordingly , our registry seems to disclose an important paradigm change in outcome and care . during most of the observation period in 2011 only the self - expanding medtronic corevalve and the balloon - expandable edwards sapien were commercially available .
accordingly , in tv procedures the medtronic corevalve prosthesis was used in 60% , whereas the ta approach was largely dominated by edwards sapien valves .
there was a trend that ta procedures had a higher mortality when compared with the tv approach .
furthermore , this technique is frequently used as an alternate route of access when the femoral approach is not feasible leading to a certain degree of pre - selection bias .
the difference should also not be related to the valve types , since mortalities in the tv groups were the same .
since residual aortic regurgitation has been described as independent risk factor for mortality , it was reassuring that the success rate seen in our registry was very high ( residual aortic regurgitation grade 1 in 92.7% with tv - avi and even 96.0% in ta - avi ) .
the yet unknown durability will stay a matter of debate . with respect to complications , stroke during valve replacement
however , the rate of strokes was similar in the tv and the ta approach and was in the range of patients undergoing combined valve and bypass surgery .
the rate for new pacemakers was several folds higher than in conventional surgery and as expected from previous reports more frequent in the corevalve patients and therefore more frequent after the tv approach .
the very low rates of coronary occlusions in all groups is reassuring especially for the tavi approach , in which this complication has long been feared . with the exception of vascular complications
the current data are reassuring that the results seen in the randomized trials as well as in other registries are reproducible in such a large - scale data collection .
most other studies primarily report the 30 days outcome , which , however , is very close to the in - hospital outcome in our study .
the length of hospitalization was rather similar and accordingly no critical factor in comparing the techniques .
the experience with the procedure varied considerably as many centres just started the catheter valve programme and were still in the learning curve or just released from proctoring .
one aim of this registry is to monitor the quality of indications and procedural outcome , and to provide a benchmark report back to the individual centres .
several centres joined the registry only in the course of 2011 and only 78 out of 96 potential centres contributed to gary , with the result that only 55% of all procedures performed in germany at that year have been captured .
however , through verification of the reported data with the compulsory quality reports ensured a high grade of completeness as far as possible .
in addition , registries have the inherent limitation to be not completely controlled with the risk of under - reporting of events or complications .
however , only all - comer registers allow to assess the penetration and use of a new technology and become particularly important when a traditional approach like conventional surgery is under debate . furthermore , it is usually difficult to enter suitable patients in adequate numbers into randomized trials , which leads to selection bias .
the high number of patients in registries must therefore , at least partly , be used for further placing new technology in patient care .
the in - hospital outcome results of this registry confirm that conventional surgery yields excellent results in all risk groups and that catheter - based aortic valve replacements are an alternative to conventional surgery in high risk and elderly patients .
although the results are very promising , long - term follow - up needs to confirm this conclusion in terms of mortality and quality of life .
the gary registry will over the next years provide solid data to further define the role of catheter - based aortic valve procedures .
the responsible body of the registry is a nonprofit organization named deutsches aortenklappenregister ggmbh founded by the dgk and dgthg .
the registry receives financial support in the format of unrestricted grants by medical device companies ( edwards lifesciences , jenavalve technology , medtronic , sorin , st .
conflict of interest : cwh received speakers honoraria from medtronic and edwards and serves in the advisory board of medtronic . hm received proctor salary and/or speakers honoraria from abbott , medtronic , edwards , st .
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### Summary:
: backgroundaortic stenosis is a frequent valvular disease especially in elderly patients .
catheter - based valve implantation has emerged as a valuable treatment approach for these patients being either at very high risk for conventional surgery or even deemed inoperable . the german aortic valve registry ( gary )
provides data on conventional and catheter - based aortic procedures on an all - comers basis.methods and resultsa total of 13 860 consecutive patients undergoing repair for aortic valve disease [ conventional surgery and transvascular ( tv ) or transapical ( ta ) catheter - based techniques ] have been enrolled in this registry during 2011 and baseline , procedural , and outcome data have been acquired .
the registry summarizes the results of 6523 conventional aortic valve replacements without ( avr ) and 3464 with concomitant coronary bypass surgery ( avr + cabg ) as well as 2695 tv avi and 1181 ta interventions ( ta avi ) .
patients undergoing catheter - based techniques were significantly older and had higher risk profiles .
the stroke rate was low in all groups with 1.3% ( avr ) , 1.9% ( avr + cabg ) , 1.7% ( tv avi ) , and 2.3% ( ta avi ) .
the in - hospital mortality was 2.1% ( avr ) and 4.5% ( avr + cabg ) for patients undergoing conventional surgery , and 5.1% ( tv avi ) and avi 7.7% ( ta avi).conclusionthe in - hospital outcome results of this registry show that conventional surgery yields excellent results in all risk groups and that catheter - based aortic valve replacements is an alternative to conventional surgery in high risk and elderly 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:
: in india , as a result of the change in the age composition over the decades , there has been a progressive rise in the number and proportion of elderly , aged 60 years and above .
today india is home to one out of every ten senior citizens of the world where 75% reside in rural areas .
inadequate income is a major problem of elderly in india with nearly half of them fully dependent on others for their maintenance . as the size of
the dependent elderly population is fast growing ; there is an emerging need to pay greater attention to aging - related oral health issues . according to the national oral health survey ,
the prevalence of subjects wearing prosthesis in upper and lower dental arches in the age group of 65 - 74 years was 10.2% and 11.1% , respectively , and the most prevalent prosthesis was complete dentures .
candida - associated denture stomatitis is a common inflammatory process affecting around 60 - 65% of denture wearers and is usually found on the palatal mucosa beneath the fitting surface of the upper denture .
it has multifactorial etiology but deficient denture hygiene habit is one of the most prominent contributing factor .
there are many specialized products on the market for denture cleansing , but the dependent elderly population using dentures have decreased access to a continuous supply of such materials .
hence there is a need to introduce a few natural products to clean dentures , which are easily and economically available .
triphala ( phyllanthus emblica , terminalia chebula and terminalia belerica fruits powders in equal proportion ) , aloe vera , and cashew leaves known for their medicinal properties have been traditionally used in india as therapeutic and antimicrobial aids in various ailments and are potent antifungal products effective against candida .
aqueous , ethyl acetic , and ethanolic fractions of terminalia chebula has shown a significant inhibitory effect on candida species .
aloe vera contains six antiseptic agents as lupeol , salicylic acid , urea nitrogen , cinnamonic acid , phenols , and sulfur , and have inhibitory action on fungi , bacteria , and viruses .
there is a need to test the anticandidal efficacy of these easily available products as denture cleansers .
hence the objective of this study was to compare the anticandidal efficacy of denture cleansing tablet , triphala , aloe vera , and cashew leaves on complete dentures of institutionalized elderly .
the study population consisted of 50 institutionalized elderly wearing maxillary complete dentures residing in old age homes of mangalore city .
five groups were given either of the five measures : denture cleansing tablets ( sodium bicarbonate and sodium perborate monohydrate ) , triphala churna , aloe vera , cashew leaves , or water for cleaning their dentures .
selection of the study participants were based on the following inclusion and exclusion criteria : volunteers consenting to participate in the study and those who had a complete acrylic upper denture were included in the study . participants with partial dentures or lower dentures ; those who had used a denture cleanser within the previous 2 weeks ;
participants taking antifungal agents or antiseptic mouthwashes ; those with systemic diseases or conditions making them prone to candida infections and patients with denture stomatitis were excluded from the study . in the denture cleansing tablet group ,
the participants were advised to put the tablet into water and place denture into effervescing solution and leave it in solution for 30 min . in the triphala group , the participants were advised to clean the dentures using triphala churna . in the aloe vera group ,
the participants were provided with a freshly cut piece of the leaf , which was trimmed on the sides , and they were advised to clean the denture using the cut surface . in the cashew leaf group ,
the participants were advised to remove the midrib , and fold the leaf lengthwise with glossy surfaces facing each other , rolled into a cylindrical pack and one end was frayed off 2 - 3 mm to create a raw surface , which was used to clean the denture . in the control group , the subjects were advised to clean their dentures under running tap water using a toothbrush .
swabs for culture were taken from the palatal surface of the upper denture according to a 2 2 cm template collected before and after use of the cleanser .
the swabs were placed in a test tube containing 1 ml sterile distilled water , vortexed for 1 min . then using a 4-mm loop ,
the sample was spread in sabouraud dextrose agar medium , incubated at 37c for 48 h. swabs for culture were taken from the palatal surface of the upper denture according to a 2 2 cm template collected before and after use of the cleanser .
the swabs were placed in a test tube containing 1 ml sterile distilled water , vortexed for 1 min . then using a 4-mm loop ,
the sample was spread in sabouraud dextrose agar medium , incubated at 37c for 48 h. the colonies were identified using :
colony morphology : in sabouraud dextrose agar medium , the candidal colonies appear as cream , pasty , and smooth coloniesmicroscopy : in 10% potassium hydroxide mount , the candidal colonies appear oval , budding , and yeast like cellson gram staining : they appear as gram - positive oval yeast like budding cellsurease test : candida gives a negative test on carrying out urease test .
colony morphology : in sabouraud dextrose agar medium , the candidal colonies appear as cream , pasty , and smooth colonies microscopy : in 10% potassium hydroxide mount , the candidal colonies appear oval , budding , and yeast like cells on gram staining : they appear as gram - positive oval yeast like budding cells urease test : candida gives a negative test on carrying out urease test .
numbers of colony forming units were multiplied by the dilution factor to obtain the number of colony forming units/4 cm .
the investigator and the microbiologist were blinded to the allocation of participants to different groups .
the difference in the number of colony forming units of microorganisms between first swab ( baseline before use of cleanser ) and second swab ( after use of cleanser ) was noted to assess the effectiveness of cleansers in reducing the total candida count .
one way analysis of variance ( anova ) followed by tukey 's test were used to compare the reduction of candida count between different denture cleansers .
a difference was considered to be of statistical significance if the p value was < 0.05 .
volunteers consenting to participate in the study and those who had a complete acrylic upper denture were included in the study .
participants with partial dentures or lower dentures ; those who had used a denture cleanser within the previous 2 weeks ; participants taking antifungal agents or antiseptic mouthwashes ; those with systemic diseases or conditions making them prone to candida infections and patients with denture stomatitis were excluded from the study . in the denture cleansing tablet group ,
the participants were advised to put the tablet into water and place denture into effervescing solution and leave it in solution for 30 min . in the triphala group , the participants were advised to clean the dentures using triphala churna . in the aloe vera group ,
the participants were provided with a freshly cut piece of the leaf , which was trimmed on the sides , and they were advised to clean the denture using the cut surface . in the cashew leaf group ,
the participants were advised to remove the midrib , and fold the leaf lengthwise with glossy surfaces facing each other , rolled into a cylindrical pack and one end was frayed off 2 - 3 mm to create a raw surface , which was used to clean the denture . in the control group , the subjects were advised to clean their dentures under running tap water using a toothbrush .
swabs for culture were taken from the palatal surface of the upper denture according to a 2 2 cm template collected before and after use of the cleanser .
the swabs were placed in a test tube containing 1 ml sterile distilled water , vortexed for 1 min . then using a 4-mm loop ,
the sample was spread in sabouraud dextrose agar medium , incubated at 37c for 48 h. swabs for culture were taken from the palatal surface of the upper denture according to a 2 2 cm template collected before and after use of the cleanser .
the swabs were placed in a test tube containing 1 ml sterile distilled water , vortexed for 1 min . then using a 4-mm loop ,
the sample was spread in sabouraud dextrose agar medium , incubated at 37c for 48 h. the colonies were identified using :
colony morphology : in sabouraud dextrose agar medium , the candidal colonies appear as cream , pasty , and smooth coloniesmicroscopy : in 10% potassium hydroxide mount , the candidal colonies appear oval , budding , and yeast like cellson gram staining : they appear as gram - positive oval yeast like budding cellsurease test : candida gives a negative test on carrying out urease test .
colony morphology : in sabouraud dextrose agar medium , the candidal colonies appear as cream , pasty , and smooth colonies microscopy : in 10% potassium hydroxide mount , the candidal colonies appear oval , budding , and yeast like cells on gram staining : they appear as gram - positive oval yeast like budding cells urease test : candida gives a negative test on carrying out urease test .
numbers of colony forming units were multiplied by the dilution factor to obtain the number of colony forming units/4 cm .
the investigator and the microbiologist were blinded to the allocation of participants to different groups .
the difference in the number of colony forming units of microorganisms between first swab ( baseline before use of cleanser ) and second swab ( after use of cleanser ) was noted to assess the effectiveness of cleansers in reducing the total candida count .
one way analysis of variance ( anova ) followed by tukey 's test were used to compare the reduction of candida count between different denture cleansers .
a difference was considered to be of statistical significance if the p value was < 0.05 .
a total of 50 volunteers participated in the study out of which 82% were females and 18% were males .
figure 1 shows the mean reduction in candida count obtained after using different denture cleansers .
this value was obtained by calculating the difference in the number of colony forming units of microorganisms between the first swab ( baseline before use of cleanser ) and second swab ( after use of cleanser ) .
graph showing mean reduction in total candida count after using denture cleansers in colony forming units/4 cm the mean reduction in total candida count after using denture cleansing tablet was the highest , followed by triphala , aloe vera , cashew leaves , and water , with a reduction of 319.25 10 cfu/4 cm , 292.5 10 cfu/4 cm , 103.67 10 cfu/4 cm , 68.75 10 cfu/4 cm , 13.75 10 cfu/4 cm , respectively .
table 1 shows the comparison of different denture cleansers analyzed using one way anova followed by tukey 's test , and a p value of < 0.05 was considered to be statistically significant .
there was no significant difference between the effectiveness of denture cleansing tablet and triphala ( p > 0.05 ) , and a significant difference between triphala and water ( p < 0.05 ) .
there was no significant difference between the effectiveness of aloe vera , water , and cashew leaf ( p > 0.05 ) .
the requirements of ideal denture cleansers are that they should have antibiofilm activity , exhibit bactericidal and fungicidal effects ; should be non - toxic , compatible with denture materials , short acting , easy to use ; should have an acceptable taste ; and should be cost effective .
review of literature suggests that though the antifungal and antimicrobial activity of triphala , aloe vera , and cashew leaves have been established , the potential use of these products as denture cleansers have not been evaluated . in the present study , though all the denture cleansers showed a reduction in total candida count compared with control , only denture cleansing tablet and triphala showed a statistically significant reduction .
triphala , which is an important therapeutic and antimicrobial aid in various ailments , is a combination of three tropical fruits preparation , which has been established as potent antimicrobial and antifungal agents .
the natural products used in the present study were nontoxic , inexpensive , easy to use , and readily available .
more studies are required to evaluate the long - term effects of these natural - based products as denture cleansers .
in the present study , though aloe vera and cashew leaves showed a reduction of total candida count , only denture cleansing tablet and triphala showed a significant reduction in comparison to control ( water ) .
people with less access to oral hygiene measures will be benefitted by the use of these products .
the potential use of such natural products should be further explored to reduce the microbial load and improve the overall oral health of the people .
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### Summary:
: with an increase in the number of dependent elderly , there is a need to introduce few natural products for denture cleansing , which are easily and economically available .
hence the aim of this study was to compare the anticandidal efficacy of denture cleansing tablet ( sodium bicarbonate and sodium perborate monohydrate ) , triphala ( phyllanthus emblica , terminalia chebula and terminalia belerica fruits powders in equal proportion ) , cashew leaf , aloe vera and water ( control ) on complete dentures of institutionalized elderly .
study population consisted of 50 institutionalized elderly of mangalore , karnataka , with 10 in each group .
swabs were collected from the dentures before and after the use of denture cleansing tablet , triphala , cashew leaf , aloe vera , and water ( control ) .
thereafter , the swabs were cultured on sabouraud dextrose agar and the total candida counts were determined .
denture cleansing tablet and triphala churna showed a statistically significant reduction in candida counts ( p < 0.05 ) .
denture cleansing tablet and triphala churna were found to be more effective .
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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:
: normal tissue function depends on the coordinated action of a large number and diverse variety of cell types that must proliferate , function , and ultimately die at precisely defined times and places , and this intricate choreography relies heavily on a rich and continuous dialogue between individual cells and between cells and their environment .
cell biologists have long assumed that the words of this conversation are largely biochemical in nature , ie , that cells base their actions primarily on the concentrations of soluble signals to which they are exposed
. however , one of the most exciting breakthroughs in cell biology in the past decade is the recognition that the physical microenvironment of a cell , including applied mechanical forces and the geometric arrangement , protein density , and mechanical compliance of the extracellular matrix ( ecm ) , can regulate cell behavior in equally profound ways ( discher et al 2005 ) .
for example , individual mesenchymal stem cells differentiate into adipocytes ( fat cells ) when they are prevented from completely spreading , even when they are saturated with growth factors that would normally induce them to form bone cells ( mcbeath et al 2004 ) .
similarly , mammary epithelial cells assemble into normal tubular structures when cultured in relatively compliant ( soft ) ecms ; when they are cultured in ecms that are slightly more stiff , these cells form abnormal structures , detach from their neighbors , and proliferate more rapidly all hallmarks of a developing breast tumor ( paszek and weaver 2004 ) . for this reason ,
any attempt to control or exploit cell behavior in a technological context must pay attention to how the physical microenvironment influences cell physiology
. viewed another way , physical crosstalk between the cell and its surroundings represents a design parameter that may be modulated to achieve a desired physiological outcome .
the crosstalk between cells and their surroundings is mediated by an intimately connected and interdependent set of structures that range in size from single molecules to networks that span the whole cell over tens of microns .
the coordinated action of these nano - and microstructures lies at the heart of many of the characteristic processes of living cells , including adhesion , motility , and maintenance of shape .
for example , cells adhere to specific extracellular matrix ( ecm ) components through transmembrane integrin proteins , which spatially cluster upon engagement and serve as nucleation sites for focal adhesion complexes between the cell and ecm .
these micron - scale complexes contain literally dozens of distinct proteins that physically connect integrins to the cellular cytoskeleton , sense and biochemically transduce mechanical forces , and regulate the presentation and activity of various transmembrane receptors that initiate signaling ( ingber 2003 ; vogel and sheetz 2006 ) .
as cells spread and grip the ecm , they must assemble strong focal adhesion complexes that are capable of supporting increasing tractional forces generated by cellular contractile elements .
equally importantly , directional cell motility on a planar substrate depends on the ability to assemble focal adhesion complexes at the leading edge of the cell and disassemble them at the trailing edge ( lauffenburger and horwitz 1996 ) .
thus , to dissect the molecular mechanisms through which cells sense and respond to their physical microenvironment , it is critical to understand how all elements in the cytoskeleton , focal adhesions , and the ecm come together in an organized fashion to allow the cell to generate and sense mechanical forces .
this requires the ability to precisely and quantitatively measure a wide variety of biophysical properties , including binding and polymerization kinetics , dynamics , and mechanical properties .
traditionally , the vast majority of these measurements have been obtained in purified systems , ie , systems in which molecular components have been purified and removed from their cellular contexts . while these approaches enable precise , quantitative measurements that have contributed greatly to our understanding of cell structure and function , they can not recapture the spatial and temporal architecture that is essential to transmission of mechanical information in living systems and enables such life - defining processes as locomotion . over the past decade
, however , a remarkable set of technologies has emerged that seeks to satisfy both goals by obtaining quantitative measurements in living cells .
some of these technologies represent increasingly sensitive ways to image and measure the dynamics and mechanics of structures on the molecular scale , and others represent platforms with which to directly manipulate micro - and nanoscale cell structural elements . here
, we review three of these technologies : subcellular laser ablation , advanced live - cell fluorescence imaging methods ( including fluorescence recovery after photobleaching and fluorescent speckle microscopy ) , and cellular micropatterning .
these technologies promise both to dramatically advance our ability to understand the conversation between cells and their physical environment and to build our own vocabulary of commands as we attempt to exploit this knowledge in the design of technologies that interface with living systems .
mechanical inputs from the ecm represent one of the most important and well - studied classes of cues in the cellular microenvironment . because the cellular cytoskeleton confers shape and mechanical properties to the whole cell
, it is absolutely critical to a cell s ability to detect , process , and respond to these mechanical cues .
more specifically , by setting its composition , three - dimensional architecture , and contractile state , the cytoskeleton serves as both a passive structural network through which environmental forces are distributed and an active generator of forces that deform the ecm and permit cell spreading and motility . while it is clear that the cytoskeleton is key to cell structure and mechanics in a global sense , considerably less
is known about the loads borne by specific cytoskeletal filaments in living cells , or how individual filaments contribute to the structure and mechanics of the whole cell . answering these questions requires methods capable of selectively probing and disrupting individual cytoskeletal structures in living cells .
ideally , these methods should be capable of interrogating living cells on the submicron length scale in a minimally invasive fashion without killing them in the process .
pioneered in the late 1970 s by michael berns and colleagues ( strahs and berns 1979 ; koonce et al 1982 ; berns et al 1991 ; berns 1998 ; botvinick et al 2004 ) , and then refined over the next two decades by the laboratories of karsten konig ( konig et al 1999 ; tirlapur et al 2001 ; tirlapur and konig 2002 ) , conly rieder ( khodjakov and rieder 2001 ; faruki et al 2002 ; maiato et al 2005 ) , and others , this technique utilizes a focused laser beam to selectively ablate nano - to microscale structures in living cells .
while the first applications of this method used continuous - wave visible - range or ultraviolet lasers , more recently , pulsed lasers have become the norm . in particular ,
ultrashort laser pulses ( eg , nano - to femtosecond ) are focused through a high - numerical aperture objective lens onto an intracellular target that may be visualized by phase contrast or fluorescence .
material at the focus undergoes nonlinear multiphoton absorption of laser energy , leading to optical breakdown and photoablation .
ideally , the laser energy is delivered quickly enough to prevent energy dissipation by heat transfer , but at a sufficiently low energy and pulse frequency to limit the zone of damage .
for this reason , pulse energy , pulse width , and repetition rate have all been shown to be important parameters in limiting the precision of this method .
for example , in chemically fixed cells , delivery of femtosecond laser pulses at kilohertz repetition rates and at pulse energies ranging from 1.4 nj to 2.3 nj can produce zones of photodamage between 0 and 1 m .
importantly , the spatial values were determined by transmission electron microscopy ( tem ) imaging of cells that had been fixed and fluorescently stained ; regions of cells irradiated at the lowest energies ( 1.4 nj ) were rendered nonfluorescent even though subsequent tem failed to reveal damage , demonstrating that those regions had been photo - bleached rather than damaged ( heisterkamp et al 2005 ) .
thus , in interpreting these experiments , it is important to distinguish between photobleaching and photoablation .
subcellular laser ablation has emerged as a powerful tool for the measurement of mechanical properties of load - bearing cytoskeletal elements in their living , intracellular context .
perhaps the most closely studied cytoskeletal structures by this method are actomyosin stress fiber bundles , which are contractile structures that connect to the cell - ecm interface and enable cells to exert tractional forces on their surroundings . in one of the first applications of laser ablation in living cells , berns and coworkers visualized stress fibers by phase contrast microscopy , irradiated them with a laser microbeam , and observed their retraction and subsequent repair on a time scale of several hours ( strahs and berns 1979 ) .
in later work , they showed that the rate of stress fiber repair depended on the integrity of the microtubule and fine actin cytoskeleton and not , surprisingly , cellular protein synthesis ( koonce et al 1982 ) . in recent work , laser ablation has been used to study the mechanics of single stress fibers in living cells and their contributions to cell shape and ecm strain ( figure 1 ) . here , the authors visualized the actin cytoskeleton in living endothelial cells using yellow fluorescent protein ( yfp)-tagged actin and severed stress fibers at the cell base with femtosecond laser pulses ( kumar et al 2006 ) . following irradiation , the ends of the stress fibers retracted in a straight line ( ie , in parallel with the axis of the fiber ) with viscoelastic recoil dynamics with characteristic times of 1520 sec ; in some cases , it was possible to puncture , rather than incise , stress fibers , yielding holes with diameters as small as 300 nm that distended into ellipses as the weakened stress fiber retracted .
importantly , the degree to which incision of one stress fiber influenced the cytoskeletal architecture and shape of the rest of the cell depended strongly on the compliance of the ecm on which cells were cultured .
for cells cultured on rigid substrates ( eg , glass ) , incision of a single stress fiber , or even multiple parallel stress fibers , produced essentially no rearrangements in cell structure .
conversely , incision of even one stress fiber in cells cultured on compliant ( 4 kpa ) polyacrylamide substrates produced cellular elongation and widespread rearrangements of cytoskeletal structures many microns from the site of incision . in the latter case , traction force microscopy measurements revealed that dissipation of tractional stresses into the ecm substrate were concentrated near sites of stress fiber insertion into the ecm ; ie , focal adhesion complexes . in related studies ,
subcellular laser ablation was used to locally dissipate tension on focal adhesions by severing adjacent stress fibers , resulting in accelerated turnover of specific focal adhesion proteins .
this result was consistent with results obtained upon global dissipation of cellular tension through the use of compliant culture substrates or through treating the cell with contractility - inhibiting drugs ( lele et al 2006a ) .
for example , laser ablation has been used to disrupt various parts of the mitotic spindle in dividing yeast in order to determine the distribution of tensile and compressive loads among astral and kinetochore microtubules ( khodjakov et al 2004 ; tolic - norrelykke et al 2004 ) .
more recently , this method has been applied to cortical microtubules , which play mechanical roles in establishing and stabilizing cellular structure .
( botvinick et al 2004 ) used a picosecond laser to irradiate and sever cytoplasmic microtubules tagged with various green fluorescent protein variants , including yfp and cyan fluorescent protein ( cfp ) ; as expected , following microtubule incision , one of the severed ends rapidly depolymerized , corresponding to the exposure of a bare minus end .
interestingly , based on subsequent tem imaging of the ablated cells , the degree of damage differed significantly depending on whether cfp or yfp was used as a fluorescent tag , and both cases differed from green fluorescent protein ( gfp ) .
this strongly suggested that the mechanism of photodamage is different for each fluorophore , which in turn results from differences in their respective absorption spectra associated with differences in amino acid composition .
( heisterkamp et al 2005 ) used a femtosecond laser to sever a curved gfp - tagged microtubule beneath the nucleus of living cells . following laser severing ,
the bent microtubule rapidly straightened and then depolymerized , reflecting the release of stored elastic bending energy .
an important step in elucidating the influence of the physical microenvironment on cell function is to understand both the dynamics of structural elements in living cells , and how mechanical loads borne by these structures translate into specific biochemical changes at precise cellular times and locations .
first , traditional biochemical assays rely on average measurements of populations of cells at fixed points in time , which , by definition , fail to capture information about events in specific portions of specific cells .
second , structures may appear relatively static macroscopically despite the presence of active and rapid molecular - scale remodeling events , such as subunit binding and unbinding ; thus , even prolonged imaging of subcellular structures may fail to capture these subtle yet potentially important dynamics .
third , when fluorescently labeled , many cellular structural elements such as microtubules and intermediate filaments fluoresce along their entire length , thereby offering little to no negative contrast to track internal rearrangements in the body of the filament .
fluorescence recovery after photobleaching ( frap ) has proved a powerful means to address all of these issues . in frap ,
regions of a fluorescently - tagged structure are selectively rendered nonfluorescent through irradiation with a pulse of high - intensity light at the excitation wavelength of the fluorophore , thereby photobleaching the population of fluorescent subunits in the region and rendering them optically invisible . unlike subcellular laser ablation , frap does not destroy material or compromise protein function and only affects fluorescently tagged molecules whose excitation wavelength corresponds to the wavelength of irradiation . because the loss of fluorescence in a bleached fluorophore is permanent on the time scale of the experiment , any recovery of fluorescence in the targeted structure must be due to a combination of the departure of the bleached subunits and the arrival of new , unbleached fluorophores into the bleached region .
both of these processes may result from either a combination of transport of material within the structure ( eg , diffusion ) or exchange of subunits between the material and the surrounding medium ( ie , binding and unbinding ) .
thus , given a physical model that describes the dynamics of subunit binding and dynamics , frap data ( fluorescence vs. time ) may be fitted to the model to extract kinetic parameters that describe the binding and transport properties of the labeled molecule .
frap has been extensively applied to interrogate the dynamics of complex and heterogeneous cytoskeletal systems , particularly intermediate filaments and actin - based structures . in one study ( yoon et al 2001 )
, frap was used to probe the network dynamics of keratin intermediate filaments within cultured epithelial cells .
here , cells were transfected with fluorescently - tagged keratin subunits which then incorporated into the tonofibril network ( parallel bundles of keratin - rich cables ) of cultured epithelial cells , thereby labeling the tonofibrils .
when a line was bleached across many tonofibrils , the bleached spots recovered very slowly ( half - times of 12 hours ) , thus yielding a relatively stable fiduciary marker to track internal tonofibril dynamics .
surprisingly , bleached zones on adjacent tonofibrils often moved in opposite directions and at different rates , thereby revealing for the first time the complexities of assembly of keratin transport and turnover in these cells .
similarly - inspired studies with the nuclear envelope proteins lamin a and lamin b1 provided insights into the molecular - scale dynamics of envelope assembly and disassembly during cell division ( moir et al 2000 ) .
frap has also yielded tremendous insight into the internal dynamics of actin - based structures relevant to cell adhesion , mechanics , and motility , including actomyosin stress fiber bundles .
peterson et al ( peterson et al 2004 ) expressed fluorescently - tagged -actinin and myosin , two actin - binding proteins found in stress fibers , in cultured fibroblasts and used frap to investigate the binding kinetics of these proteins to various regions of the stress fibers .
interestingly , they found that both proteins exchange more rapidly at the center of stress fibers than near their peripheral attachments to focal adhesions ; together with high - resolution imaging of myosin distributions during cell contraction , the frap data enabled the authors to demonstrate that stress fibers are capable of simultaneously stretching and contracting along their length . in another study ,
frap was used to examine the exchange kinetics of -smooth - muscle - actin ( sma ) in the presence of an sma peptide fragment ( clement et al 2005 ) . by showing that a peptide derived from the amino terminal sequence of sma slowed recovery of sma fluorescence and therefore retarded sma exchange , the authors were able to develop a model in which the amino terminus of sma facilitates incorporation of the protein into stress fibers .
more recently , frap measurements have helped to elucidate the influence of the mechanical microenvironment , including mechanical force and ecm rigidity , on the unbinding kinetics of specific focal adhesion proteins at the cell - ecm interface .
these studies were made possible by new innovations in the acquisition and analysis of frap data that permit separation of contributions from molecular binding and diffusion to the recovery curve ( lele et al 2004 ) . in one study ,
the authors measured dissociation rates of zyxin and vinculin from focal adhesions before and after dissipating intracellular tension by a variety of methods , including adding contractility inhibitors , culturing the cells on compliant ecms , and severing attached stress fibers by laser ablation ( lele et al 2006a ) .
these studies revealed that the unbinding rate of zyxin , but not vinculin , increased when tension on the stress fiber was released .
thus , zyxin was postulated to serve as a molecular mechanosensor whose binding properties , and presumably conformational properties , are highly sensitive to the tensile state of the cell ( figure 2 ) .
this approach has since been extended to the measurement of binding interactions between nuclear histone proteins and chromatin , thereby lending new insight into the biophysical basis of transcriptional control ( lele et al 2006b ) .
fluorescent speckle microscopy ( fsm ) represents another powerful tool for the characterization of the microscale internal dynamics of cellular structural elements ( danuser and waterman - storer 2006 ) ( figure 3 ) .
in contrast to frap , which derives its ability to probe molecular dynamics from the selective inactivation of fluorophores within a continuously fluorescent structure , fsm follows the motions of fluorescent subunits within an otherwise nonfluorescent structure ; this discontinuous fluorescence gives the structure a speckled appearance from which the name of the method is derived .
intracellular structures are typically made fluorescent in fsm experiments by either microinjecting a very low concentration of fluorescently - tagged proteins into a cell , or by expressing the protein as a gfp fusion construct at very low levels .
while fsm may be performed with a wide - field epifluorescence microscope , it is increasingly being used in the context of total internal reflection fluorescence microscopy , which permits high - resolution imaging of structures at the cell - substrate interface such as the cortical cytoskeleton and focal adhesions .
fsm has been used with great success to follow the internal dynamics of microtubules ( waterman - storer and salmon 1998 ) , actin filaments within cellular networks ( ponti et al 2004 ) , and a wide variety of focal adhesion proteins , including vinculin , paxillin , and talin ( geiger et al 2001 ) .
whereas early fsm experiments were analyzed by manually tracking the motions of fluorescent particles , advanced automated tracking algorithms have emerged which allow rapid and highly quantitative interpretation of fsm data , leading to the direct estimation of local cellular viscoelastic properties and measurements of the degree of kinematic coupling between different cellular structural complexes ( waterman - storer and salmon 1998 ) .
fsm has uncovered particularly exciting details of the dynamics of the actin cytoskeleton in migrating cells . in a seminal fsm study
( ponti et al 2004 ) , rhodamine - actin was microinjected into cultured epithelial cells , and the resulting actin speckles were utilized to track zones of actin polymerization and depolymerization near the leading edges of cells during migration . by carefully tracking the growth , disappearance , and trajectories of actin speckles ,
the authors constructed high - resolution spatial maps of actin flow which defined two distinct dynamic networks : the lamellipodium , a zone of fast , retrograde actin flow within 13 m from the leading edge of the cell , and the lamella , an adjacent and much broader zone of slower retrograde flow .
subsequent immunofluorescence imaging revealed that the lamellipodium was enriched in the actin branch - promoting factors adf / cofilin and arp 2/3 , and the lamella was enriched with the contractile proteins myosin ii and tropomyosin .
these observations , together with pharmacological inhibition data , supported a model in which the lamellipodium gives rise to protrusion of the leading edge , and the lamella drives advancement of the whole cell through actomyosin contraction .
thus , detailed analysis of a simple yet elegant fsm experiment provided rich and novel insight into the contributions of different portions of the actin cytoskeleton to coordinated cell movement .
all of the above methods represent ways of studying the molecular aspects of crosstalk between cells and their physical microenvironment by observing and manipulating structures inside living cells .
we now turn to technologies that have been created to tap into this crosstalk by engineering the geometry of the extracellular matrix of cells . in some cases ,
these approaches have been used to study the role of cellular structure in driving cell function , and in others they have been used to measure physical interactions between cells and their surroundings at the micro - and nanoscale .
direct patterning of extracellular matrix proteins by microcontact printing offers a powerful way to control the geometry of single cells and small groups of cells in two - dimensional culture .
analogous to conventional ink - stamp printing , microcontact printing is based on the controlled deposition of ecm proteins by apposition of a protein - coated stamp with a cell culture substrate ( eg , glass ) and subsequent passivation of the non - stamped regions of the substrate . by controlling the topographical relief pattern on the stamp
, one may create micron - sized islands of defined location , size , and shape that in turn dictate the distribution and geometry of cells cultured on the substrate ( chen et al 1997 ; lauer et al 2001 ; brock et al 2003 ; mcbeath et al 2004 ) .
typically , photolithography is used to create the inverse of the desired relief pattern on a silicon wafer that will serve as a master . a layer of photoresist ( eg , su-8 ) is spun onto the wafer at a controlled thickness .
the photoresist layer is then selectively exposed to uv light via a photomask of the desired pattern .
finally , the resist is developed by application of a developer solution that , in the case of negative resist , removes the unexposed regions of the photoresist , leaving behind the desired microtopographical pattern on the wafer .
an elastomer , frequently poly(dimethylsiloxane ) ( pdms ) , is then cast and crosslinked atop the master ; separation of the polymer and master yields a flexible stamp with the desired microtopographical pattern on its surface .
importantly , many pdms stamps can be cast from the same master making this a highly cost - effective , reproducible , and high - throughput means of pattering proteins .
often , in order to facilitate adsorption of ecm proteins , the surface of the pdms stamp is modified from a methyl - terminated surface to a hydrophilic hydroxyl - terminated surface with either air plasma or ultraviolet ozone ( ye et al 2006 ) . following passive adsorption of ecm protein ,
the coated surface is placed into conformal contact with a substrate , stamping the ecm protein into the desired pattern .
non - stamped regions of the substrate are often passivated with an amphiphilic block copolymer ( eg , pluronic ) to inhibit protein adsorption and cell binding .
ingber , whitesides and coworkers have used microcontact printing to create two - dimensional fibronectin islands of defined geometry for the culture of single cells , a technique that has enabled them to study the effect of cell size on cell fate independent of ecm protein density , cell - cell contacts , or media conditions ( singhvi et al 1994 ; chen et al 1997 ) ( figure 4a ) .
endothelial cells cultured on the adhesive islands conformed to the size and geometry of the stamped ecm , and cell spreading could be promoted by patterning either a single , cell - sized ecm island ( eg , 900 m ) or multiple small focal adhesion - sized islands distributed over a cell - sized area .
importantly , spreading area strongly influenced whether cells proliferated or underwent apoptosis ; specifically , as cells were allowed to spread to larger and larger areas , the frequency of proliferating cells increased whether the ecm was presented as a large , continuous island or multiple , discontinuous islands distributed over a large area ( chen et al 1997 ) .
mcbeath and coworkers ( mcbeath et al 2004 ) leveraged this approach to investigate the role of cell area in driving differentiation of human mesenchymal stem cells ( hmscs ) . remarkably , they found that hmscs confined to small ( 1024 m ) islands appeared round and differentiated exclusively into adipocytes , whereas hmscs cultured on large ( 10,000 m ) islands spread and differentiated exclusively into osteoblasts .
cells cultured on islands of intermediate size ( 2025 m ) yielded mixed populations of adipocytes and osteoblasts .
the authors hypothesized that these cell area - dependent effects were due to changes in intracellular contractility ; ie , cells allowed to spread to larger areas generated more contractile forces than those confined to small areas . to test this hypothesis directly , the authors manipulated hmsc contractility by controlling the activity of the small gtpase rhoa , which strongly promotes actomyosin activation , by transfecting hmscs with either a constitutively active or a dominant negative version of rhoa .
cells made to express constitutively active rhoa predominantly differentiated into osteoblasts , while cells made to express dominant negative rhoa predominantly differentiated into adipocytes .
remarkably , this result held even when the hmscs were cultured in media normally expected to promote proliferation or differentiation into the other cell type ; eg , hmscs with abrogated rhoa activity differentiated into adipocytes even when cultured in osteogenic media .
thus , the degree to which hmscs can generate tensile forces against the ecm figures centrally in the fate decision between adipogenesis and osteogenesis . these studies , which provided fundamental insight into our understanding of hmsc physiology , would not have been possible without microcontact printing technology .
more recent studies have taken advantage of microcontact printing to control the geometry and distribution of individual focal adhesion complexes between the cell and ecm ( goffin et al 2006 ) ( figure 4b ) . here
, arrays of fibronectin islets spaced several microns apart with a constant width ( 1.25 m ) and lengths ranging from 220 m were printed on a rigid , planar substrate .
cells cultured on these substrates formed focal adhesion complexes that assumed the size and shape of the patterned islands .
varying the length of the focal adhesion sites influenced the biochemical composition of the associated intracellular stress fiber bundles ; in particular , stress fibers associated with long ( > 8 m ) islands , and hence long focal adhesion complexes , preferentially incorporated -smooth muscle actin ( -sma ) , a marker of high contractility .
the robustness of this system allowed for the simultaneous alteration of several mechanical cues including ecm elasticity and density as well as islet spacing and size . by systematically varying each parameter , the authors demonstrated that islet size dominantly influenced -sma localization to stress fibers .
direct patterning of extracellular matrix proteins by microcontact printing offers a powerful way to control the geometry of single cells and small groups of cells in two - dimensional culture .
analogous to conventional ink - stamp printing , microcontact printing is based on the controlled deposition of ecm proteins by apposition of a protein - coated stamp with a cell culture substrate ( eg , glass ) and subsequent passivation of the non - stamped regions of the substrate . by controlling the topographical relief pattern on the stamp
, one may create micron - sized islands of defined location , size , and shape that in turn dictate the distribution and geometry of cells cultured on the substrate ( chen et al 1997 ; lauer et al 2001 ; brock et al 2003 ; mcbeath et al 2004 ) .
typically , photolithography is used to create the inverse of the desired relief pattern on a silicon wafer that will serve as a master . a layer of photoresist ( eg , su-8 ) is spun onto the wafer at a controlled thickness .
the photoresist layer is then selectively exposed to uv light via a photomask of the desired pattern .
finally , the resist is developed by application of a developer solution that , in the case of negative resist , removes the unexposed regions of the photoresist , leaving behind the desired microtopographical pattern on the wafer .
an elastomer , frequently poly(dimethylsiloxane ) ( pdms ) , is then cast and crosslinked atop the master ; separation of the polymer and master yields a flexible stamp with the desired microtopographical pattern on its surface .
importantly , many pdms stamps can be cast from the same master making this a highly cost - effective , reproducible , and high - throughput means of pattering proteins .
often , in order to facilitate adsorption of ecm proteins , the surface of the pdms stamp is modified from a methyl - terminated surface to a hydrophilic hydroxyl - terminated surface with either air plasma or ultraviolet ozone ( ye et al 2006 ) . following passive adsorption of ecm protein ,
the coated surface is placed into conformal contact with a substrate , stamping the ecm protein into the desired pattern .
non - stamped regions of the substrate are often passivated with an amphiphilic block copolymer ( eg , pluronic ) to inhibit protein adsorption and cell binding .
ingber , whitesides and coworkers have used microcontact printing to create two - dimensional fibronectin islands of defined geometry for the culture of single cells , a technique that has enabled them to study the effect of cell size on cell fate independent of ecm protein density , cell - cell contacts , or media conditions ( singhvi et al 1994 ; chen et al 1997 ) ( figure 4a ) .
endothelial cells cultured on the adhesive islands conformed to the size and geometry of the stamped ecm , and cell spreading could be promoted by patterning either a single , cell - sized ecm island ( eg , 900 m ) or multiple small focal adhesion - sized islands distributed over a cell - sized area .
importantly , spreading area strongly influenced whether cells proliferated or underwent apoptosis ; specifically , as cells were allowed to spread to larger and larger areas , the frequency of proliferating cells increased whether the ecm was presented as a large , continuous island or multiple , discontinuous islands distributed over a large area ( chen et al 1997 ) .
mcbeath and coworkers ( mcbeath et al 2004 ) leveraged this approach to investigate the role of cell area in driving differentiation of human mesenchymal stem cells ( hmscs ) .
remarkably , they found that hmscs confined to small ( 1024 m ) islands appeared round and differentiated exclusively into adipocytes , whereas hmscs cultured on large ( 10,000 m ) islands spread and differentiated exclusively into osteoblasts .
cells cultured on islands of intermediate size ( 2025 m ) yielded mixed populations of adipocytes and osteoblasts .
the authors hypothesized that these cell area - dependent effects were due to changes in intracellular contractility ; ie , cells allowed to spread to larger areas generated more contractile forces than those confined to small areas . to test this hypothesis directly
, the authors manipulated hmsc contractility by controlling the activity of the small gtpase rhoa , which strongly promotes actomyosin activation , by transfecting hmscs with either a constitutively active or a dominant negative version of rhoa . cells made to express constitutively active rhoa predominantly differentiated into osteoblasts , while cells made to express dominant negative rhoa predominantly differentiated into adipocytes .
remarkably , this result held even when the hmscs were cultured in media normally expected to promote proliferation or differentiation into the other cell type ; eg , hmscs with abrogated rhoa activity differentiated into adipocytes even when cultured in osteogenic media .
thus , the degree to which hmscs can generate tensile forces against the ecm figures centrally in the fate decision between adipogenesis and osteogenesis
. these studies , which provided fundamental insight into our understanding of hmsc physiology , would not have been possible without microcontact printing technology .
more recent studies have taken advantage of microcontact printing to control the geometry and distribution of individual focal adhesion complexes between the cell and ecm ( goffin et al 2006 ) ( figure 4b ) . here
, arrays of fibronectin islets spaced several microns apart with a constant width ( 1.25 m ) and lengths ranging from 220 m were printed on a rigid , planar substrate .
cells cultured on these substrates formed focal adhesion complexes that assumed the size and shape of the patterned islands . varying
the length of the focal adhesion sites influenced the biochemical composition of the associated intracellular stress fiber bundles ; in particular , stress fibers associated with long ( > 8 m ) islands , and hence long focal adhesion complexes , preferentially incorporated -smooth muscle actin ( -sma ) , a marker of high contractility . the robustness of this system allowed for the simultaneous alteration of several mechanical cues including ecm elasticity and density as well as islet spacing and size . by systematically varying each parameter
while the earliest applications of soft lithography to cell biology focused almost exclusively on the control of cell size and shape , more recent approaches have sought to measure functional properties , including the spatial distribution of cell - ecm traction forces .
for example , tan and coworkers ( tan et al 2003 ) developed a microfabricated post array detector ( mpad ) system to measure cell traction forces and contractility .
for this technology , the authors fabricated arrays of deformable , cell - adhesive microposts , schematically similar to a bed of needles ( figure 5a ) . as cells spread and exerted tractional forces on these microposts , they elastically deformed them ; from the magnitude and direction of the deformation , the tractional force on a given micropost could be directly determined .
the mechanical properties of each mpad system , and therefore the range of measurable forces , could be tuned through the geometry of the constituent microposts ( eg , 210 m in diameter and 350 m in height ) .
furthermore , by using modified microcontact printing methods to selectively stamp fibronectin islands onto each mpad , the researchers added another dimension of control by controlling of area available for cell spreading . by varying the area of the stamped islands
, the authors demonstrated that the total area of focal adhesions regulated the magnitude of traction force across the whole cell .
moreover , as spreading area increased , total tractional force increased ; as expected , tractional force could be altered by manipulating intracellular rhoa activity .
a similar technique was subsequently used to study traction forces exerted by an epithelial monolayer ( du roure et al 2005 ) ( figure 5b ) . here , the authors fabricated a substrate of narrow , densely packed pdms micropillars ( 2 m diameter , 1 m post - post spacing ) in an effort to improve the spatial resolution of the force measurements . in an important extension of the earlier technology ,
the authors examined cell - ecm tractional mechanics in a monolayer patch of epithelial cells , rather than only those of isolated cells .
the authors found that the greatest force was exerted at the edge of the monolayer , and that tractional forces exerted by these cells exceeded those generated by isolated cells , suggesting cooperative mechanical behavior within the monolayer .
this finding was later confirmed and significantly extended in a multicellular study with the mpad technology ( nelson et al 2005 ) .
surface patterning can also be a useful tool on a scale unachievable with microcontact printing .
arnold and colleagues ( arnold et al 2004 ) utilized a diblock copolymer micelle self - assembly system to pattern 8 nm diameter gold nanodots in a rigid hexagonal pattern with precise interparticle spacings ( 28 , 53 , 73 , 85 nm ) .
the dots were then functionalized with cyclic arginine - glycine - aspartate ( rgd)-containing peptides that enabled ligation of transmembrane integrins . importantly
, the small size of each dot permitted conjugation of a single peptide , which in turn bound only a single integrin receptor .
thus , by controlling the spacing of the dots , the authors were able to precisely manipulate spacing between adjacent integrins .
as expected , small spacing between dots permitted enhanced integrin clustering , which in turn promoted cell adhesion and spreading as well as formation of robust focal adhesion complexes and stress fiber bundles .
conversely , greater separation distances between the dots ( 73 nm ) precluded integrin clustering and severely limited cell attachment and spreading .
traditional approaches to studying cell physiology have emphasized treating cultured cells with defined concentrations of soluble cues and characterizing their responses .
while these studies have established the foundation for our modern understanding of receptor - mediated signal transduction , hormonal physiology , and other fundamental aspects of cell biology , it is becoming increasingly clear that these kinds of inputs do not tell the whole story .
in particular , the physical microenvironment in which cells exist can provide signals that strongly modulate or even oppose the effects of these soluble cues , suggesting that elements of the physical microenvironment may provide an important but largely underappreciated role in regulating cell behavior and consequently tissue assembly , development , and pathology .
this growing recognition is spawning an entirely new generation of cell biological experiments in which parameters such as ecm stiffness , geometry , and topography have been included as experimental variables , which has in turn created a need for entirely new platforms and tools to create the appropriate experimental conditions .
because much of the cellular machinery that senses , processes , and responds to these physical inputs range in size from single molecules to tens of microns , methods capable of probing nano - and microscale phenomena in living cells have proven tremendously useful in elucidating these signaling mechanisms and serving as a handle with which to engineer cell behavior . in this review , we have discussed three foundational technologies that are beginning to make particularly significant impact : subcellular laser ablation , advanced live - cell fluorescence methods including frap and fsm , and cellular micropatterning .
the first two methods have enabled examination of subcellular mechanics and dynamics at unprecedented spatial and temporal resolution , and the third method has permitted both the precise engineering of cell structure and quantitative measurement of the mechanics of cell - ecm adhesion and traction .
several challenges remain to be tackled in the future . in the case of subcellular laser ablation
, efforts are ongoing to increase the spatial and temporal resolution of material destruction by using pulsed lasers that offer optimal combinations of pulse width , repetition rate , and energy ( vogel et al 2005 ) .
moreover , because lasers may be used for capturing particles ( eg , through an optical trap ) , cell stretching , and a variety of other processing modalities , efforts are beginning to emerge to incorporate laser ablation into multimodular laser processing systems , enabling microdissection and capturing capabilities in a single platform ( stuhrmann et al 2006 ) .
similarly , because laser ablation is a multiphoton process that may be induced with the same sorts of near - infrared lasers that are typically used for multiphoton imaging , it has become attractive to develop combined systems for imaging and ablation . for example , the same femtosecond laser system was recently used to image drosophila melanogaster embryos by both third harmonic generation and two - photon modalities as well as to ablate multicellular regions of the embryo ( supatto et al 2005 ) . in this way
, the authors were able to correlate expression of a fluorescent , mechano - sensitive reporter gene with local disruptions of the multicellular force balance between cells in different portions of the embryo .
finally , one of the key limitations of subcellular laser ablation is the lack of intrinsic molecular specificity ; in other words , all material at the laser focus is destroyed rather than specifically - tagged macromolecules . here ,
a complementary technique known as chromophore assisted laser inactivation ( cali ) is beginning to address this need ; cali is based on irradiation of a fluorophore - tagged intracellular target at the fluorophore s excitation wavelength , but at a much higher intensity than would be required for imaging ( rajfur et al 2002 ; tour et al 2003 ; tanabe et al 2005 ; tour 2005 ) .
the resulting laser - induced photochemical reaction leads to highly localized production of short - lived reactive oxygen species , which then inactivate the tagged protein .
first , beyond tracking the dynamics of single structural elements , frap and fsm are increasingly being used to study correlations between the dynamics of different structural complexes in relation to one another .
for example , danuser , waterman - storer and colleagues have begun to fluorescently label and simultaneously obtain fsm data for both actin and focal adhesion proteins in an effort to understand how focal adhesions mediate mechanical coupling between the cytoskeleton and ecm ( danuser and waterman - storer 2006 ) .
moreover , frap has been combined with various mechanical measurements or perturbations to gain insight into the connection between intracellular molecular dynamics and communication with the physical microenvironment .
earlier , we discussed the combination of frap with sla and contractility - inhibiting drugs to study mechanical regulation of focal adhesion turnover ( lele et al 2006a ) .
frap has also recently been combined with osmotic pressure manipulations to probe the effect of mechanical force on lipid mobility in outer hair cells ( de monvel et al 2006 ) , and frap has been used in parallel with optical trapping methods to correlate focal adhesion protein turnover with force - induced cytoskeletal remodeling ( von wichert et al 2003 ) . with the expanding battery of methods to measure and deliver force to cells at ever - smaller length scales , these types of studies will increase and promise to revolutionize our understanding of how cells couple mechanics and biochemistry on the nanoscale .
one important challenge that remains is to develop patterning strategies that realistically capture the architecture of multicellular tissues .
for example , nelson and coworkers have cultured endothelial cells on micron - to - millimeter - sized ecm islands , thereby permitting adhesion of many cells in a confined area ( nelson et al 2005 ) .
careful examination of proliferation rates in different portions of the island revealed that cells proliferate most rapidly at the edges , even when n - cadherin - mediated cell - cell contacts were broken .
finite - element calculations and mpad force measurements demonstrated that cells at the edges of the islands also experienced the highest net mechanical forces , suggesting an intrinsic connection between mechanical force and cell fate determination .
micropatterning strategies are also increasingly being used to support co - culture of heterogeneous collections of cells , in an effort to work towards bottom - up engineering of functional tissues ( bhatia et al 1998 ; bhatia et al 1999 ; tourovskaia et al 2003 ) .
perhaps the greatest unmet challenge in this area is to develop three - dimensional patterning strategies for single cells with precise control of ecm geometry and biochemistry .
the creation of microwell - like structures that simulate a three - dimensional environment but still allow controlled ecm biochemistry while isolating cells appears to be one promising approach ( ostuni et al 2001 ) ; the culture of cells on substrates with topographically - defined three - dimensional structures is certainly another ( norman and desai 2005 ; norman and desai 2006 ) .
the intersection between cell biology and the micro - and nanosciences has never been greater .
as cell biologists and bioengineers seek to understand the molecular - scale mechanisms that facilitate crosstalk between cells and their physical microenvironment with greater precision and sophistication , tools designed to interface with cells at mesoscopic length scales will become indispensable .
while the technologies described in this review all began as highly specialized methods and in many cases were first developed by physicists and engineers , they are all rapidly becoming accessible to traditional cell biologists and are being closely integrated with the standard tools of cell and molecular biology .
we are headed toward a future in which the well - rounded practice of cell biology will require comfort and facility with the micro - and nanotechnologies ; if the nascent efforts described in this review are any indication , this will be a bright future indeed for our understanding of cellular structure and function .
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### Summary:
: the structure , physiology , and fate of living cells are all highly sensitive to mechanical forces in the cellular microenvironment , including stresses and strains that originate from encounters with the extracellular matrix ( ecm ) , blood and other flowing materials , and neighbouring cells .
this relationship between context and physiology bears tremendous implications for the design of cellular micro - or nanotechnologies , since any attempt to control cell behavior in a device must provide the appropriate physical microenvironment for the desired cell behavior .
cells sense , process , and respond to biophysical cues in their environment through a set of integrated , multi - scale structural complexes that span length scales from single molecules to tens of microns , including small clusters of force - sensing molecules at the cell surface , micron - sized cell - ecm focal adhesion complexes , and the cytoskeleton that permeates and defines the entire cell .
this review focuses on several key technologies that have recently been developed or adapted for the study of the dynamics of structural micro - and nanosystems in living cells and how these systems contribute to spatially - and temporally - controlled changes in cellular structure and mechanics .
we begin by discussing subcellular laser ablation , which permits the precise incision of nanoscale structural elements in living cells in order to discern their mechanical properties and contributions to cell structure .
we then discuss fluorescence recovery after photobleaching and fluorescent speckle microscopy , two live - cell fluorescence imaging methods that enable quantitative measurement of the binding and transport properties of specific proteins in the cell .
finally , we discuss methods to manipulate cellular structural networks by engineering the extracellular environment , including microfabrication of ecm distributions of defined geometry and microdevices designed to measure cellular traction forces at micron - scale resolution . together , these methods form a powerful arsenal that is already adding significantly to our understanding of the nanoscale architecture and mechanics of living cells and may contribute to the rational design of new cellular micro - and nanotechnologies .
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: hypertension contributes significantly to global cardiovascular morbidity and mortality . it appears to have a multifaceted connection with endothelial dysfunction that arises before the development of adverse cardiovascular events .
hypertension is associated with endothelial dysfunction in the peripheral , coronary , and renal circulations in the majority of studies , indicating an important mechanism whereby hypertension promotes the development of vascular disease [ 14 ] .
the endothelium is currently recognized to be essential for the regulation of the vascular tone and structure .
functional and structural vascular changes can develop in the presence of cardiovascular risk factors , enhancing the process of atherosclerosis .
in this situation , there is a imbalance between endothelium - derived nitric oxide ( no ) and other vasoprotective factors .
moreover , an excessive production of proinflammatory and vasoconstrictors substances such as angiotensin ii , endothelin 1 ( et-1 ) , and reactive oxygen species ( ros ) may contribute to impairment of endothelial function , increasing the peripheral vascular resistance which contributes to blood pressure raise and cardiovascular remodeling .
in fact , endothelial dysfunction is one of the main characteristics of chronic hypertension , and it is characterized by impaired no bioactivity determined by increased levels of ros .
other systems contribute to this imbalance such as renin - angiotensin and et-1 which may participate in the pathogenesis of endothelial dysfunction .
endothelial dysfunction is not specific to primary hypertension since it may be associated with other risk factors and cardiovascular diseases .
furthermore , there is no correlation between the severity of endothelial dysfunction and blood pressure levels .
these two considerations indicate that blood pressure raise is not determined by impairment of endothelial function . on the other side
, it has been reported that an impaired response to acetylcholine correlates with carotid intima - media thickening in patients with essential hypertension .
the presence of coronary endothelial dysfunction has also been associated with cardiovascular events in longitudinal studies .
therefore , further studies are required to ascertain a direct relationship between endothelial dysfunction and cardiovascular events in patients with essential hypertension .
primary hypertension is characterized by an increase in peripheral vascular resistance . in animal models of hypertension small arteries ( lumen diameter between 100 and 400 m ) develop lesions induced by hypertension , and can be subjected to ex vivo studies .
the main determinant of an increase in peripheral vascular resistance is the reduction in lumen diameter . according to poiseuille 's law
, resistance varies inversely with the fourth power of the blood vessel radius . as a consequence , small reductions in vascular lumen
three important vascular components are affected by hypertension : vascular structure , vascular mechanics ( stiffness ) , and vascular function .
structural modifications involve the reduction of lumen diameter and the thickening of the vascular media , causing an increase in the media / lumen ratio . the increase in media / lumen ratio can result from a reduction of external diameter , causing a narrowing of the lumen without an increase in total diameter ( eutrophic remodelling ) or can occur due to media thickening ( hypertrophic remodeling ) .
hypertension can also determine modifications in the mechanical properties of an artery , promoting an increase in vascular stiffness .
these modifications can involve the expression and localization of extracellular matrix components , such as collagen and integrins .
the hyperactivity of the renin - angiotensin system is the main trigger for these alterations .
in addition , it has been previously demonstrated that angiotensin ii - induced vascular changes were at least partially prevented by aldosterone antagonism , indicating that some vascular actions of angiotensin ii may be mediated by aldosterone . on the other hand ,
functional impairment reflects a reduction in vasodilation induced by nitric oxide , also called endothelium - dependent response , measured by the acetylcholine response curve .
no is one of the most important vasodilating substances released by the endothelium , acting as a vasodilator and inhibiting growth and inflammation . impaired endothelial function has been directly associated with decreased bioavailability of no which can be originated mainly from oxidative stress and inflammation .
in fact , c - reactive protein has been shown to diminish endothelial no synthase ( enos ) , the enzyme that produces no using l - arginine as substrate . moreover , both processes are connected since reactive oxygen species ( ros ) are able to upregulate intercellular adhesion molecule1 ( icam-1 ) , vascular adhesion molecule1 ( vcam-1 ) , and macrophage chemoattractant peptide1 ( mcp-1 ) . in human hypertension and in animal models of hypertension , nad(p)h
oxidase has been demonstrated to be the main source for oxidative excess , although other sources , such as xanthine oxidase and mitochondria , have also been described [ 21 , 22 ] . in experimental models of hypertension with hyperactivity of renin - angiotensin system , such as angiotensin ii - infused rats ,
animal models of hyperhomocysteinemia have been associated with endothelial dysfunction even with no elevation of blood pressure .
mild hyperhomocysteinemia has also been linked to stiffer small arteries with increased collagen deposition in the vascular wall .
it is well known that no is a volatile substance , with a very short half - life .
therefore , its bioavailability is usually evaluated by measuring the vasodilation induced by the local no production stimulated by specific external mechanical and pharmacological agent , that is , through vascular reactivity tests .
the main purpose of large arteries is to transport a satisfactory blood supply from the heart to peripheral tissues .
in addition to conduit function , large arteries have a cushioning function that consists to transform the pulsatile flow of arterial vessels into the steady flow required for oxygen supply .
interactions between macro- and microvascular changes seem to contribute to end - organ damage in hypertension .
the properties of conduit arteries are affected by hypertension resulting in reduced arterial compliance and distensibility . at the microvascular level ,
central pulse pressure may be transmitted to microcirculation in circumstances where the autoregulatory mechanisms normally protecting vital organs are offset .
in fact , a microvascular disease is commonly observed in association with end - organ damage .
after ventricular ejection , blood pressure propagates along the arterial tree as a wave . mainly at arteriolar branching , this wave may be reflected and then becomes retrograde . in young individuals ,
the wave summation takes place in early diastole , thus improving the diastolic coronary perfusion without disturbing cardiac afterload .
a stiffer aorta implicates in greater pulse wave velocity , causing the reflections to occur in late systole rather than in diastole as in healthy subjects . under this condition ,
it has been hypothesized that increased arterial stiffness of the large arteries may lead to microvascular changes due to increased pulsatile flow
. pulse pressure and mean arterial pressure ( map ) have been considered risk factors for cardiovascular disease .
map is the steady component of the blood pressure curve and it is determined by cardiac output and microvascular resistance . on the other hand ,
pulse pressure is the pulsatile component that is determined by left ventricular ejection , the compliance of the large arteries , and the intensity of wave reflections from the microcirculation .
. showed that forearm flow - mediated dilation ( fmd ) responses were affected by arterial stiffness .
in addition , parvathaneni et al . showed a linear correlation between fmd responses and both small and large arterial stiffness . on the other hand ,
neither large nor small arterial stiffness was considered viable indicators of endothelial or microcirculatory reactivity in healthy young males .
chronic inhibition of no synthase by n - nitro - l - arginine methyl ester ( l - name ) in adult rats produces endothelial dysfunction with increase of vascular responsiveness to adrenergic stimuli associated with perivascular inflammation . vascular remodeling ,
renin - angiotensin system , sympathetic nervous system , and endothelium - derived constricting factors ( edcf ) also play a role in l - name - induced hypertension [ 28 , 29 ] . obviously , reduced no synthesis is the main mechanism for the blood pressure elevation induced by l - name .
interestingly , continuation of l - name administration from 4 to 8 weeks further increases blood pressure , but not enhancing the impairment of endothelium - dependent relaxation .
it has been recently reported that , after 4 weeks of l - name treatment , endothelial no synthase ( enos ) expression in the heart was significantly increased and this increase was amplified after 7 weeks of treatment .
this finding suggests that the upregulation of enos protein expression represents one of counterregulatory mechanisms activated to compensate the blood pressure raise .
impairment of no signaling has been improved after the cessation of l - name administration .
however , persisting arterial structural alterations and enhanced edcf formation may decelerate blood pressure reduction even after the restoration of no synthase activity . spontaneously hypertensive rats ( shr ) seem to be the experimental model most similar to the human primary hypertension .
notably , endothelium - dependent dilation is preserved in the prehypertensive and early hypertensive stages of shr . moreover , impaired endothelium - dependent relaxation was not found in rats with borderline hypertension .
this has been supported by the finding that their aortic no production was even elevated in comparison with normotensive rats .
it has been recently demonstrated that inhibition of angiotensin converting enzyme lowers blood pressure in shr by attenuating sympathetic tone .
when comparing shr with no - deficient rats , it has been shown that alterations in the vascular wall in both groups of animals but the endothelium - dependent dilation in aorta is clearly reduced in no - deficient rats while relatively preserved in shr .
this finding indicates that endothelial dysfunction in hypertension is not related to vascular structural changes . in salt - dependent hypertension , the reduction of no bioavailability caused by increased ros levels seems to play a significant role in the pathogenesis of blood pressure elevation and endothelial dysfunction .
particularly , renin - angiotensin system does not contribute to hypertension in this experimental model .
on the other hand , sympathetic hyperactivity has been shown in salt - hypertensive dahl rats leading to vasoconstriction which becomes superior to no - dependent vasodilation .
in some experimental studies , an artery can be dissected , immediately immersed in cold physiological salt solution ( pss ) , and cleaned of adipose or connective tissue to be mounted as ring - shaped preparations in the small vessel wire myograph .
two 40 m stainless steel wires are passed through the lumen of the vessel , and mounted in the jaws of the wire myograph .
after 30 min equilibration in oxygenated ( 5% co2 , 95% o2 mixture ) pss , a standardized computer - assisted normalization procedure is performed to set the pre - tension of the arteries .
this defines the lumen diameter that the artery would have had in vivo when relaxed and under a transmural pressure of 100 mmhg .
the arteries were then set to the lumen diameter of 90% of the normalized inner diameter when active force development was maximal . before the start of measurements ,
thus , increasing concentrations of the vasodilator acetylcholine are added in cumulative manner to perform endothelium - dependent concentration - response curves .
there are many agents , such as histamine , bradykinin , atp , and serotonin , which produce arterial relaxation either by direct action on the smooth muscle cell or by indirect action mediated by activation of endothelial receptors .
however , acetylcholine is the more commonly used substance to activate endothelial receptors in this setting .
a technique that provides important information about structural , mechanical , and functional properties in small vessels is the pressurized myography ( figure 1 ) .
this method offers advantages for the analysis of structural features compared to conventional histology techniques , because it observes the vessel in ex vivo preparation , without the artefacts induced by tissue fixation . in the pressurized myograph ,
the vessel is dissected and cannulated in both ends with micropippetes that are connected to intraluminal pressure transducers , allowing pressure control .
the perfusion chamber where the vessel is immersed is supplied with a perfusion system that keeps changing a physiological solution continuously .
this allows the infusion of pharmaceuticals with different concentrations for the evaluation of vascular diameter , indicating its functional properties .
the vessel image is obtained with the aid of optic microscopy , recorded by a video camera and exposed in a video monitor .
this image is analysed for the determination of wall thickness and vascular diameter [ 42 , 43 ] . from data obtained with the pressurized myograph
, we can gather information about arterial structure , employing formulas that take into account the cylindrical geometry of the vessel . as a result ,
when we apply to the vessel a constant intraluminal pressure of 45 mmhg , the media cross - sectional area ( csa ) is obtained subtracting the external from the internal vascular transversal area :
( 1)csa=[(4)(de2 di2 ) ] ,
where de and di are the external and internal diameters , respectively .
it is also possible to adjust intraluminal pressure , in order to observe the variations in the external diameter of the vessel , which correspond to the extent of vascular stiffness . in vascular mechanics
evaluation , resistance arteries must be previously deactivated by extraluminal perfusion with calcium - free pss for 30 min in order to eliminate any myogenic tone .
intraluminal pressure is then increased to 140 mmhg three times , and the cannula must be adjusted until the artery walls are straight and parallel to each other .
a servo - controlled pump is used to increase intraluminal pressure in increments of 10 mmhg until a pressure of 40 mmhg is achieved , and then in 20 mmhg increments until a pressure of 140 mmhg is reached .
media thickness and lumen diameter must be assessed at each pressure level at different points along the vessel , and the average is used in subsequent calculations .
the initial diameter is measured at 3 mmhg unless the vessel collapses . in these cases ,
lumen diameter has to be estimated by fitting the intraluminal pressure - lumen diameter data with a third - order polynomial equation .
the incremental distensibility is the percentage of change in lumen diameter ( d / d ) for a given change in intraluminal pressure ( p ) :
( 2)incremental distensibility=(1p)(dd)100 .
circunferencial strain ( ) is calculated as = ( d d0)/d0 , where d is the lumen diameter observed in a given intraluminal pressure and d0 corresponds to the original diameter or estimated with intraluminal pressure of 3 mmhg . the circumferential stress ( ) is calculated as = ( pd)/2 m , where p is intraluminal pressure , d and m are luminal diameter and media thickness , respectively . pressure is converted from mmhg to dyn / cm ( 1 mmhg = 1,334 10 dyn / cm ) .
in conclusion , although not specific to hypertension , endothelial dysfunction frequently develops in hypertensive animals .
the reduction of no bioavailability caused by increased ros is the main mechanism involved in the pathogenesis of endothelial dysfunction .
nevertheless , hyperactivity of renin - angiotensin system , endothelin , sympathetic activation , and inflammation may also contribute to oxidative stress and endothelial dysfunction .
wire myograph and pressurized myograph are the key methods for vascular evaluation in the experimental setting . along with endothelial function evaluation , analysis of vascular mechanics
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### Summary:
: endothelial dysfunction is one of the main characteristics of chronic hypertension and it is characterized by impaired nitric oxide ( no ) bioactivity determined by increased levels of reactive oxygen species .
endothelial function is usually evaluated by measuring the vasodilation induced by the local no production stimulated by external mechanical or pharmacological agent .
these vascular reactivity tests may be carried out in different models of experimental hypertension such as no - deficient rats , spontaneously hypertensive rats , salt - sensitive rats , and many others .
wire myograph and pressurized myograph are the principal methods used for vascular studies . usually , increasing concentrations of the vasodilator acetylcholine
are added in cumulative manner to perform endothelium - dependent concentration - response curves .
analysis of vascular mechanics is relevant to identify arterial stiffness . both endothelial dysfunction and vascular stiffness
have been shown to be associated with increased cardiovascular risk .
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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:
: all patients were admitted to local hospitals and clinical samples for microbiological investigations were sent to the nearest laboratories .
c. diphtheriae isolates were sent to national institute of public health national institute of hygiene for confirmation and toxigenicity testing , biotyping , pulsed - field gel electrophoresis ( pfge ) , multilocus sequence typing ( mlst ) , and ribotyping .
data collected for epidemiologic analysis included location ; type of infection ; year of presentation ; and patient age , sex , concomitant diseases , socioeconomic status , and intravenous drug use ( ivdu ) .
all isolates from local and invasive infections were identified as biotype gravis , except for the isolate from patient loc-05 , which was identified as biotype mitis . all 25 isolates were characterized by pfge , and 20 isolates ( 18 from invasive and 2 from local infections ) were characterized by mlst ( 35 ) .
all the isolates except the mitis isolate belonged to the same pulsotype revealed by pfge .
eight of the isolates ( 5 from invasive and 3 from local infections ) also were genotyped by using ribotyping .
all but 1 invasive infection were identified in male patients , whereas local infections affected male and female patients similarly .
age groups of patients most affected by invasive infections were 3140 years , followed by 5160 years ; for local infections , persons 5160 years of age were mostly affected ( figure ) .
epidemiologic data analysis revealed that predisposing factors of nontoxigenic c. diphtheriae invasive infections were related to conditions associated with low socioeconomic status , such as alcoholism , homelessness , and dental caries , as well as to hepatic cirrhosis . for 3 ( 17% ) patients ( inv-08 , inv-09 , inv-13 ) , no concomitant diseases or predisposing factors were identified .
these were healthy men aged 17 , 24 , and 37 years of age , respectively .
the sources of all infections described in the study were not identified . despite ivdu being regarded as a risk factor for c. diphtheriae invasive infection ,
only 150 cases were reported in european union and european economic area / european free trade association countries .
most of the cases ( 114 cases ) occurred in latvia , where diphtheria is endemic .
the other diphtheria cases were reported in france ( 10 cases ) , germany ( 6 ) , sweden ( 2 ) , united kingdom ( 16 ) , and norway ( 4 ) ( 6 ) .
however , infections from nontoxigenic c. diphtheriae have been reported in several european countries , such as germany ( 7 ) , united kingdom ( 8) , france ( 5 ) , switzerland ( 9 ) , and italy ( 10 ) , during the past few years . in poland ,
persons most affected were 3140 years and 5160 years of age , whereas in other countries most patients were younger ( up to 34 years of age ) .
no c. diphtheriae infections among children were recorded in poland , whereas in france , almost 20% of invasive infections were diagnosed in children . on the other hand , in italy and the united kingdom , 70% and 13% of isolates , respectively , originated from patients < 15 years of age ( 5,8,10 ) . in poland ,
all but 1 strain isolated from local and invasive infections belonged to biotype gravis , whereas biotype mitis dominated among the invasive isolates in switzerland and france , and biotype gravis dominated among isolates from local infections in italy and the united kingdom ( 5,810 ) .
all but 1 isolate from poland represent a single clone despite isolation of the strains in different part of the country over a 9-year period .
this raises a valid question : is a single clone of c. diphtheriae circulating in poland or does the identified clone have increased pathogenic properties ?
this question remains unanswered because the carrier state of c. diphtheriae has not been examined in the polish population .
taking these data and the literature review into consideration , c. diphtheriae infections frequently are associated with endocarditis .
( 12 ) demonstrated that most patients with c. diphtheriae endocarditis have underlying cardiac disease , prosthetic valves , or a history of ivdu .
the portal of entry for invasive nontoxigenic c. diphtheriae infection has not been fully elucidated . however , some authors shown that skin lesions are the most likely sources ( 9,13,14 ) . in the cases presented here , skin ulceration was uncommon ( 1 case ) , but dental caries were found in > 22% of cases .
nevertheless , nontoxigenic c. diphtheriae can be concluded to be an emerging pathogen in poland and has the potential to cause serious infections .
the number of nontoxigenic c. diphtheriae infections might be higher because reporting of only toxigenic c. diphtheriae infections is mandatory in poland . moreover , in clinical settings , detection of coryneform bacteria in blood cultures is often dismissed as contamination , and in severe cases of the disease , c. diphtheriae might never be identified as the etiologic agent of bloodstream infection .
homelessness , alcohol abuse , ivdu , and diabetes mellitus were mentioned in the literature as risk factors for c. diphtheriae invasive infections . in the cases presented here , 31% of patients were homeless , and
hepatic cirrhosis was ascertained , which suggests that it also may be another predisposing factor to infection .
moreover , dental caries is a highly probable portal of entry of c. diphtheriae invasive infection and has not been documented by other authors .
diphtheria toxoid vaccination schedule in poland , case classification , and methods of identification and characterization of the isolates .
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### Summary:
: twenty - five cases of nontoxigenic corynebacterium diphtheriae infection were recorded in poland during 20042012 , of which 18 were invasive .
alcoholism , homelessness , hepatic cirrhosis , and dental caries were predisposing factors for infection .
however , for 17% of cases , no concomitant diseases or predisposing factors were found .
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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:
: hepatocellular carcinoma ( hcc ) , the most common type of liver cancer , is the fifth most common malignant tumor type worldwide and the second leading cause of cancer - related deaths ( 1 ) .
tumor cells continuously integrate external stress signals and determine if the cell should die or survive .
these determinations are made by a wide range of signaling events that are controlled by kinases .
myosin ii activation is essential for stress fiber and focal adhesion formation , and is implicated in integrin - mediated signaling events .
integrin ligation by the extracellular matrix ( ecm ) plays a crucial role in organizing the cytoskeleton ( 3 ) , and the loss of substrate attachment is known to induce a type of apoptosis called anoikis ( apoptosis upon loss of anchorage detachment from ecm ) ( 4).therefore , interactions between cells and the ecm play an important role in cell survival ( 5).the actin - myosin ii interaction in smooth muscle and nonmuscle cells is regulated by the phosphorylation of serine 19 of the 20-kda light chain of myosin ii ( mlc ii ) ( 6 ) .
mlck , also known as calcium ( ca2+)/calmodulin - dependent protein kinase , plays a major role in the formation and stability of a cell s cytoskeleton .
mlck , when activated or overexpressed , has been found to contribute to the proliferation of tumor cells ( 9 , 10 ) .
hyper phosphorylated mlc ii induces stress fiber formation and integrin clustering that link cell surface cytoskeletal proteins such as focal adhesion kinase ( fak ) to actin ( 11 , 12 ) .
fak is a member of a focal adhesion family that mediates integrin - mediated signal transduction associated with a variety of cellular functions , including cellular adhesion , proliferation and migration ( 13 ) .
integrins contribute to signal transduction from the extracellular environment to the intracellular network mediated by integrin - activated signaling molecules , such as fak .
the tumor suppressor p53 is a downstream signaling pathway to fak , which regulates cell death pathway ( 14 ) .
there is some evidence suggesting that bax , a proapoptotic member of the bcl-2 family of cell death - regulating genes , is involved in p53- induced apoptosis .
one set of molecules that appear to be modulated by the presence of bax are the caspases ( 15 ) .
caspase-3 , one of a family of caspase proteases implicated in the commitment and execution of apoptotic cell death , exists as a proenzymes35kdauntil cleaved in response to active apoptotic stimuli ( 19kda and 17kda ) ( 16 ) .
matrine , a natural alkaloid component derived from a species of leguminosae plant ( sophora flavescens ait . ) , has been found to significantly inhibit the proliferation and migration of various types of tumor cells ( 17 - 22 ) . in -
vitro studies have demonstrated that matrine can promote the apoptosis of liver tumor cells and inhibit their proliferation ( 23 - 26 ) . in - vivo , matrine has been found to prevent and treat the occurrence of diethyl nitrosamine ( dena)-induced hcc as well as the proliferation of liver tumor cells ( 27 , 28 ) .
however , the mechanism by which matrine inhibits the proliferation of primary hcc cells and promotes the apoptosis of hcc cells , both in - vivo and in - vitro , remains unclear . in this study
, we used a rat model of hcc to investigate the inhibitory effects of matrine on the proliferation of hcc cells .
we also examined if matrine induced apoptosis in hcc cells via the down - regulation of mlck overexpression and the activation of the p53 pathway and if matrine can inhibit the proliferation of hcc cells in - vivo .
animals and chemicals
seventy sprague - dawley rats , weighing 70.3 6.2 g , were purchased from the animal center of changlinhe pharmaceutic co. , ltd .
all of the rats were housed in cages under a 12 h light - dark cycle and fed a standard laboratory rat diet with water ad libitum .
8910m047 on the use and care of laboratory animals and with the guidelines established by the institute for experimental animals of anhui science and technology university and were approved by the university committee for animal experiments .
matrine ( concentration 99% ) was obtained from the national institutes for food and drug control of beijing , china .
a quantitative determination kit for -fetoprotein ( afp ) was purchased from y - y chemical reagents co. , ltd .
( hubei , china ) . a bicinchoninic acid ( bca ) protein assay kit was purchased from sangon biotech co. , ltd ( shanghai , china ) .
anti - procaspase-3 and anti - cleaved - caspase-3 were purchased from biosynthesis biotechnology co. , ltd ( beijing , china ) .
rabbit anti - rat monoclonal mlck antibody igg and horseradish peroxidase - labeled antibody igg were purchased from hangzhou huaan biotechnology co. , ltd .
beta - actin rabbit polyclonal antibody igg was purchased from shanghai kexing biotechnology co. , ltd .
chemiluminescent substrates were purchased from cell signaling technology ( beverly , ma , usa ) .
experimental design
the rats were acclimatized for one week and then randomly assigned to either a control ( n=12 ) or hcc group ( n=58 ) .
the rats in the control group were given access to tap water for the duration of the experiment , while the rats in the hcc group were given access to a 0.01% dena solution for the first 10 weeks of the experiment and then tap water for the remainder ( 29 ) .
after 20 weeks , blood samples were collected , and the afp concentration in the serum was determined .
rats with an afp concentration of more than 200 g / l were used for the hcc model .
forty - eight hcc model rats were further randomized into four groups : one model group ( n=12 ) and three matrine - treated groups ( n=12 for each group ) .
the rats in the matrine - treated groups labeled as group - low ( l ) , group - medium ( m ) and group - high ( h ) according to the dosage administered were treated by intraperitoneal injections of matrine .
the dosage of matrine for each group was as follows : group - l received 12.5 mg / kg body weight , group - m received 25 mg / kg body weight and group - h received 50 mg / kg body weight .
the rats of the three matrine - treated groups were treated by intraperitoneal injections of matrine for six consecutive weeks from the twentieth week .
for the 12 h before they were sacrificed , the rats were restricted from food but not water .
tissue collection and elisa analysis
after 26 weeks , the rats were weighed , sacrificed under anesthesia induced by 3% pentobarbital sodium , and blood samples were collected .
the afp concentration in the serum was quantitated using enzyme - linked immunosorbent assay ( elisa ) methods and a rat afp assay kit ( y - y chemical reagents co. , ltd .
the experiment was repeated in triplicate . according to the method previously published by bishayee et al .
( 30 ) , the rats livers were excised and weighed , and the number of visible hepatocyte nodules was recorded .
a portion of the liver tissue was fixed , dehydrated in graded ethanol and embedded in paraffin .
some liver tissue was then sectioned into thicknesses of 5 m , and used for cell apoptosis and immunohistochemical analyses .
the remaining liver tissue was either used for western blot analysis or stored at -80 c for further use .
the tunel ( terminal transferase dutp nick end labeling ) staining was performed in order to determine the effect of matrine on apoptosis by using an in situ cell death detection kit ( boster , wuhan , china ) according to the manufacturer s instructions .
the detection was performed using peroxidase ( pod ) and diaminobenzidine ( dab ) substrate ( boster , wuhan , china ) .
the number of apoptotic cells in the tissues of control and matrine - treated rats was determined by counting the stained cells in 12 fields , each of which contained at least 50 cells under the light microscope with 400magnification for each section .
the cell count was performed by an investigator who was blinded to the experimental protocol . the apoptotic index ( ai )
was calculated as follows : ai = ( number of apoptotic cells / total number of cells ) 100% .
western blot analysis
the rat liver tissues without nodule were homogenized in cold ripa lysis buffer ( sangon , shanghai , china ) and the protein concentrations were determined by bca assay kits ( sangon , shanghai , china ) .
equal amounts of protein were separated using sds - page gels for p53 , bax , and cleaved - caspase-3 , respectively .
the membranes were blocked with 5% fat - free milk in pbs with 0.1% tween 20 ( pbst ) for one hour at room temperature and then incubated with different primary antibodies including anti--actin ( 1:1000),anti - p53,anti - bax and anti - cleaved - caspase-3 ( 1:1000 ) overnight at 4 c .
after washing the membrane 3 times with pbst , secondary antibody hrp - labeled goat - anti - rabbit igg was added to the membrane according to the vendor s recommendation ( 1:2000 ) and incubated for 1h at room temperature .
the bound antibodies were detected by using an ecl western blotting kit ( sangon , shanghai , china ) .
the relative protein level of p53 , bax , and cleaved - caspase-3 was calculated relative to that of -actin .
immunohistochemistry
liver tissue sections were deparaffinized and hydrated according to the methods detailed in the immunohistochemistry kit .
the sections were incubated with the rabbit anti - rat monoclonal mlck antibody igg ( primary antibody , 1:600 dilution ) and then with the immunohistochemistry kit ( secondary antibody ) .
phosphate buffered saline ( pbs ) was used as a negative control , replacing the primary antibody .
the sections were then treated with 3,3-diaminobenzidine ( dab ) and examined under a microscope for positive signals . in our analysis , positive signals were yellowish brown .
for each rat , three different images ( at a magnification of 400 ) were taken using an image analysis system .
all of the data are presented as the mean the standard deviation ( mean s.d . ) and was analyzed statistically using spss 17.0 software .
the average of each sample was then compared using variance analysis and a multiple comparison method . the enhanced chemiluminescence ( ecl )
western blot images were semi - quantitatively analyzed using image - pro plus 6.0 software .
the effect of matrine on the body weights , liver weights and liver weight to body weight ratios of rats
table 1 shows that the rats in the model group has significantly lower body weights ( p < 0.01 ) and higher liver weight - to - body weight ratios ( p < 0.01 ) than the control group , indicating that substantial hcc cell proliferation occurs in the model group . the rats of groups - l , -m and -h had significantly higher body weights ( p < 0.01 ) , lower liver weights ( p < 0.01 ) and lower liver weight - to - body weight ratios ( p < 0.01 ) than the model group , potentially indicating matrine inhibits the proliferation of hcc cells .
the effects of matrine on the body weights , liver weights and liver weight to body weight ratios in rats ( mean s.d . )
the effect of matrine on the number of hepatocyte nodules and the serum concentration of afp in rats
no natural occurrence of hcc was found in the rats of the control group , as indicated by the lack of visible hepatocyte nodules in their livers ( table 2 ) .
the liver size of the rats in the model group was increased dramatically , all of the hepatic lobes were greyish white in color due to the presence of hepatocyte nodules .
from the tissue sections , we found that the hepatocyte nodules were hcc and cholangiocarcinoma of different grades .
compared with the rats in the model group , the rats in groups - l , -m and -h had relatively smooth liver surfaces and significantly fewer hepatocyte nodules ( p < 0.01 ) .
this result corroborated the suggested inhibition effect of matrine on hcc cell proliferation in rats .
additionally , the afp concentrations in the rats of the matrine - treated and model groups were significantly increased when compared with the control group , but the afp concentrations in all three matrine - treated groups were significantly lower ( p < 0.01 ) than in the model group .
the effects of matrine on the numbers of hepatocyte nodules and the serum afp concentrations in rats ( means.d . )
the effect
of matrine on hcc cell
apoptosis the cells of the positive control ( a slice given in the apoptosis kit ) were almost entirely apoptotic ( figure 1a ) .
hcc cell apoptosis in the liver of the model rats ( figure 1c ) was greatly inhibited compared to the normal control group ( figure 1b ) , though the other liver tissue cells continued to undergo programmed cell death
. a larger number of apoptotic hcc cells were found in the liver of the matrine - treated rats ( figure 1d ; 1e ; 1f ) than in those of the model group ( figure 1c ) .
the ai of the model liver tumor cells ( 14.3 5.2 ) was significantly smaller ( p < 0.05 ) than that of the normal tissue cells ( 31.7 7.6 ) .
the ais of the tumor cells in the livers of the matrine - treated rats ( group - l : 36.7 12.5 ) ( p < 0.05 ) ( group - m : 68.2 18.6 ; group - h : 78.9 15.6 ) ( p < 0.01 ) were significantly greater than those of the model group .
a tunel analysis of cell apoptosis ( 400 ) was performed in the liver tissues of control , model , and matrine - treated rats , and their apoptotic indexes were calculated .
a. positive control ( slice obtained from the apoptosis kit , set to 100% ) ; b. normal control group ; c. model control group ; d. matrine - treated group - l ; e. matrine - treated group - m ; and f. matrine - treated group - h .
p < 0.05 vs the control group;p < 0.05 and p < 0.01 vs the model group matrine effected on activation of cleaved caspase-3 via modulation of p53 and bax expression .
we then investigated if the mechanism of matrine - induced liver tumor cell apoptosis through activation of cleaved capase-3 expression depends on modulation of the p53 and bax pathway .
western blot analysis was used to test the effect of matrine on p53 and bax proteins expression .
figure 2 indicated shows that matrine can significantly up - regulate p53 and bax expression . at the same time , protein levels of -actin , and cleaved caspase-3 were detected in the livers of hcc model and matrine - treated rats ( figure 3 ) .
as can be seen in figure 3 , treatment with matrine increased the level of cleaved caspase-3 relative to -actin in the hcc rats .
quantitative analysis by densitometry scan showed that levels of cleaved caspase-3 relative to -actin were increased in dose - dependent manner .
the cell lysates were analyzed by western blotting with antibodies for p53 , bax and -actin .
a. normal control group ; b. model control group ; c. matrine - treated group - l ; d. matrine - treated group - m ; and e. matrine - treated group - h the dose - dependent effect of matrine on cleaved capase-3 expression .
a. normal control group ; b. model control group ; c. matrine - treated group - l ; d. matrine - treated group - m ; and e. matrine - treated group - h
semi - quantitative analysis of mlck expression levels
by
western blot
the ratio of mlck to - actin in the rats of the normal group was set to 100 and used as the basis for comparison with the other groups . the ratio of mlck to - actin in the model rats ( 242 45 ) was significantly higher ( p < 0.01 ) than that of the rats in the normal control group .
the mlck / - actin ratios of the rats in the matrine - treated groups ( group - l : 205 23 , p < 0.05 ; group - m : 171 16 ; group - h : 153 18 , p < 0.01)were significantly lower than that of the rats in the model group .
this result suggests that matrine inhibits the mlck overexpression caused by hcc ( figure 4 ) .
the effect of matrine on mlck immunochemistry in hcc tissues
figure 5 shows the mlck expression levels in the livers of the control , model , and matrine - treated rats .
mlck expression in the livers of the model rats was higher than the control group s levels and expression in matrine - treated rats .
matrine - treated rats was lower than that of the model group . the mlck integral absorbance in the livers of the model rats ( 285 75 ) was significantly higher ( p < 0.01 ) than that of the control group ( 81 12 ) .
the mlck integral absorbances of the treated rats ( group - l : 243 47 , p < 0.05 ; group - m : 192 38 ; group - h : 163 29 , p < 0.01 ) were all significantly lower than that of the model group .
immunohistochemical analyses of immuno- staining for mlck - positive foci ( 400 ) were performed on liver tissues from control , model and matrine - treated rats .
a. normal control group ; b. model control group ; c. matrine - treated group - l ; d. matrine - treated group - m ; and e. matrine - treated group - h .
0.01 vs the control group ; p < 0.05 and p < 0.01 vs the model group
apoptosis plays an important role in the matrine - induced inhibition of tumor cell proliferation . in this study
, we found that this apoptosis is mediated by the action of caspases , a group of cysteine proteases that can be activated through the p53 pathway .
the results verified that p53 is a major player in the apoptosis process that is activated when hcc cells are exposed to matrine ( 31 ) .
our results demonstrated the ability of matrine to significantly induce p53 expression , which is essential for the therapeutic effect of some clinical cancer drugs ( 32 - 34 ) .
the main function of the tumor suppressor p53 is to limit cellular proliferation by inducing apoptosis in response to matrine .
our results also demonstated that p53 mediates the apoptosis induced by matrine through a linear pathway involving bax transactivation and the activation of caspase-3 .
mlck hyperphosphorylated mlc ii induces stress fiber formation and integrin clustering that link cell surface cytoskeletal proteins such as focal adhesion kinase ( fak ) to actin ( 11 , 12 ) .
our immunohistochemistry results showed that mlck expression increased dramatically at the tumor site in the rats of the model group , while mlck expression in the matrine - treated rats was much lower .
western blot analysis further showed that in the rats of the model group , the mlck expression level increased significantly .
we confirmed that matrine could induce apoptosis in hcc cells and ultimately inhibit the proliferation of hcc cells by reversing mlck overexpression .
matrine s ability to inhibit the proliferation of hcc cells by regulating mlck expression has not been reported previously , either in china or elsewhere .
these results may indicate that matrine can be used as a component of tumor treatment and that mlck can be a novel target for treating hcc .
mlck is closely associated with tumors and plays an important role in tumor cell proliferation , its specific inhibitor ml-7 has been reported to directly block tumor cell proliferation ( 9 , 10 ) .
this study revealed that the inhibitory effect of matrine on hcc cell proliferation is associated with down - regulation of mlck overexpression via the p53 apoptosis pathway .
matrine may thus be used as a potentially promising reagent to inhibit hcc cell proliferation and mlck may be a novel target for the treatment of hcc .
in conclusion , we revealed that the mlck expression was higher in the livers of hcc rats than in normal and matrine - treated rats .
high level of mlck expression was associated with inducing liver tumor cell proliferation and anti - apoptotic effects .
matrine inhibits hcc cell proliferation in rats through inducing apoptosis via p53 , bax - dependent caspase-3 activation pathway and down - regulating mlck overexpression .
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### Summary:
: the proliferation of hepatocellular carcinoma ( hcc ) cells is one of the leading causes of liver cancer mortality in humans .
the inhibiting effects of matrine on hcc cell proliferation have been studied , but the mechanism of that inhibition has not been fully elucidated . since , apoptosis plays an important role in hcc cell proliferation .
we examined the apoptosis - inducing effect of matrine on tumor cells .
western blot analysis of p53 , bax , cleaved caspase-3 and myosin light chain kinase ( mlck ) revealed that matrine induced tumor cell apoptosis by controlling anoikis .
it activated p53 , bax - dependent caspase-3 and blocked the ecm - integrin mediated cell survival pathway through down - regulating mlck over - expression in the liver of rats with diethyl nitrosamine ( dena)-induced hcc . our results suggest that matrine can inhibit the proliferation of hcc cells through inducing tumor cell apoptosis via activation of the p53 pathway and inhibition of mlck overexpression .
matrine may thus be used as a potentially promising reagent to inhibit hcc cell proliferation and mlck may be a novel target for the treatment of 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:
: turner syndrome is a common genetic disorder resulting from partial or complete absence of one sex chromosome and occurring in approximately 1 per 2,500 live - born females ( 1 , 2 ) .
the association of turner syndrome with strong susceptibility to autoimmune disorders , including diabetes mellitus , hypothyroidism and inflammatory bowel disease ( ibd ) ( 3 ) , especially in a subgroup with a chromosomal structural abnormality , has recently been well established ( 2 , 4 ) .
ibd is comprised of two major disorders , crohn s disease ( cd ) and ulcerative colitis ( uc ) .
the development of ibd early in life has implications that are not encountered in adults .
uc is a chronic inflammatory disorder of the intestine characterized by dysregulated mucosal immune response .
although the etiology of uc has not been fully clarified , genetic analysis has recently revealed several susceptibility genes for ibd ( 5 ) . although an association between turner syndrome and ibd has been described ( 3 , 4 ) , the incidence of turner syndrome with ibd is rare ( 6 ) , and the pathogenic mechanism linking turner syndrome with ibd has not been elucidated .
we describe here a patient with a 46,x , i(xq ) karyotype pattern who developed uc during growth hormone therapy .
a 10-yr - old japanese female was referred to our pediatric endocrinology clinic for evaluation of short stature .
the prenatal course was uncomplicated , and she was born after full - term gestation with a birth weight of 3,000 g and a birth height of 47.8 cm .
yr old , her height was 122.2 cm ( 3.1 sd for a normal 10-yr - old japanese female and + 1.4 sd for a 10-yr - old ) .
turner syndrome female without genital bleeding and her weight was 32.8 kg ( 0.5 sd for a normal 10-yr - old japanese female ) ; a high arched palate and cubitus valgus were noted ( fig .
longitudinal growth curve plotted against cross - sectional growth charts for japanese female ( 018 yr ) 2000 .
were the webbing of the neck , low hairline , shield chest with widely spaced nipples and facial features characteristic of turner syndrome .
her breasts and pubic hair were tanner stage i. endocrinological evaluation revealed growth hormone deficiency according to insulin tolerance test ( peak gh : 4.37 ng / ml ) and hypergonadotropic hypogonadism .
turner syndrome was diagnosed on the basis of her physical examination , endocrinological evaluation and karyotype .
growth hormone treatment ( 0.35 mg / kg / wk ) was initiated at age 11 yr old
longitudinal growth curve plotted against cross - sectional growth charts for japanese female ( 018 yr ) 2000 .
5-asa : ( 5-aminosalicylic acid ) . at the age of 13 yr and 9 mo , she presented with intermittent abdominal discomfort and mucoid bloody diarrhea .
the cramping abdominal pain gradually worsened over the following 3 mo , and the frequency of bloody diarrhea increased .
she was admitted to our hospital with these symptoms at the age of 13 yr and 11 mo . on admission ,
her height was 136.3 cm ( 3.6 sd for a normal 14-yr - old japanese female and + 1.0 sd for a 14-yr - old ) .
turner syndrome japanese female without genital bleeding and her weight was 30.5 kg ( 2.3 sd for a normal 14-yr - old japanese female ) .
her body temperature was 37.3c , her pulse was 96 beats per minute and her blood pressure was 106/44 mmhg .
laboratory findings on admission were as follows : wbc , 5,700/l ; hb , 9.4 g / dl ; ht , 29.7% ; plt , 34.5 10/l ; ast , 7 u / l ; alt , 5 u / l ; ldh , 144 u / l ; ck , 31 u / l ; amylase , 161 u / l ; crp , 0.23 mg / dl ; and an erythrocyte sedimentation rate ( esr ) of 22 mm / h .
she was diagnosed with presumed infectious enterocolitis and was hydrated intravenously and treated empirically with antibiotics .
after 7 d with minimal response to therapy , she underwent barium enema , flexible sigmoidoscopy ( fig .
barium enema revealed punctate collections of barium suggesting microulcerations in the descending and sigmoid colon with loss of haustra .
flexible sigmoidoscopy showed that the mucosa was erythematous and friable upon touch and that the wall had frank hemorrhage and inflammatory polyp formation from the anal verge through the splenic flexure . ) and biopsies .
barium enema showed a diffusely reticulated pattern with superimposed punctate collections of barium in microulcerations and loss of haustra in the descending colon and sigmoid colon .
flexible sigmoidoscopy showed touch friability , frank hemorrhage , erythematous mucosa and pseudopolyps in a diffuse circumferential distribution from the anal verge to the splenic flexure .
histological features included mucosal and submucosal inflammation , cryptitis , and crypt abscess formation in the descending colon and sigmoid colon .
oral administration of 5-aminosalicylic acid ( 5-asa , 50 mg / kg / d ) and dietary treatment were initiated .
her abdominal symptoms , frequency of bloody diarrhea , serum crp , esr and hb were rapidly ameliorated by this treatment .
four weeks after initial treatment , however , her abdominal symptoms and a blood examination indicated recurrence of uc .
her clinical symptoms improved as a result , and no symptoms indicating recurrence of uc were observed at discharge .
barium enema revealed punctate collections of barium suggesting microulcerations in the descending and sigmoid colon with loss of haustra .
flexible sigmoidoscopy showed that the mucosa was erythematous and friable upon touch and that the wall had frank hemorrhage and inflammatory polyp formation from the anal verge through the splenic flexure .
spontaneous secondary sexual development was arrested at 15 yr old , and hormone replacement therapy was started with a low dose of conjugated estrogen for induction of secondary sexual development . at 17 yr
oral prednisolone ( 1.0 mg / kg / d ) was immediately re - administrated to treat the recurrence of uc . her abdominal symptoms improved dramatically within a short time after resumption of the medication and dietary treatment .
oral prednisolone was administrated for 2 mo . at the age of 17 yr and 10 mo
, progesterone was added to the hormone replacement therapy for maintenance of sexual development and induction of cyclic uterine bleeding .
the prevalence of turner syndrome is approximately 1 per 2,500 live - born females ( 1 , 2 ) , while the prevalences of cd and uc are 1050 and 3090 per 100,000 , respectively ( 4 ) .
turner syndrome is associated with a strong susceptibility to autoimmune disorders , with an increased risk of developing ibd .
calculated a 2-fold increase in the risk of developing ibd in women with turner syndrome ( 6 ) .
they reported that the prevalences of both cd and uc were 1.48% and 1.48% , respectively , in a series of 135 patients with turner syndrome , which when compared with the general population , constituted a 30-fold and 16-fold increase , respectively ( 7 ) .
gastrointestinal symptoms in ibd often develop at a young age , and the median age of onset is 16 yr old .
( range 940 yr old ) ( 2 ) . moreover , ibd is often severe in women with turner syndrome . in the case
reported here , the turner syndrome patient also developed gastrointestinal symptoms at age 13 yr old .
although an association between turner syndrome and ibd has been described , the pathogenic mechanism has not been elucidated .
evidence exists suggesting a cytogenetic basis for the severity of the symptoms in turner syndrome .
the pure 45,x monosomy is the most common karyotype and is associated with the most severe symptoms .
estimated that 57% of patients with turner syndrome have the karyotype 45,xo , while 17% of patients have one normal x chromosome and one isochromosome that comprises two long arms instead of one long and one short arm ; this isochromosome may be observed either in all cells or as a mosaic ( 4 ) .
turner mosaics usually have a less severe phenotype , and up to 40% of these individuals enter puberty spontaneously before developing gonadal failure ( 8) . the isochromosome xq is the most common structural abnormality and is associated with autoimmune disorders , but congenital abnormalities are conspicuously absent ( 9 ) .
women with the isochromosome xq karyotype are particularly susceptible , accounting for 52% of the reported cases of ibd in women with turner syndrome ( 2 ) .
although the causes of ibd are not fully known , immunological dysfunction is thought to play an important role .
additionally , the increased risk of ibd in turner syndrome , particularly in the presence of an x isochromosome , would suggest that perhaps a gene on the long arm of the x chromosome may be associated with immune dysfunction . in our case ,
the patient , with karyotype 46,x , i(xq ) , had a less severe phenotype , but developed ulcerative colitis at adolescence .
we have reported here a karyotype 46,x , i(xq ) turner syndrome patient with uc .
the severity of uc was moderate to severe and improved after treatment with 5-asa , prednisolone and dietary therapy .
this case supports the idea that the x chromosome partly contributes to susceptibility to uc and may modulate the severity of inflammation in this condition .
turner syndrome patients are susceptible to a number of medical problems , including cardiovascular disease , osteoporosis and other endocrine , gastrointestinal and renal disorders ( 10 ) .
they require long - term follow - up so that early medical intervention may reduce morbidity and improve life expectancy .
ibd should be ruled out in women with turner syndrome with unexplained abdominal discomfort and bloody diarrhea .
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### Summary:
: turner syndrome is a chromosomal disease frequently associated with autoimmune disorders including diabetes mellitus , thyroid disease and inflammatory bowel disease ( ibd ) .
although the etiology of ibd has not been fully elucidated , genetic analysis has recently revealed several susceptibility genes .
recently , cases with turner syndrome associated with ibd have been reported .
we report here a 13-yr - old girl with turner syndrome associated with ulcerative colitis .
the patient was undergoing growth hormone treatment and presented with abdominal discomfort and bloody diarrhea .
her karyotype pattern was 46,x , i(xq ) .
barium enema revealed punctate collections of barium suggesting microulcerations in the descending and sigmoid colon with loss of haustra .
flexible sigmoidoscopy showed that the mucosa was erythematous and friable upon touch and that the wall had frank hemorrhage and inflammatory polyp formation from the anal verge through the splenic flexure .
histologically , mucosal and submucosal inflammation was prominent , suggesting cryptitis and crypt abscess formation .
based on these findings , she was diagnosed as having ulcerative colitis , and 5-aminosalicylic acid , prednisolone and dietary therapy were initiated .
our observations in this patient suggest that x chromosome abnormality may influence the development of ibd and that screening for gastrointestinal disease in patients with turner syndrome may help lengthen life expectancy in these 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:
: compartment syndrome has been defined as any condition in which pressure build - up within closed osteofascial space compromises tissue circulation and function .
the resultant ischemia can quickly cause irreversible muscle and nerve damage leading to musculotendinous contractures and sensorimotor deficits .
urgent diagnosis and surgical treatment with decompressive fasciotomy is the key to optimizing functional outcome .
diagnosis of compartment syndrome heavily depends on clinical presentation and becomes increasingly difficult in patients who are unconscious , intoxicated , or have altered mental status .
measurement of compartmental pressures using various devices has been shown to help facilitate diagnosis in such patients .
compartment syndrome of the upper extremity has been extensively described and reported in the hand , forearm , and upper arm , with the forearm most commonly affected .
a literature review returned only 4 other case reports termed compartment syndrome of the periscapular fascial compartments of the supraspinatus or infraspinatus .
some authors suggest that the rarity of upper extremity and shoulder region compartment syndrome may be due to the blending of fascial communications seen between the infraspinatus , deltoid , pectoralis , and brachial fascia , which may help to dissipate pressure build - up . to our knowledge ,
we report the only case of a patient with a comminuted scapular fracture that developed an acute compartment syndrome of both the supraspinatus and infraspinatus , diagnosed via intracompartmental pressure measurements and treated with emergent decompressive fasciotomy .
a 64-year - old male involved in a motor vehicle collision presented with left shoulder and facial pain .
examination revealed a swollen , soft shoulder [ figure 1 ] with scapular and acromioclavicular ( ac ) joint tenderness and painful motion .
x - rays showed a comminuted scapular body and spine fracture extending to acromion base with ac joint widening [ figures 2a , b and 3 ] .
the patient 's airway later became compromised secondary to facial fracture swelling , requiring intubation .
posterior view of left shoulder showing extensive swelling , ecchymosis , and abrasion ( a and b ) ap and lateral plain radiographs of left shoulder injury demonstrating ac joint widening , acromion base fracture , scapular spine and body fracture 3d reconstruction ct scan of left scapula showing segmental fracture of scapular spine and extensive comminution of scapular body later , evaluation revealed increased swelling and tenseness over the left scapula .
supraspinatus and infraspinatus compartment pressures were measured at 49 mmhg and 32 mmhg , respectively , with a diastolic blood pressure of 43 mmhg .
fifteen hours after presentation , emergent fasciotomy was performed . the incision extended over the scapular spine similar to a modified judet incision . upon release
, the supraspinatus and infraspinatus compartments showed good muscle escape , beefy red coloration , adequate bleeding , and contracture with stimulation [ figure 4 ] .
elevated serum myoglobin levels prior to fasciotomy were 2705 ng / ml , which declined to 1221 ng / ml and 630 ng / ml on postoperative day # 1 and # 2 , respectively . the combination of scapular spine , acromion base , and ac joint separation prompted plans for open reduction internal fixation ( orif ) , which were delayed until hospital day # 13 due to pneumonia [ figure 5 ] .
twenty - week post - op examination revealed active shoulder motion of 50 requiring removal of the ac plate and manipulation under anesthesia .
final 10-month follow - up revealed full strength and near - full flexion and abduction with complete radiographic bony healing . there were no signs of sequelae from compartment syndrome at any point .
intraoperative view after fascial release of the infraspinatus and supraspinatus postoperative ap shoulder plain radiograph after scapular spine and ac joint fixation
to our knowledge , we report the only case of a patient with a comminuted scapular fracture that developed an acute compartment syndrome of both the supraspinatus and infraspinatus , diagnosed via intracompartmental pressure measurements and treated with emergent decompressive fasciotomy . the diagnosis of compartment syndrome is frequently a clinical diagnosis based primarily on findings of pain out of proportion and pain on passive stretch of involved muscles .
the unconscious or obtunded patient at risk of compartment syndrome presents a difficult challenge for the physician in that these findings are either unreliable or unobtainable .
the use of additional diagnostic modalities of intracompartmental pressure monitors has been found to be useful in such patients .
the unfamiliarity and rarity of reported scapular compartment syndrome requires adherence to thorough physical examination , a high index of suspicion , and when necessary , the utilization of compartment pressure monitoring to prevent missed diagnosis . in 1992 , landi et al .
the first case described a patient with extensive necrosis of the infraspinatus encountered during exploration of a non - healing pressure ulcer .
the second case described a patient with a scapular fracture with increasing pain and swelling .
intracompartmental pressure measurements revealed an absolute pressure of 75 mmhg , which continued to decline on subsequent measurements .
follow - up demonstrated full motion , and absence of pain with no sequelae of an untreated compartment syndrome .
the diagnosis of compartment syndrome based on absolute pressure measurements alone has been challenged in several studies and its acceptance has diminished .
their study measured compartment pressures in 19 lower extremity fractures , all lacking clinical signs of compartment syndrome .
ninety - five percent of patients had at least one compartment measurement > 30 mmhg and 84% had measurements within 30 mmhg of diastolic pressure .
to our knowledge , there is no similar study to that of prayson et al . involving baseline upper extremity fracture compartment measurements .
further study may be useful to help guide treatment and evaluate injury location as a possible variable in the development of compartment syndrome .
compartment syndrome is not only the result of an increased volume within a fixed space , but rather the body 's inability to compensate for a change in the microvascular pressure gradient within a compartment .
once pressures have exceeded capillary perfusion pressure , the ability to exchange oxygen and clear waste is hindered .
the resolving clinical signs and lack of sequelae despite the elevated compartmental pressures as seen in landi et al .
's case further substantiates that compartment syndrome is not purely related to an increase in volume but involves other confounding variables .
the relationship between the measured compartmental pressure and diastolic pressure gives a more accurate insight into the dynamic compartmental environment .
this pressure differential value , as originally described by whiteside et al . as significant when absolute pressure measurement is within 30 mmhg of the diastolic pressure , has become more widely accepted as the diagnostic criterion compared to the use of an absolute pressure alone . as seen in our case , patients with hypotension have lower intravascular pressures and may have inadequate tissue perfusion even at mild increases in intracompartmental pressure .
a normotensive or hypertensive state in our patient may have been protective against rising compartment pressures .
the patient denied any history of trauma , but admitted intensive upper extremity weight lifting prior to a plane flight .
diagnosis of compartment syndrome was made based on magnetic resonance imaging ( mri ) findings of an enlarged and edematous supraspinatus .
emg 15 months after insult demonstrated persistent injury to the supraspinatus with shoulder abduction limited to < 30. takakuwa et al . presented a similar case of a patient with shoulder pain after performing bayonet - thrusting exercises while wearing tight - fitting shoulder equipment .
the authors made a delayed diagnosis of compartment syndrome based on mri findings of diffuse supraspinatus edema , elevated serum creatinine phosphokinase ( cpk ) and lactate dehydrogenase .
. 's and takakuwa et al . 's patients were observed ; however , the latter lacked uncontrollable pain and clinical sequelae of compartment syndrome , making the diagnosis of severe overuse synfrome of the supraspinatus
graves et al . made two diagnoses based on elevated creatinine kinase ( ck ) levels and mri findings of marked swelling and high - intensity supraspinatus signaling , similar to those of takakuwa et al . and
the authors chose to consider these cases overuse syndromes with rhabdomyolysis instead of compartment syndrome due to the absence of tense compartments , improved symptoms without fasciotomy , and lack of compartment syndrome sequelae .
four cases , termed either infraspinatus or supraspinatus compartment syndrome , have been reported in the english literature [ table 1 ] . however , several of these cases lacked clinical compartment syndrome signs of tenseness and swelling , were diagnosed via mri and lab values , or were successfully treated non - operatively .
, a diagnosis of overuse syndrome may better suit some initial reported diagnoses of supraspinatus compartment syndrome , as nonsurgical management may be used to adequately treat overuse injuries of the supraspinatus that result in rhabdomyolysis and not compartment syndrome . to our knowledge
, we have described here the first case of both supraspinatus and infraspinatus compartment syndrome and its successful surgical treatment with decompressive fasciotomy .
due to devastating complications and functional loss of a missed diagnosis of compartment syndrome , a high index of clinical suspicion for developing compartment syndrome must be maintained in every fracture setting , regardless of anatomic location or rarity of reported cases .
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### Summary:
: acute compartment syndrome occurs when pressure within a confined fascial space rises to a level impairing microvascular perfusion to surrounding tissues.[1234567 ] the majority of the reported literature is based on lower extremity compartment syndrome , but any muscle group within an osteofascial compartment has the potential to develop compartment syndrome .
we report a case of a 64-year - old male who developed an acute compartment syndrome of both the supraspinatus and infraspinatus after sustaining a severely comminuted scapula fracture .
diagnosis of compartment syndrome was made after intracompartmental pressure measurements of the supraspinatus and infraspinatus revealed pressures within 30 mmhg of the diastolic blood pressure , prompting emergency decompressive fasciotomy . at final follow - up ,
the examination revealed full shoulder strength with near - full range of motion .
there were no signs of sequelae from compartment syndrome at any point .
few case reports describe compartment syndrome of the periscapular fascial compartments .
however , these cases were either retrospectively diagnosed[89 ] or diagnosed via magnetic resonance imaging ( mri ) findings and lab values.[910 ] surgical management of acute compartment syndrome of the supraspinatus has been reported in only one other case.[10 ] to our knowledge , we report the only case of a patient with acute compartment syndrome of both the supraspinatus and infraspinatus compartments treated with emergent decompressive fasciotomy . due to the devastating complications and functional loss of a missed diagnosis of compartment syndrome , a high index of clinical suspicion for developing compartment syndrome must be maintained in every fracture setting , regardless of anatomic location or rarity of reported cases .
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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 stroke until the age of 45 is called juvenile cerebral infarction. in contrast to strokes in the elderly , juvenile strokes are often caused by rare pathologies , including dissections of the brain - supplying arteries , paradoxical embolism and thrombophilias .
cervical dissections are the most frequent singular cause of juvenile strokes and account for approximately 20% of acute strokes in young patients .
they are acquired on the basis of connective tissue disease ( e.g. marfan , ehlers - danlos syndrome ) or other predisposing factors [ 1 , 12 ] . a specific constellation is a dissection of the brain - supplying arteries due to a trauma .
traumatic craniocervical dissections result from excessive speed , rotating or lash - like head movements , such as falls , car accidents or other mild traumas .
traumatic dissections are often diagnosed too late due to a lack of awareness of potential initial signs .
the incidence of dissections of the internal carotid artery after a trauma ranges from 0.08 to 3.7% .
. it can be ensured more than half of the patients with dissections suffer from delayed cerebral infarctions or transient ischemic episodes . over
the rest occur partially up to a month later , some by formation of pseudoaneurysms and subsequent embolism .
clinical predictors of possible dissections of the carotid arteries include visible skull fractures , e.g. le fort type ii and iii and diffuse brain injuries ( glasgow coma scale of < 6 ) .
furthermore , strangulating traces by a seat belt injury , cervical swelling , cervical sounds under auscultation , expanding cervical hematomas , or focal neurological deficits ( particularly painful horner 's syndrome ) are suspicious .
a 16-year - old patient suffered from injuries sustained in a car accident by a collision with another vehicle .
there were multiple contusions and bruises , including the left knee , the chest ( seat belt injury ) and the left neck .
a massive hematoma with severe restriction of movement was found in the left leg . in hospital , a concussion , a cervical spine sprain and multiple bruises were diagnosed .
three months later , the patient came to our hospital emergency department after he suddenly developed a sensorimotor hemiparesis on the right .
the mri showed an embolic infarction of the left anterior basal ganglia and the left internal capsule ( fig .
over the course of one month the patient displayed an almost complete recovery with remaining mild facial palsy on the right .
in the present case , signs of a traumatic cervical artery dissection immediately after the accident were overlooked . in the acute setting , focal neurological deficits were absent .
an expanding cervical hematoma was initially documented and primarily attributed to a typical seat belt injury .
targeted investigations of the brain - supplying arteries were not done , resulting in the serious complication of a stroke in the region of the basal ganglia , occurring with a time lag of three months .
this case illustrates the importance of awareness for clinical signs of cervical artery dissections after a polytrauma , especially as we know about the high incidence of trauma in the groups of younger - aged and middle - aged patients and the known coincidence between polytrauma and stroke .
an incalculable factor is a delayed rupture of the intramural hematoma , which can lead to subsequent embolism by the formation of pseudoaneurysms .
there exists no special therapeutic guideline for traumatic cervical artery dissection of patients with polytrauma .
the medical treatment of traumatic cervical artery dissection is similar to spontaneous cervical artery dissections . in the acute phase of an ischemia as a result of a cervical artery dissection ,
a systemic thrombolysis is a possible therapeutic strategy according to stroke guidelines [ 1 , 7 ] .
however , the balance between beneficial effects and side effects of thrombolysis in patients with polytrauma must carefully be considered .
even more important is the initiation of an appropriate preventive strategy to avoid thromboembolic complications caused by the dissected artery .
different studies show that both antiplatelets and anticoagulation are effective without any clear advantage for one of the two therapies .
it has been proposed that an induced hypertension or an endovascular intervention for improving perfusion is justified in single cases . according to guidelines [ 1 , 4 ] , it is suggested to start with heparin followed by an anticoagulation therapy for 324 months .
a long - term treatment with aspirin is recommended because the risk of an ischemic complication in the future is not predictable . in chronic stage after 6 months of anticoagulation , if an aneurysms or a high - grade carotid stenosis persisted or have newly developed , a surgical intervention could be considered to prevent further ischemic events [ 11 , 14 ] . in the present case we recommended continuing the oral anticoagulation for 6 months .
we agreed a check - up 6 months after discharge with an imaging control to discuss the further procedure . in summary ,
multiple trauma patients have an almost 4% risk of a cervical internal carotid artery dissection .
to reduce the long - term morbidity or mortality of multiple trauma patients , an early detection of cervical carotid and vertebral dissections is strictly necessary .
diagnosis must particularly be precluded by the presence of skull fractures or when a cervical sound is noticed under auscultation , or an expanding cervical hematoma or other focal neurological symptoms ( especially horner 's syndrome ) exist .
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### Summary:
: dissections of the cervical arteries cause about 20% of total juvenile strokes .
approximately 4% of the carotid artery dissections are due to a ( poly)trauma such as car accidents . despite improved diagnostic facilities ,
traumatic dissections are often underdiagnosed or diagnosed too late due to a lack of awareness of potential initial signs and symptoms.we report here a case of a delayed embolic stroke after a car accident caused by a dissection of the carotid artery and subsequent pseudoaneurysm.to reduce the long - term morbidity or mortality of multiple trauma patients , an early detection of cervical carotid and vertebral dissections is strictly necessary .
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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:
: management of patients with poorly controlled narrow angle glaucoma due to extensive peripheral anterior synechiae ( pas ) is difficult .
several glaucoma procedures have been advocated to open the angle in patients with extensive pas , eg , surgical goniosynechiolysis1,2 and nd : yag laser - assisted goniosynechiolysis.3 these procedures have often been associated with significant side effects , including hemorrhage and damage to the angle.13 viscogonioplasty , which is a technique for breaking pas in acute angle closure glaucoma and chronic narrow angle glaucoma using a heavy viscoelastic , has previously been described by the authors.4,5 phacoemulsification and implantation of a foldable intraocular lens in glaucomatous eyes can , in itself , decrease the intraocular pressure and the number of antiglaucoma medications required.6 however , the effect of phacoemulsification and intraocular lens implantation in patients with poorly controlled narrow angle glaucoma and pas has not been extensively studied .
one study did demonstrate a potential benefit from surgical goniosynechiolysis performed in conjunction with phacoemulsification,2 but this was a nonrandomized clinical trial .
a pilot study using viscogonioplasty in combination with cataract extraction in patients with poorly controlled narrow angle glaucoma showed promising results , with a reduction in intraocular pressure , but the exact contribution of cataract removal in lowering intraocular pressure when combined with viscogonioplasty was unclear.4,5 a randomized controlled trial was therefore conducted to confirm the effect , if any , of viscogonioplasty combined with cataract extraction compared with cataract extraction alone on lowering intraocular pressure in patients with poorly controlled narrow angle glaucoma . to the best of our knowledge
the study protocol followed the tenets of the declaration of helsinki and was approved by the local sunderland research ethics committee .
informed written consent was obtained from every study patient after the nature and scope of the study protocol were explained .
patients with chronic narrow angle glaucoma who were scheduled for cataract extraction between april 2006 and may 2007 were prospectively enrolled .
all patients had an intraocular pressure that was judged to be too high , despite a patent iridotomy and use of antiglaucomatous medications .
thirty - eight patients ( 50 eyes ) who met the inclusion criteria were recruited for the study ( table 1 ) .
patients were randomized using a random number generator to receive phacoemulsification with viscogonioplasty ( 25 cases ) or phacoemulsification alone ( 25 controls ) .
patients were aged between 59 and 92 years , with a mean age of 72.40 years in the cases and 72.96 years in the controls ( table 2 ) .
all patients underwent a complete ophthalmic examination by the same consultant ophthalmologist with an interest in glaucoma , including refraction , visual acuity testing , slit lamp biomicroscopy , applanation tonometry , fundus examination , and gonioscopy using a zeiss four - mirror contact lens . each patient
s antiglaucomatous treatment was quantified using a scoring system devised by kubota et al8 where 1 point is assigned for each antiglaucomatous topical treatment and 2 points for oral acetazolamide .
patients were then randomized by a third party using a random number generator to receive either cataract extraction alone or cataract extraction with viscogonioplasty .
phacoemulsification was performed via a 3.2 mm temporal incision as a standard method , and a 5.5 mm foldable acrylic posterior chamber intraocular lens was implanted in the bag in all eyes .
the surgeon did not know which group the patients were randomized to until after the phacoemulsification was completed , when he was instructed either to perform viscogonioplasty or to inject balanced salt solution into the angle . in patients receiving viscogonioplasty ,
a heavy viscoelastic was injected near the angle ( without touching the trabecular meshwork ) following intraocular lens implantation to break the pas , taking care to avoid inducing ciliary body recession and inadvertent injury to the surrounding tissues .
care was also exercised while injecting the heavy viscoelastic in order to avoid inadvertent release of the cannula and damage to the drainage angle .
no surgical instrument was used to physically break the pas . upon completion of viscogonioplasty ,
viscoelastic was aspirated using automated irrigation / aspiration . in order to duplicate every step in the cases and controls , balanced salt solution was injected into the angle , instead of the heavy viscoelastic , in the controls .
all patients received oral acetazolamide 250 mg four times a day for 24 hours , as well as topical 1% prednisolone acetate four times a day and topical ketorolac eye drops four times a day to the operated eye .
one investigator examined all patients postoperatively on the first day , and at months 3 , 6 , and 12 postoperatively .
the investigator was masked to the status ( ie , cases or controls ) of the study patients . at each postoperative examination ,
the intraocular pressure , number of antiglaucomatous medications , and gonioscopic angle appearance were recorded .
analysis of parameters was conducted using analysis of variance t - tests , the fisher exact test , or the wilcoxon signed rank test as appropriate , depending on the variable analyzed .
patients with chronic narrow angle glaucoma who were scheduled for cataract extraction between april 2006 and may 2007 were prospectively enrolled .
all patients had an intraocular pressure that was judged to be too high , despite a patent iridotomy and use of antiglaucomatous medications .
thirty - eight patients ( 50 eyes ) who met the inclusion criteria were recruited for the study ( table 1 ) .
patients were randomized using a random number generator to receive phacoemulsification with viscogonioplasty ( 25 cases ) or phacoemulsification alone ( 25 controls ) .
patients were aged between 59 and 92 years , with a mean age of 72.40 years in the cases and 72.96 years in the controls ( table 2 ) .
all patients underwent a complete ophthalmic examination by the same consultant ophthalmologist with an interest in glaucoma , including refraction , visual acuity testing , slit lamp biomicroscopy , applanation tonometry , fundus examination , and gonioscopy using a zeiss four - mirror contact lens . each patient
s antiglaucomatous treatment was quantified using a scoring system devised by kubota et al8 where 1 point is assigned for each antiglaucomatous topical treatment and 2 points for oral acetazolamide .
patients were then randomized by a third party using a random number generator to receive either cataract extraction alone or cataract extraction with viscogonioplasty .
phacoemulsification was performed via a 3.2 mm temporal incision as a standard method , and a 5.5 mm foldable acrylic posterior chamber intraocular lens was implanted in the bag in all eyes .
the surgeon did not know which group the patients were randomized to until after the phacoemulsification was completed , when he was instructed either to perform viscogonioplasty or to inject balanced salt solution into the angle .
in patients receiving viscogonioplasty , a heavy viscoelastic was injected near the angle ( without touching the trabecular meshwork ) following intraocular lens implantation to break the pas , taking care to avoid inducing ciliary body recession and inadvertent injury to the surrounding tissues .
care was also exercised while injecting the heavy viscoelastic in order to avoid inadvertent release of the cannula and damage to the drainage angle .
no surgical instrument was used to physically break the pas . upon completion of viscogonioplasty ,
viscoelastic was aspirated using automated irrigation / aspiration . in order to duplicate every step in the cases and controls , balanced salt solution was injected into the angle , instead of the heavy viscoelastic , in the controls .
all patients received oral acetazolamide 250 mg four times a day for 24 hours , as well as topical 1% prednisolone acetate four times a day and topical ketorolac eye drops four times a day to the operated eye .
one investigator examined all patients postoperatively on the first day , and at months 3 , 6 , and 12 postoperatively .
the investigator was masked to the status ( ie , cases or controls ) of the study patients . at each postoperative examination ,
the intraocular pressure , number of antiglaucomatous medications , and gonioscopic angle appearance were recorded .
analysis of parameters was conducted using analysis of variance t - tests , the fisher exact test , or the wilcoxon signed rank test as appropriate , depending on the variable analyzed .
baseline characteristics of both patient groups showed no evidence of difference in age , angle characteristics , antiglaucoma medication , and baseline intraocular pressure using analysis of variance ( table 2 ) .
no patients in the study had any complications associated with either cataract removal or viscogonioplasty .
postoperatively , the intraocular pressure in the viscogonioplasty group was lower , despite the fact that the average intraocular pressure was higher preoperatively in this group .
this difference increased up to 12 months , ie , the endpoint of the study . using an analysis of covariance , adjusting from baseline intraocular pressure
mean intraocular pressure ( standard deviation ) at 12 months postoperatively in cases was 13.7 ( 2.89 ) mmhg compared with 16.2 ( 3.55 ) mmhg in controls ( p = 0.009 ) .
thirteen of 25 eyes ( 52% ) cases were controlled without any antiglaucoma therapy versus 9 of 25 ( 36% ) in the controls . at 12-month review
, there was a greater reduction in the mean number of antiglaucoma medications in cases than in controls ( p = 0.005 ) .
gonioscopic measurements taken throughout the study indicated an improvement in angle width in cases compared with controls ( p < 0.001 ) . at the time of this study , anterior segment optical coherence tomography was not available , so the analysis was subjective .
postoperatively , the intraocular pressure in the viscogonioplasty group was lower , despite the fact that the average intraocular pressure was higher preoperatively in this group .
this difference increased up to 12 months , ie , the endpoint of the study . using an analysis of covariance , adjusting from baseline intraocular pressure
mean intraocular pressure ( standard deviation ) at 12 months postoperatively in cases was 13.7 ( 2.89 ) mmhg compared with 16.2 ( 3.55 ) mmhg in controls ( p = 0.009 ) .
thirteen of 25 eyes ( 52% ) cases were controlled without any antiglaucoma therapy versus 9 of 25 ( 36% ) in the controls . at 12-month review
, there was a greater reduction in the mean number of antiglaucoma medications in cases than in controls ( p = 0.005 ) .
gonioscopic measurements taken throughout the study indicated an improvement in angle width in cases compared with controls ( p < 0.001 ) . at the time of this study ,
. this may be due to increased anterior chamber depth and consequent widening of the anterior chamber angle , but a proportion still have persistently high intraocular pressure following phacoemulsification , which either requires long - term topical treatment or further surgical intervention . in the presence of uncontrolled glaucoma and coexisting cataract , the surgeon has three possible options : ie , performing cataract surgery alone , performing glaucoma surgery followed by later cataract surgery , or performing combined cataract and glaucoma surgery .
glaucoma surgery for such cases has been substantially enhanced by the adjunctive use of antimetabolites in recent years , but vision - threatening complications , including hypotony , maculopathy , flat anterior chamber , and bleb infection , are not uncommon , and therefore suitable alternatives would be desirable .
they are seen as the hallmark of primary angle closure , and the extent of pas correlates with the likelihood of glaucomatous optic neuropathy in this condition .
several glaucoma procedures have been advocated to open the angle in patients with extensive pas , but these procedures have been associated with significant side effects .
goniosynechiolysis is one such surgical procedure where pas are broken in order to restore trabecular filtration .
conventionally , this has been performed using surgical instruments or by nd : yag laser.13 however , complications reported with this procedure include mild to severe hemorrhage from the iris or trabecular meshwork , fibrin exudation , choroidal hemorrhage , choroidal detachment , shallow anterior chamber , and transient elevation of intraocular pressure in the immediate postoperative period .
we have previously shown , in eyes with acute angle closure glaucoma , the efficacy of performing viscogonioplasty following cataract extraction to produce further intraocular pressure reduction.4 in a further study in narrow angle glaucoma patients , phacoemulsification combined with viscogonioplasty appeared to not only lower intraocular pressure in the immediate postoperative period but also maintain a sustained effect over a significant period of time.5 however , due to lack of controls , it was difficult to conclude whether it was cataract surgery itself or the additional procedure of viscogonioplasty that offered the significant lowering of intraocular pressure .
this current randomized controlled trial has allowed us to examine our original findings and has made it clear that although some lowering of intraocular pressure is seen following cataract surgery alone , in eyes with narrow angles an additional lowering of intraocular pressure is achieved with simultaneous viscogonioplasty .
in addition , we have demonstrated a reduction in the number of drops required to maintain lower intraocular pressure .
gonioscopic appearance showed an improvement in appearance of the drainage angle in both groups but noticeably more in the viscogonioplasty group .
we have shown an overall improvement in appearance on gonioscopic views , which is encouraging , but this was unfortunately subjective and will require a repeat study using anterior segment optical coherence tomography .
our study does have some limitations in that our follow - up data published here were measured over a 12-month period .
we are continuing to monitor our patients intraocular pressure for a longer period to demonstrate stability with and without treatment .
we are also , in the longer term , looking at any differences in visual field loss between the two groups .
one other limitation is that the technique used for viscogonioplasty is not in widespread use , and we are aware that if the findings from our paper are to be used in general ophthalmic practice then there will be a learning curve in the provision of this treatment .
this study demonstrated a pronounced and prolonged intraocular pressure reduction following cataract extraction and viscogonioplasty in eyes with chronic narrow angle glaucoma compared with cataract extraction alone .
we suggest that because of viscogonioplasty s ease , safety , and potential benefit , eyes with narrow angles undergoing cataract extraction should have viscogonioplasty following intraocular lens implantation .
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### Summary:
: purpose : to determine the effect of viscogonioplasty and cataract extraction on intraocular pressure in patients with narrow angle glaucoma.methods:this was a double - masked randomized controlled trial involving 50 eyes ( 25 cases and 25 controls ) from 38 consecutive patients . all patients underwent phacoemulsification with or without viscogonioplasty .
the main outcome measures were intraocular pressure post - treatment and number of glaucoma medications post-treatment.results:cases had a greater reduction in intraocular pressure than controls , with a mean intraocular pressure ( standard deviation ) at 12 months of 13.7 ( 2.89 ) mmhg compared with 16.2 ( 3.55 ) mmhg in controls ( p = 0.009 ) .
cases had a greater reduction in mean number of antiglaucoma medications than controls at 12-month review , with 13 of 25 eyes ( 52% ) of cases controlled without any antiglaucoma therapy versus 9 of 25 ( 36% ) of the controls ( p = 0.005).conclusions : viscogonioplasty combined with cataract extraction has a significantly greater effect than cataract extraction alone on lowering intraocular pressure in patients with poorly controlled narrow angle glaucoma and should therefore be considered as a treatment option for patients with this condition .
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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:
: malignant gliomas ( high - grade gliomas ) are the most common primary brain tumors in adults , accounting for approximately 60% of them . among these
, glioblastoma multiforme ( gbm ) is the most lethal subtype of glioma , classified as a who grade 4 infiltrative glioma and associated with a median survival time of approximately 18 months as well as a poor response to chemotherapeutic drugs [ 1 , 2 , 3 ] .
the etiology of gbm remains unknown and risk factors can be identified only in a small minority .
exposure to irradiation , especially in childhood , is the only risk factor that has been identified .
notably , among pediatric long - term survivors exposed to prophylactic cranial irradiation for acute leukemia , the incidence of primary brain tumors is 2.3% , approximately a fourfold increase over the expected rate .
there are many hereditary syndromes affecting the cns , and in these patients , gbm can occur in more than one related family member .
the purpose of this case report is to describe an unrelated married couple who developed gbm within an interval of 1 month .
the husband was a 76-year - old man who presented with headache , vague balance difficulties , left hemisensory and hemiparetic deficits in february 2012 .
he was admitted to another institution before he came to our institution , from which he was discharged with a clinical and neuroimaging diagnosis of hemorrhagic stroke ( fig .
c ) . over the next 2 months , the patient did not complain about any discomfort except for mild - to - moderate left hemidysesthesia . in april 2012 ,
a brain mri showed resorption of the bleeding and clear evidence of a large , right parietal , extra - axial mass ( fig .
the patient had no history of diabetes , hypertension or coagulation disorders and no history of trauma .
he pointed to his use of cell phones , which had started only a few years earlier , however , and occurred with moderate frequency .
the patient underwent a subtotal resection of the intracranial mass through a right temporoparietal approach .
pathologic evaluation showed a gbm tumor cell proliferation index as evaluated by anti - ki-67 mib1 antibody ( rabbit monoclonal antibody , diluted 1:100 ; neomarkers , inc . , fremont , calif .
, usa ) of about 5565% , an egfr of about 65% and p53 was negative .
the final pathologic diagnosis was grade iv gbm according to the who 2007 grading system . in may 2012 ,
a brain mri confirmed the lesion mass with a further bleeding . considering the patient 's clinical conditions and neuroimaging findings , we opted for supportive care and therapy with corticosteroids .
the patient continued supportive care waiting for the clinical conditions to allow treatment , but unfortunately , he died of his primary brain tumor in july 2012 .
the wife was a 72-year - old woman who presented in march 2012 with ingravescent , vague balance difficulties . a brain mri ( fig .
2 ) showed a large , inhomogeneous , irregularly gadolinium - enhancing , right , paratrigonal , intra - axial mass .
the patient grew up in the same small town as her spouse , had always worked as a nurse and was retired at the time of diagnosis .
she had been married for 46 years , with no evidence of possible consanguinity with her husband .
she reported that use of cell phones had occurred only within the last 10 years , with a very moderate frequency and only upon need .
pathologic evaluation showed a gbm tumor cell proliferation index as evaluated by anti - ki-67 mib1 antibody ( rabbit monoclonal antibody , diluted 1:100 ; neomarkers , inc . , fremont , calif .
a diagnosis of grade iv gbm according to the who 2007 grading system was rendered . a follow - up brain mri 1 month after surgery showed a volumetric increase of the right temporoparietal intra - axial mass with a mass effect on the ventricular system and midbrain , causing subfalcine herniation and a midline shift .
the patient started treatment with temozolomide ( tmz ) in combination with adjuvant radiation therapy and corticosteroids .
after she had finished radiotherapy , she was started on a 6-month tmz treatment . however , after only two cycles of tmz , our patient went into a coma and died in july 2012 .
the husband was a 76-year - old man who presented with headache , vague balance difficulties , left hemisensory and hemiparetic deficits in february 2012 .
he was admitted to another institution before he came to our institution , from which he was discharged with a clinical and neuroimaging diagnosis of hemorrhagic stroke ( fig .
c ) . over the next 2 months , the patient did not complain about any discomfort except for mild - to - moderate left hemidysesthesia . in april 2012 ,
a brain mri showed resorption of the bleeding and clear evidence of a large , right parietal , extra - axial mass ( fig .
the patient had no history of diabetes , hypertension or coagulation disorders and no history of trauma .
he pointed to his use of cell phones , which had started only a few years earlier , however , and occurred with moderate frequency .
the patient underwent a subtotal resection of the intracranial mass through a right temporoparietal approach .
pathologic evaluation showed a gbm tumor cell proliferation index as evaluated by anti - ki-67 mib1 antibody ( rabbit monoclonal antibody , diluted 1:100 ; neomarkers , inc . , fremont , calif .
, usa ) of about 5565% , an egfr of about 65% and p53 was negative .
the final pathologic diagnosis was grade iv gbm according to the who 2007 grading system . in may 2012 ,
a brain mri confirmed the lesion mass with a further bleeding . considering the patient 's clinical conditions and neuroimaging findings , we opted for supportive care and therapy with corticosteroids .
the patient continued supportive care waiting for the clinical conditions to allow treatment , but unfortunately , he died of his primary brain tumor in july 2012 .
the wife was a 72-year - old woman who presented in march 2012 with ingravescent , vague balance difficulties . a brain mri ( fig .
2 ) showed a large , inhomogeneous , irregularly gadolinium - enhancing , right , paratrigonal , intra - axial mass .
the patient grew up in the same small town as her spouse , had always worked as a nurse and was retired at the time of diagnosis .
she had been married for 46 years , with no evidence of possible consanguinity with her husband .
she reported that use of cell phones had occurred only within the last 10 years , with a very moderate frequency and only upon need .
pathologic evaluation showed a gbm tumor cell proliferation index as evaluated by anti - ki-67 mib1 antibody ( rabbit monoclonal antibody , diluted 1:100 ; neomarkers , inc . , fremont , calif .
a diagnosis of grade iv gbm according to the who 2007 grading system was rendered . a follow - up brain mri 1 month after surgery showed a volumetric increase of the right temporoparietal intra - axial mass with a mass effect on the ventricular system and midbrain , causing subfalcine herniation and a midline shift .
the patient started treatment with temozolomide ( tmz ) in combination with adjuvant radiation therapy and corticosteroids .
after she had finished radiotherapy , she was started on a 6-month tmz treatment . however , after only two cycles of tmz , our patient went into a coma and died in july 2012 .
gbm is the most common and aggressive primary malignant brain tumor in humans and appears to occur most frequently in males and whites . despite continuous advances in diagnosis , classification and therapy ,
. the median overall survival of < 18 months is due to the resistance to radiotherapy and chemotherapy following surgery . unlike other malignancies , gmb does not share common associations as others tumors do .
notably , the etiology and main risk factors leading to gmb are still mostly unknown .
although most gbms appear to be sporadic without any genetic predisposition , there are many hereditary syndromes affecting the cns , including neurofibromatosis type 1 and 2 , li - fraumeni syndrome , von hippel - lindau syndrome , and turcot 's syndrome that seem to predispose to the development of other cns tumors ( astrocytomas , meningiomas and medulloblastoma ) rather than gbm . in both patients
described herein , a genetic screening was performed and resulted negative for hereditary syndromes . however , as patient 2 had an associated pituitary macroadenoma and a meningioma , the occurrence of three intracranial tumors raised the question of their genetic determinance .
other agents and specifically virus infections are also assumed to be involved in the development of brain tumors .
indeed , viral infections such as sv40 or cytomegalovirus have already been suggested as a possible origin of malignant glioma .
furthermore , lehrer showed an increased incidence of brain tumors following malaria outbreaks in the united states and mentioned the anopheles mosquito as another possible source for brain tumors . in the patients
reported herein , we were unable to clearly identify any virus as a risk factor , since the most important viral antigens were nonsignificant during the illness .
exposure to toxins was also taken into consideration as a potential etiological factor in specific professions because a higher incidence of tumors has been registered in farmers and petrochemical workers , who are exposed to a variety of chemical products . however , both patients had no history of occupational exposure .
a 24-urine screening for a metal test was performed in both spouses ; however , there were no significant results .
the role of nonionizing radiation emitted by cell phones seems to be more controversial , since the link between the use of cell phones and brain tumors has been widely investigated .
however , the results have no definitive conclusion . on may 31 , 2011 , the who announced their classification of radiofrequency electromagnetic fields emitted from cell phones as
however , a danish study on the use of cell phones performed with a large cohort of cancer patients from a national registry concluded that there was little evidence for a causal association and therefore no increased risk of cns tumors .
another recent study by little et al . suggested that there is little evidence linking cell phone use to a higher risk for glioma . on the other hand
, the researchers noted that the higher risks previously seen were not consistent with the incidence trends they found in the american population .
thus , the issue of the possible role of nonionizing radiation emitted by cell phones is far from been solved .
an analysis of exposure to nonionizing electromagnetic fields ( transmitters , cell phones , radio alarm clocks , electrical appliances , electrical circuits ) and ionizing radiations ( natural radiations and possible contaminations ) was performed in the couple 's house and surrounding environment ( furniture , tools , fields and orchards ) , but the results were within normal ranges . upon further investigation of the couple 's habits , it was found that they both regularly used trichloroethylene solvents to clean the house floors .
however , the role of this component appeared scarcely relevant , as it is currently not known to cause tumors of the brain . as reported in the literature
, the risk of simultaneous tumor occurrence is in the order of 1 in 185 million .
the synchronous occurrence of gbm in a husband and a wife within an interval of 2 years has already been described in 1986 by grifin et al . .
the year before , in 1985 , tupchong et al . described the development of the same brain tumor in a husband and a wife within an interval of 18 months .
the case reported herein is the first to describe the event occurring within an even shorter period of only 1 month .
however , in all reported cases , the investigators were unable to identify the specific etiology , including the current report .
nonetheless , because the simultaneous occurrence of such tumors is so rare , the hypothesis of random occurrence of these tumors should be rejected . in conclusion
, we presented a case of synchronous occurrence of gbm in a husband and a wife that developed within an interval of 1 month .
no specific cause was identified as environmental exposure was negative for risk factors such as electromagnetic fields and ionizing radiation , and there were no incidences of cancer in both patient families . to date , there are few data supporting the hypothesis of a common environmental exposure that predisposes couples to develop a brain tumor , but at the same time , it is very difficult to think of such simultaneously occurring tumors as a rare coincidence .
thus , further reports on similar cases are needed before an evident etiologic factor can be determined .
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### Summary:
: glioblastoma multiforme ( gbm ) is the most lethal subtype of glioma , classified as a who grade 4 infiltrative glioma .
the etiology of gbm remains unknown and risk factors can be identified only in a small minority .
we report the synchronous occurrence of gbm in an otherwise unrelated married couple , i.e. a husband and his wife , who developed gbm within an interval of 1 month .
no specific causative environmental factors were identified for both patients , and the genetic screens were negative for hereditary syndromes .
family history was negative for tumors , and no other incidence of cancer in either siblings , parents or other children was reported .
an analysis of the couple 's exposure to nonionizing electromagnetic fields and ionizing radiations revealed values within the normal ranges usually found in homes .
overall , conjugal tumors are rarely reported .
however , the case reported herein raises important questions about possible etiologic factors .
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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:
: fluorescence spectroscopy is a classical method for studying the structural and dynamical aspects of biological systems such as proteins , membranes and living cells [ 13 ] .
the excited states of the fluorophores have indeed lifetimes in the range of a few picoseconds to some tens of nanoseconds .
since this corresponds to the time scale of many important biological processes , such as the protein folding dynamics , the protein - dna interactions , the diffusion of small molecules , the rotational and internal motions , the proton transfer and the energy transfer mechanism [ 46 ] , the time resolved fluorescence has became an important investigation tool . despite the great advances in measurement techniques over the recent years , the analysis of fluorescence decays belongs to the difficult tasks in data analysis .
indeed , a parametric multi - exponential model function is usually fitted with the experimental data by non linear least squares methods . besides a difficulty to find the global overall minimum of the chi - squared function by the parametric minimization procedure , this statistical criteria very rarely allowed to fit the analysed decay curve by more than three exponential functions .
moreover , there are many situations where the time resolved fluorescence profile is described by a continuous lifetime distribution rather than a discrete number of exponential decays . for example , the tryptophan residues in the exited state are usually involved in a energy transfer process to intra - molecular acceptors that depends on the relative distance and affects the fluorescence lifetime [ 4 , 8 ] .
this behaviour of the tryptophan is used to get structural informations on the intermediate forms of proteins that characterise their folding process from an extended random polypeptide chain . in complex situations , such as those encountered even in small proteins ,
the rate of energy transfer and thus the intra - molecular distances can be described by a continuum distribution due to heterogeneity of the structure that turns out to a continuum lifetime distribution for the fluorescence decay [ 912 ] . in these cases , the analysis for recovering the distribution takes advantages of a regularizing function in addition to the chi - squared statistic for forcing the data to choose one member out of the set of the feasible distributions .
the skilling entropy s is one of these regularizing functions and it is maximized subjected to the constraint ~1 by the maximum entropy method ( mem ) thus determining the desired distribution with no assumptions about its functional form [ 1421 ] .
the mem is a mathematically complex algorithm that seeks the stationary point of the lagrange function = s + ( 1 ) , being the so - called lagrange multiplier , that turns out to be the solution of the set of non linear equations resulting from \documentclass[12pt]{minimal }
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\begin{document}$\nabla \lambda=0$\end{document}. due to the once limited computer memory and low performing computational time , the conjugate gradient method ( cg ) has been the iterative method widely spread for the solution of equation systems .
the necessary compromise between the accuracy of the solution and the convergence speed of the algorithm limited both the number of data points and the number of lifetimes used for reconstructing the desired distribution to a maximum values of about 1,000 and 200 respectively , with the obvious limitation of the information content in the mem distribution [ 25 , 26 ] .
nowadays , the extensive computing power of a standard home computer makes possible the adoption of new iterative approaches to the mem based on direct methods . in this paper
we present a new procedure based on the newton - raphson method for solving the lagrange multiplier problem associated to the mem constrained problem . a method for the solution of the equation system \documentclass[12pt]{minimal }
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\begin{document}$\nabla \lambda=0$\end{document } through iterative linear approximations and lu decomposition is extensively discussed .
the implementation of the mem is carried out using a homebuilt routine package written in matlab ( version 7.14 , the mathworks inc . ,
the accuracy of the algorithm is investigated through comparisons with numerical simulations of fluorescence decay data .
it results that the mem algorithm proposed can analyse datasets with up to 4,096 data points , that is a typical value of an experimental set up based on a time - correlated single photon counting technique , by considering distributions with a number of lifetimes that ranges from 100 to 1,000 .
the time - resolved fluorescence decay data \documentclass[12pt]{minimal }
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\begin{document}$\lbrace e_m \rbrace$\end{document } can be described by a function t(t ) defined as a discrete convolution product of the intensity decay function i(t ) by the impulse response function r(t ) :
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\begin{document}$$ t(t ) = \sum\limits_{m=1}^{m } { r(t_m ) \cdot i(t - t_m ) } \label{t } $ $ \end{document}with tm the measurement time of the m - th data point em and m the number of data points .
the quantity r(tm ) is experimentally measured at each time tm whereas i(t ) is usually modelled as a discrete sum of exponential decays :
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\begin{document}$$ i(t ) = \sum\limits_{k=1}^{n } \alpha_k \rm{e}^{-\frac{t}{\tau_k } } , \label{i_2 } $ $ \end{document}for the purpose of numerical calculations the sum in eq .
2 is extended from the resolution limit 1 imposed by the experimental set - up to the maximum lifetime n of the chromophore observed .
the quantity n is the number of partitions of the interval [ 1 , n ] , k and k the amplitude factors and the lifetime of the k - th partition , respectively .
the expression 2 allows to write the convolution sum expressed by the eq . 1 as follows :
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\begin{document}$$ \begin{array}{rll } t(t_m ) & = & \sum\limits_{k=1}^n { c_{m , k } \cdot \alpha _ k } \\
c_{m , k } & = & \sum\limits_{i=1}^m { r(t_i}){\rm{e}^ { - \frac{{t_m - t_i}}{\tau_k } } } \label{t_2 } \end{array } $ $ \end{document}there are many sets \documentclass[12pt]{minimal }
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\begin{document}$\lbrace\alpha_k\rbrace$\end{document } physically allowable that agree with the data within the experimental precision \documentclass[12pt]{minimal }
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\begin{document}$\lbrace \sigma_k \rbrace$\end{document } and the maximum entropy method selects the distribution \documentclass[12pt]{minimal }
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\begin{document}$\lbrace\alpha_k\rbrace$\end{document } that maximizes the skilling entropy function s
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\begin{document}$$ s(\alpha_{1}, ... ,\alpha_n ) = \sum\limits_{k=1}^{n } { \alpha_k - \alpha_k \log(\alpha_k ) } \label{entropy } $ $ \end{document}subjected to the following chi - squared condition :
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\begin{document}$$ \chi^{2 } = \frac{1}{m } \sum\limits_{m=1}^{m } \frac{\left(e_{m}-t(t_m)\right)^2}{\sigma_m^2 } \sim 1 \label{chi } $ $ \end{document}with the lifetime components equally spaced in a logarithmic scale .
5 , the number m of observations is not reduced by the number n of parameters , because this condition is not used to find the optimal set of parameters in -space but it is used to test whether or not computed data is in satisfactory agreement with measured data . in the following a new algorithm for maximizing the entropy
the method of lagrange multiplier provides a strategy for finding the minimum of -s with the constraint 5 by considering the following lagrange function
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\begin{document}$$ \lambda\left(\alpha_1, ... ,\alpha_n ,
\alpha_n\right ) + \lambda \cdot \left(\chi^2 -1\right ) , \label{funcional } $ $ \end{document}where is the lagrange multiplier .
the mem solution is an extremal of for some value of the lagrange multiplier , thus it is obtained by solving the set of non linear equations \documentclass[12pt]{minimal }
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\begin{document}$\nabla \lambda = 0$\end{document } :
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\begin{document}$$ \begin{array}{rll } & & ( \nabla \lambda)_{i } = [ \nabla ( -s)]_{i } + \lambda \left(\nabla \chi^2\right)_{i } = 0 \qquad \;\ ; i = 1 .. n \\ & & ( \nabla \lambda)_{n+1 } = \chi^2 -1 = 0 \label{set } \end{array } $ $ \end{document}with
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\begin{document}$$ \begin{array}{rll } [ \nabla ( -s)]_{i } & = & \log(\alpha_i ) ; \\ ( \nabla \chi^2)_{i } & = & - \frac{2}{m } \sum\limits_{m=1}^{m } \frac{\left(e_m-\sum_{k=1}^n c_{m , k } \alpha_k\right)}{\sigma_m^2 } c_{m , i } \label{log } \end{array } $ $ \end{document}the subscript i is used to indicate the first n components of gradients \documentclass[12pt]{minimal }
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\begin{document}$\nabla \lambda$\end{document } , \documentclass[12pt]{minimal }
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\begin{document}$\nabla ( -s)$\end{document } and \documentclass[12pt]{minimal }
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\begin{document}$\nabla \chi^2$\end{document } , whereas the last component is given by the subscript n + 1 .
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\begin{document}$\textbf{f } = \nabla \lambda$\end{document}. in order to solve the set 7 , each of the equations fi = 0 is expanded in taylor series :
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\begin{document}$$ f_{i}(\mathbf{x } + \delta \mathbf{x } ) = f_{i}(\mathbf{x } ) + \sum\limits_{j=1}^{n+1 } { \frac{\partial f_i } { \partial x_j } \delta x_{j } + o\left(\delta \mathbf{x^2}\right ) } \label{eqscal } $ $ \end{document}the matrix of partial derivatives appearing in eq .
9 is the hessian matrix h of the function :
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\begin{document}$$ h_{i , j } = \frac{\partial f_i}{\partial x_j } = \frac{\partial^{2 } \lambda}{\partial x_j \partial x_i } $ $ \end{document}and its elements are given by :
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\begin{document}$$ \begin{array}{llr } \frac{\partial^2 \lambda}{\partial x_j \partial x_i } = \frac{\partial^2 \lambda}{\partial x_{i } \partial x_{j } } = \frac{\delta_{i , j}}{x_j } + \frac{2 \lambda}{m } \sum\limits_{m=1}^{m } \frac{c_{m , i } c_{m , j}}{\sigma^2_m } , & & \\ & & i , j \leq n \end{array } $ $ \end{document}11\documentclass[12pt]{minimal }
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\begin{document}$$ \begin{array}{rll } \frac{\partial^2 \lambda}{\partial x_{n+1 } \partial x_i } & = & \frac{\partial^2 \lambda}{\partial x_i \partial x_{n+1 } } = -\frac{2}{m } \\ & & \times \sum_{m=1}^{m } \frac{\left(e_m-\sum_{k=1}^n c_{m , k } x_k\right)}{\sigma_m^2 } c_{m , i } , \\ & & \quad\qquad\qquad\qquad\qquad i \leq n , j = n+1 \\ \frac{\partial^2 \lambda}{\partial x_{n+1 } \partial x_{n+1 } } & = & 0 \qquad\qquad\qquad i , j = n+1 \end{array } $ $ \end{document}in matrix notation the eq .
9 is
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\begin{document}$$ \mathbf{f}(\mathbf{x } + \delta \mathbf{x } ) = \mathbf{f}(\mathbf{x } ) + h \cdot \delta \mathbf{x } + o\left(\delta \mathbf{x^2}\right ) \label{eqvect } $ $ \end{document}by neglecting terms of order x and by setting f(x
+ x ) = 0 , we obtain a set of linear equations for the corrections x ( the newton step ) , namely
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\begin{document}$$ h \cdot \delta \mathbf{x } = - \mathbf{f } \label{apprlin } $ $ \end{document}the solution to the set of equations 7 is obtained by solving iteratively the linear set 14 that minimizes the norm f = 1/2 f f because the correction x move each function fi closer to zero simultaneously at each iteration .
the first iteration is performed by considering the distribution \documentclass[12pt]{minimal }
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\begin{document}$\lbrace\alpha_k\rbrace$\end{document } that equals the calculated total intensity to the experimental one , namely a flat distribution with a constant value of mem/ m , kcm , k for all lifetimes .
the matrix equation 13 is solved by the package linsolve of matlab that implements a lu decomposition algorithm that writes h as a product of two matrices :
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\begin{document}$$ h = l \cdot u $ $ \end{document}where l and u are respectively a lower and upper triangular matrix .
their elements are obtained by the crout s algorithm whose stability is increased by a partial pivoting technique .
the decomposition is used first for solving for the vector y such that
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\begin{document}$$ l \cdot \mathbf{y } = - \mathbf{f } $ $ \end{document}and then for solving
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\begin{document}$$ u \cdot \delta \mathbf{x } = \mathbf{y } $ $ \end{document}the advantage of breaking up the linear set 14 into two successive ones is that the solution of a triangular set of equations is quite trivial and is given by back - substitution .
once the new approximated solution x + x is obtained , one seeks negative values among its first n components because the natural logarithm in eq .
if this is the case , the positiveness is enforced by using only a fraction of the corrections x .
generally , the newton step x is a descent direction for the norm f :
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\begin{document}$$ \nabla f \cdot \delta \mathbf{x } = ( \mathbf{f } \cdot h ) \cdot ( -h^{-1 } \cdot \mathbf{f } ) = - \mathbf{f } \cdot \mathbf{f } < 0 $ $ \end{document}therefore , we always first try the full correction x because once we are close enough to the solution a quadratic convergence is given and the proposed step reduces f. conversely , if the linear approximation 12 is not satisfied , x need not decreases the norm f and a backtrack along the newton direction is adopted until an acceptable step is obtained .
particularly , one moves to a new point
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\begin{document}$$ \mathbf{x_{new } } = \mathbf{x } + \epsilon \delta \mathbf{x},~~~0 < \epsilon \leq 1 $ $ \end{document}and the parameter is chosen to minimize f in the direction x .
this goal is achieved by using the routine fminbnd of matlab that implements the golden section search algorithm .
the improved approximation xnew is used as a new starting point for the set of equations 14 and the procedure is iterated until the minimum of the functional is achieved .
the set of values \documentclass[12pt]{minimal }
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\begin{document}$\lbrace\alpha_k\rbrace$\end{document } that minimizes with ~1 is the lifetime distribution that accounts for the experimental data .
in the following the accuracy of the mem algorithm proposed in the previous section is investigated through comparisons with numerical simulations of fluorescence decay data .
synthetic data \documentclass[12pt]{minimal }
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\begin{document}$\lbrace e_m \rbrace$\end{document } are generated with time scale and time resolution that are typical in experimental set - up for time - correlated single photon counting technique ( tcspc ) .
the simulated curves consist of 4,096 data points over a time scale of 25 ns and are generated by the convolution product of a gaussian profile with full - width at half maximum ( fwhm ) of 120 ps , the impulse response function r(t ) , and a decay model function according to the eq .
the poisson noise statistics that affects the typical tcspc measurements is simulated by taking as a value for the intensity at each time a poisson - distributed random number with a mean equal to the calculated model value em .
the routine poissrnd of matalb is used to this purpose and its algorithm is extensively described in . according to this procedure for generating simulated data ,
the number of counts in each point is its variance and the peak counts can be considered as a measure of the noise content of the decay curve .
multi exponential intensity decays are usually adopted for the analysis of the fluorescence emission of proteins in aqueous solutions and lie on the border of complexity that can be handled by parametric methods . in fig . 1 we report a fluorescence decay curve ( black points ) with 10 counts in the maximum generated by three exponential functions with lifetimes 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps and amplitude j = 0.33 , j = 1, ... ,3 .
the solid red line is the curve resulting from the fitting with the mem algorithm by considering n = 400 points equally spaced in log between min = 20 ps and \documentclass[12pt]{minimal }
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\begin{document}$\tau_{\rm max}=10 ^ 4$\end{document } ps . the mem convergence is achieved for a chi - square value equals to = 1.01 and the accuracy of the algorithm is confirmed by the random distribution of the residuals around zero as it is shown in the lower panel of fig . 1 . the normalised lifetime distribution that accounts for the agreement between the mem curve and the synthetic decay data is reported in fig . 2 .
the distribution consists of multiple peaks whose mean position \documentclass[12pt]{minimal }
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\begin{document}$\langle \alpha_j \rangle$\end{document } are calculated as follows
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\begin{document}$$ \begin{array}{rll } \langle \tau_j \rangle & = & \frac{\sum_{k=1}^{n_j } \alpha_k \tau_k \delta_k}{\sum_{k=1}^{n_j } \alpha_k \delta_k } \nonumber \\
\langle \alpha_j \rangle & = & \frac{\sum_{k=1}^{n_j } \alpha_k \delta_k}{\sum_{k=1}^{n } \alpha_k \delta_k } \label{average } \end{array } $ $ \end{document}where nj is the number of lifetimes represented in each peak and k is the spacing in log. the calculated mean values \documentclass[12pt]{minimal }
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\begin{document}$\langle \alpha_j \rangle$\end{document } are reported in table 1 and are the retrieved lifetimes and the pre - exponential factors of the analysed decay curve .
similarly , the standard deviation of the data points of the peak region is considered as the uncertainty in the lifetime estimate , whereas the error of the amplitude factor is given by the standard deviation of the values calculated for a set of 20 simulated decay curves .
the parameters generated by a non linear least - square regression analysis with a three exponential model function are also shown in the table 1 for comparison .
it results a very good agreement among the estimates of the amplitudes j given by both methods .
the values retrieved by the non linear fitting are indeed within three standard deviations and have relative errors lower than 3 % , whereas the relative amplitudes calculated from the mem lifetime distribution agree with the theoretical values within 2 % . as far as it concerns the three lifetimes , the values of 1 , 2 and 3 are recovered by the mem within one standard deviation , whereas the non linear fitting procedure achieves this accuracy only for 1 , as 2 and 3 lie within two and four standard deviations , respectively . the long lifetime 3 even outside the three - sigma interval witnesses the difficulty in fitting decay curves with more than three exponential functions .
1the fluorescence decay intensity ( black points ) simulated by three exponential functions with lifetimes 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps and the same value for the relative amplitude j = 0.33 . the red solid line is the curve fitted with the mem for n = 400 exponential decays . the residuals are reported in the lower panelfig .
2the normalised lifetime distribution (t ) / (t) obtained by the mem analysis of a simulated noisy multi - exponential decay with 10 counts in the peak channel .
the simulated data consists of 4,096 data points on a time scale of 25 ns and are characterised by 3 lifetimes : 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps . the mem results are obtained for n = 400 points equally spaced in log between 20 ps and 10 ps and are reported in table 1table 1the decay parameters recovered by the mem analysis of a three exponential decay with 10 counts in the peak channelsimulated parameters1231 ( ps)2 ( ps)3 ( ps)0.330.330.331001,0004,000mem results\documentclass[12pt]{minimal }
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\begin{document}$\langle \tau_3 \rangle$\end{document}0.33 0.010.337 0.0050.333 0.00399 7970 403,970 401.01least - square fit1231 ( ps)2 ( ps)3 ( ps)0.33 0.010.332 0.0060.340 0.00499 5970 153,960 101.01the uncertainties of the lifetime estimates \documentclass[12pt]{minimal }
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\begin{document}$\langle \tau_j \rangle$\end{document } are given by the standard deviations of the data points of the peak regions , whereas the errors of the amplitude factors \documentclass[12pt]{minimal }
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\begin{document}$\langle \alpha_j \rangle$\end{document } are the standard deviations of the values calculated for a set of 20 synthetic curves .
results of non linear least - square regression analysis are also reported for comparison together with the theoretical values of the simulated curve . in this case
the uncertainties of the parameters are given by the fitting procedure the fluorescence decay intensity ( black points ) simulated by three exponential functions with lifetimes 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps and the same value for the relative amplitude j = 0.33 . the red solid line is the curve fitted with the mem for n = 400 exponential decays . the residuals are reported in the lower panel the normalised lifetime distribution (t ) / (t) obtained by the mem analysis of a simulated noisy multi - exponential decay with 10 counts in the peak channel .
the simulated data consists of 4,096 data points on a time scale of 25 ns and are characterised by 3 lifetimes : 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps .
the mem results are obtained for n = 400 points equally spaced in log between 20 ps and 10 ps and are reported in table 1 the decay parameters recovered by the mem analysis of a three exponential decay with 10 counts in the peak channel the uncertainties of the lifetime estimates \documentclass[12pt]{minimal }
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\begin{document}$\langle \tau_j \rangle$\end{document } are given by the standard deviations of the data points of the peak regions , whereas the errors of the amplitude factors \documentclass[12pt]{minimal }
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\begin{document}$\langle \alpha_j \rangle$\end{document } are the standard deviations of the values calculated for a set of 20 synthetic curves . results of non linear least - square regression analysis are also reported for comparison together with the theoretical values of the simulated curve .
in this case the uncertainties of the parameters are given by the fitting procedure the mem accuracy in reconstructing a lifetime spectrum ( ) can be analysed by considering the ratio \documentclass[12pt]{minimal }
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\begin{document}$r=\delta \tau / \langle \tau \rangle$\end{document}. in fig .
3 the values of r calculated for a single exponential decay with lifetime = 3,000 ps are reported as a function of peak counts .
the results have been obtained for a mem analysis that has considered both m = 4,096 ( black solid curves ) and m = 1,024 ( red solid curves ) data points .
a lifetime spectrum equally spaced in log between 20 ps and 10 ps has been considered with a discretization that ranges from n = 100 to n = 1,000 in order to investigate the sensitivity of the method to the number of data points and the lifetimes in log space , respectively . from inspection of the curves
it results the ratio r does not depend on the noise level when the number of counts of the peak is larger than 3 510 .
the ratio r is always smaller than 3 % and decreases as the number n of discretization of the lifetimes space increases . when n is larger than 400 r is smaller than 1 % reaching the uncertainty of the non linear fit ( black dotted curve ) when n is larger than 1,000 .
furthermore , the results obtained for m = 4,096 and m = 1,024 data points are comparable showing that the mem accuracy is not affected by the number of data points for m 1,024 .
fig .
3the ratio \documentclass[12pt]{minimal }
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\begin{document}$r=\delta \tau / \langle \tau \rangle$\end{document } calculated for the mem lifetime spectrum of a single exponential decay with lifetime = 3,000 ps as a function of peak counts .
the values of r have been calculated for different values of the number of lifetimes n = 100,200,400,1,000 that ranges from 20 ps to 10 ps .
the black solid curves are obtained by considering m = 4,096 data points in the mem analysis , whereas the red solid curves are given for m = 1,024 data points .
the black dotted curve is the uncertainty of the mean lifetime estimated by the non linear fit the ratio \documentclass[12pt]{minimal }
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\begin{document}$r=\delta \tau / \langle \tau \rangle$\end{document } calculated for the mem lifetime spectrum of a single exponential decay with lifetime
the values of r have been calculated for different values of the number of lifetimes n = 100,200,400,1,000 that ranges from 20 ps to 10 ps .
the black solid curves are obtained by considering m = 4,096 data points in the mem analysis , whereas the red solid curves are given for m = 1,024 data points .
the black dotted curve is the uncertainty of the mean lifetime estimated by the non linear fit to test the performances of our algorithm with broad lifetime distributions , we considered gaussian distributions centred at = 5,000 ps with different standards deviation = 500 ps , 1,000 ps , 1,500 ps ( i.e. 10 , 20 % and the 30 % of ) , that are assumed as a measure of their width .
a set of 20 fluorescence decays curves with m = 4,096 data points and ~510 number of counts at the maximum has been generated for each of these distributions .
n = 400 points equally spaced in log between 40 ps and 10 ps and each normalised mem spectrum ( ) has been fitted with a gaussian profile to estimate the center and the width of the distribution . in fig .
4 the typical mem spectra obtained for each set ( differently marked points ) are shown together with the gaussian fitted curves ( solid lines ) whereas the mono - modal section of the table 2 reports the mean values and the uncertainties of the center and the width of the gaussian distributions calculated for each set of curves .
the uncertainties are the standard deviations of the estimates of the parameters calculated for each set .
figure 4 shows that the mem algorithm reproduces the gaussian profile of the distributions with excellent resolution of the leading and the falling edges .
the fitting results are reported in the table 2 , where a good agreement is observed between the values estimated for the parameters of the gaussian lifetime distributions and the theoretical ones .
4the normalized lifetimes spectra ( ) reconstructed by the mem analysis performed on fluorescence decay intensities with ~5 10 counts in the peak channel by using n = 400 points equally spaced in log between 40 ps and 10 ps .
the gaussian distributions are centred at = 5,000 ps and have different standard deviations , = 500 ps ( black open circles ) , = 1,000 ps ( red open squares ) , = 1,500 ps ( blue open diamonds ) .
the solid lines are the gaussian fitted profilestable 2the center and the width of the gaussian lifetime distributions recovered by the mem and estimated through a fitting procedure gaussian 1-modal distributiongaussian 2-modal distributionnominal valuesmem resultsnominal valuesmem resultsamplitude110.92 0.021center ( ps)5,0004,990 151,0005,000985 345,016 23width ( ps)500498 153001,500319 311,515 95amplitude0.510.45 0.031center ( ps)5,0005,008 191,0005,000989 425,012 24width ( ps)1,0001,029 203001,500329 381,528 54amplitude0.2510.23 0.011center ( ps)5,0005,009 101,0005,000990 305,038 24width ( ps)1,5001,524 153001,500315 241,546 31amplitude0.110.092 0.0081center ( ps)1,0005,0001,036 875,006 17width ( ps)3001,500336491,509 31a set of 20 fluorescence decay curves with 5 10 counts in the peak channel has been generated for each distribution .
the reported values are the means and the standard deviations of the estimates of the parameters calculated for each set .
the results have been obtained by using n = 400 points equally spaced in log between 40 ps and 10 ps the normalized lifetimes spectra ( ) reconstructed by the mem analysis performed on fluorescence decay intensities with ~5 10 counts in the peak channel by using n = 400 points equally spaced in log between 40 ps and 10 ps .
the gaussian distributions are centred at = 5,000 ps and have different standard deviations , = 500 ps ( black open circles ) , = 1,000 ps ( red open squares ) , = 1,500 ps ( blue open diamonds ) .
the solid lines are the gaussian fitted profiles the center and the width of the gaussian lifetime distributions recovered by the mem and estimated through a fitting procedure a set of 20 fluorescence decay curves with 5 10 counts in the peak channel has been generated for each distribution .
the reported values are the means and the standard deviations of the estimates of the parameters calculated for each set .
the results have been obtained by using n = 400 points equally spaced in log between 40 ps and 10 ps the resolution limit of the algorithm in resolving the intensities of the lifetimes spectrum has been investigated by adding a gaussian distribution with different peak intensities on the tail of the distribution peaked at = 5,000 ps . to this purpose
4 observed for a width = 1,500 ps and added an additional distribution centred at = 1,000 ps with a width = 300 ps .
four values for the amplitude of this additional peak have been considered : 100 , 50 , 25 and the 10 % of the main peak at = 5,000 ps . as before , a set of 20 fluorescence decay curves has been generated in each case for working out the errors in recovering the characteristic parameters of these bi - modal lifetime distributions through a bi - gaussian fitting procedure . in each panel of the fig .
5 the typical mem spectrum ( black points ) and the best fit ( red curve ) by two gaussian curves have been shown .
the average for each set of decay curves of the peak position ( center ) , the height ( amplitude ) and the width ( ) are reported in table 2 .
as it can be seen , the position and the width of the main peak are estimated with an accuracy that is not affected by the presence of the secondary peak .
similar results are observed for the retrieved parameters of the secondary peak showing that our algorithm resolves two distributions even when their amplitude are in the ratio 1:10 .
5the normalized lifetimes spectra ( ) reconstructed by the mem analysis ( black points ) for a bi - modal gaussian distribution with the main peak centred at = 5,000 ps and the secondary to = 1,000 ps .
four values for the amplitude of the additional peak have been considered and they represent 100 % a , 50 % b , 25 % c and the 10 % d of the main peak . both gaussians have size equals to the 30 % of their peak location .
the results refer to fluorescence decay intensities with ~5 10 counts in the peak channel and have been obtained by using n = 400 points equally spaced in log between 40 ps and 10 ps .
the solid red line are the two gaussian fitted profiles used to estimate the characteristic parameters of the bi - modal distribution ( see table 2 ) the normalized lifetimes spectra ( ) reconstructed by the mem analysis ( black points ) for a bi - modal gaussian distribution with the main peak centred at = 5,000 ps and the secondary to = 1,000 ps .
four values for the amplitude of the additional peak have been considered and they represent 100 % a , 50 % b , 25 % c and the 10 % d of the main peak . both gaussians have size equals to the 30 % of their peak location .
the results refer to fluorescence decay intensities with ~5 10 counts in the peak channel and have been obtained by using n = 400 points equally spaced in log between 40 ps and 10 ps .
the solid red line are the two gaussian fitted profiles used to estimate the characteristic parameters of the bi - modal distribution ( see table 2 )
multi exponential intensity decays are usually adopted for the analysis of the fluorescence emission of proteins in aqueous solutions and lie on the border of complexity that can be handled by parametric methods . in fig .
1 we report a fluorescence decay curve ( black points ) with 10 counts in the maximum generated by three exponential functions with lifetimes 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps and amplitude j = 0.33 , j = 1, ... ,3 . the solid red line is the curve resulting from the fitting with the mem algorithm by considering n = 400 points equally spaced in log between min = 20 ps and \documentclass[12pt]{minimal }
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\begin{document}$\tau_{\rm max}=10 ^ 4$\end{document } ps . the mem convergence is achieved for a chi - square value equals to = 1.01 and the accuracy of the algorithm is confirmed by the random distribution of the residuals around zero as it is shown in the lower panel of fig . 1 . the normalised lifetime distribution that accounts for the agreement between the mem curve and the synthetic decay data is reported in fig . 2 .
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\begin{document}$\langle \alpha_j \rangle$\end{document } are calculated as follows
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\begin{document}$$ \begin{array}{rll } \langle \tau_j \rangle & = & \frac{\sum_{k=1}^{n_j } \alpha_k \tau_k \delta_k}{\sum_{k=1}^{n_j } \alpha_k \delta_k } \nonumber \\
\langle \alpha_j \rangle & = & \frac{\sum_{k=1}^{n_j } \alpha_k \delta_k}{\sum_{k=1}^{n } \alpha_k \delta_k } \label{average } \end{array } $ $ \end{document}where nj is the number of lifetimes represented in each peak and k is the spacing in log. the calculated mean values \documentclass[12pt]{minimal }
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\begin{document}$\langle \alpha_j \rangle$\end{document } are reported in table 1 and are the retrieved lifetimes and the pre - exponential factors of the analysed decay curve .
similarly , the standard deviation of the data points of the peak region is considered as the uncertainty in the lifetime estimate , whereas the error of the amplitude factor is given by the standard deviation of the values calculated for a set of 20 simulated decay curves .
the parameters generated by a non linear least - square regression analysis with a three exponential model function are also shown in the table 1 for comparison .
it results a very good agreement among the estimates of the amplitudes j given by both methods .
the values retrieved by the non linear fitting are indeed within three standard deviations and have relative errors lower than 3 % , whereas the relative amplitudes calculated from the mem lifetime distribution agree with the theoretical values within 2 % . as far as it concerns the three lifetimes , the values of 1 , 2 and 3 are recovered by the mem within one standard deviation , whereas the non linear fitting procedure achieves this accuracy only for 1 , as 2 and 3 lie within two and four standard deviations , respectively .
the long lifetime 3 even outside the three - sigma interval witnesses the difficulty in fitting decay curves with more than three exponential functions .
1the fluorescence decay intensity ( black points ) simulated by three exponential functions with lifetimes 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps and the same value for the relative amplitude j = 0.33 . the red solid line is the curve fitted with the mem for n = 400 exponential decays . the residuals are reported in the lower panelfig .
2the normalised lifetime distribution (t ) / (t) obtained by the mem analysis of a simulated noisy multi - exponential decay with 10 counts in the peak channel .
the simulated data consists of 4,096 data points on a time scale of 25 ns and are characterised by 3 lifetimes : 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps . the mem results are obtained for n = 400 points equally spaced in log between 20 ps and 10 ps and are reported in table 1table 1the decay parameters recovered by the mem analysis of a three exponential decay with 10 counts in the peak channelsimulated parameters1231 ( ps)2 ( ps)3 ( ps)0.330.330.331001,0004,000mem results\documentclass[12pt]{minimal }
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\begin{document}$\langle \tau_3 \rangle$\end{document}0.33 0.010.337 0.0050.333 0.00399 7970 403,970 401.01least - square fit1231 ( ps)2 ( ps)3 ( ps)0.33 0.010.332 0.0060.340 0.00499 5970 153,960 101.01the uncertainties of the lifetime estimates \documentclass[12pt]{minimal }
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\begin{document}$\langle \tau_j \rangle$\end{document } are given by the standard deviations of the data points of the peak regions , whereas the errors of the amplitude factors \documentclass[12pt]{minimal }
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\begin{document}$\langle \alpha_j \rangle$\end{document } are the standard deviations of the values calculated for a set of 20 synthetic curves
. results of non linear least - square regression analysis are also reported for comparison together with the theoretical values of the simulated curve . in this case
the uncertainties of the parameters are given by the fitting procedure the fluorescence decay intensity ( black points ) simulated by three exponential functions with lifetimes 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps and the same value for the relative amplitude j = 0.33 . the red solid line is the curve fitted with the mem for n = 400 exponential decays . the residuals are reported in the lower panel the normalised lifetime distribution (t ) / (t) obtained by the mem analysis of a simulated noisy multi - exponential decay with 10 counts in the peak channel .
the simulated data consists of 4,096 data points on a time scale of 25 ns and are characterised by 3 lifetimes : 1 = 100 ps , 2 = 1,000 ps and 3 = 4,000 ps . the mem results are obtained for n = 400 points equally spaced in log between 20 ps and 10 ps and are reported in table 1 the decay parameters recovered by the mem analysis of a three exponential decay with 10 counts in the peak channel the uncertainties of the lifetime estimates \documentclass[12pt]{minimal }
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\begin{document}$\langle \tau_j \rangle$\end{document } are given by the standard deviations of the data points of the peak regions , whereas the errors of the amplitude factors \documentclass[12pt]{minimal }
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\begin{document}$\langle \alpha_j \rangle$\end{document } are the standard deviations of the values calculated for a set of 20 synthetic curves
. results of non linear least - square regression analysis are also reported for comparison together with the theoretical values of the simulated curve . in this case
the uncertainties of the parameters are given by the fitting procedure the mem accuracy in reconstructing a lifetime spectrum ( ) can be analysed by considering the ratio \documentclass[12pt]{minimal }
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\begin{document}$r=\delta \tau / \langle \tau \rangle$\end{document}. in fig .
the results have been obtained for a mem analysis that has considered both m = 4,096 ( black solid curves ) and m = 1,024 ( red solid curves ) data points . a lifetime spectrum equally spaced in log between 20 ps and
10 ps has been considered with a discretization that ranges from n = 100 to n = 1,000 in order to investigate the sensitivity of the method to the number of data points and the lifetimes in log space , respectively . from inspection of the curves it results the ratio r
does not depend on the noise level when the number of counts of the peak is larger than 3 510 .
the ratio r is always smaller than 3 % and decreases as the number n of discretization of the lifetimes space increases . when n is larger than 400 r is smaller than 1 % reaching the uncertainty of the non linear fit ( black dotted curve ) when n is larger than 1,000 .
furthermore , the results obtained for m = 4,096 and m = 1,024 data points are comparable showing that the mem accuracy is not affected by the number of data points for m 1,024 .
fig .
3the ratio \documentclass[12pt]{minimal }
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\begin{document}$r=\delta \tau / \langle \tau \rangle$\end{document } calculated for the mem lifetime spectrum of a single exponential decay with lifetime
the values of r have been calculated for different values of the number of lifetimes n = 100,200,400,1,000 that ranges from 20 ps to 10 ps .
the black solid curves are obtained by considering m = 4,096 data points in the mem analysis , whereas the red solid curves are given for m = 1,024 data points .
the black dotted curve is the uncertainty of the mean lifetime estimated by the non linear fit the ratio \documentclass[12pt]{minimal }
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\begin{document}$r=\delta \tau / \langle \tau \rangle$\end{document } calculated for the mem lifetime spectrum of a single exponential decay with lifetime
the values of r have been calculated for different values of the number of lifetimes n = 100,200,400,1,000 that ranges from 20 ps to 10 ps .
the black solid curves are obtained by considering m = 4,096 data points in the mem analysis , whereas the red solid curves are given for m = 1,024 data points .
the black dotted curve is the uncertainty of the mean lifetime estimated by the non linear fit
to test the performances of our algorithm with broad lifetime distributions , we considered gaussian distributions centred at = 5,000 ps with different standards deviation = 500 ps , 1,000 ps , 1,500 ps ( i.e. 10 , 20 % and the 30 % of ) , that are assumed as a measure of their width .
a set of 20 fluorescence decays curves with m = 4,096 data points and ~510 number of counts at the maximum has been generated for each of these distributions .
each curve of every set has been analysed with the mem by using n = 400 points equally spaced in log between 40 ps and 10 ps and each normalised mem spectrum ( ) has been fitted with a gaussian profile to estimate the center and the width of the distribution . in fig .
4 the typical mem spectra obtained for each set ( differently marked points ) are shown together with the gaussian fitted curves ( solid lines ) whereas the mono - modal section of the table 2 reports the mean values and the uncertainties of the center and the width of the gaussian distributions calculated for each set of curves .
the uncertainties are the standard deviations of the estimates of the parameters calculated for each set .
figure 4 shows that the mem algorithm reproduces the gaussian profile of the distributions with excellent resolution of the leading and the falling edges .
the fitting results are reported in the table 2 , where a good agreement is observed between the values estimated for the parameters of the gaussian lifetime distributions and the theoretical ones .
4the normalized lifetimes spectra ( ) reconstructed by the mem analysis performed on fluorescence decay intensities with ~5 10 counts in the peak channel by using n = 400 points equally spaced in log between 40 ps and 10 ps .
the gaussian distributions are centred at = 5,000 ps and have different standard deviations , = 500 ps ( black open circles ) , = 1,000 ps ( red open squares ) , = 1,500 ps ( blue open diamonds ) .
the solid lines are the gaussian fitted profilestable 2the center and the width of the gaussian lifetime distributions recovered by the mem and estimated through a fitting procedure gaussian 1-modal distributiongaussian 2-modal distributionnominal valuesmem resultsnominal valuesmem resultsamplitude110.92 0.021center ( ps)5,0004,990 151,0005,000985 345,016 23width ( ps)500498 153001,500319 311,515 95amplitude0.510.45 0.031center ( ps)5,0005,008 191,0005,000989 425,012 24width ( ps)1,0001,029 203001,500329 381,528 54amplitude0.2510.23 0.011center ( ps)5,0005,009 101,0005,000990 305,038 24width ( ps)1,5001,524 153001,500315 241,546 31amplitude0.110.092 0.0081center ( ps)1,0005,0001,036 875,006 17width ( ps)3001,500336491,509 31a set of 20 fluorescence decay curves with 5 10 counts in the peak channel has been generated for each distribution .
the reported values are the means and the standard deviations of the estimates of the parameters calculated for each set .
the results have been obtained by using n = 400 points equally spaced in log between 40 ps and 10 ps the normalized lifetimes spectra ( ) reconstructed by the mem analysis performed on fluorescence decay intensities with ~5 10 counts in the peak channel by using n = 400 points equally spaced in log between 40 ps and 10 ps .
the gaussian distributions are centred at = 5,000 ps and have different standard deviations , = 500 ps ( black open circles ) , = 1,000 ps ( red open squares ) , = 1,500 ps ( blue open diamonds ) .
the solid lines are the gaussian fitted profiles the center and the width of the gaussian lifetime distributions recovered by the mem and estimated through a fitting procedure a set of 20 fluorescence decay curves with 5 10 counts in the peak channel has been generated for each distribution .
the reported values are the means and the standard deviations of the estimates of the parameters calculated for each set .
the results have been obtained by using n = 400 points equally spaced in log between 40 ps and 10 ps the resolution limit of the algorithm in resolving the intensities of the lifetimes spectrum has been investigated by adding a gaussian distribution with different peak intensities on the tail of the distribution peaked at = 5,000 ps . to this purpose , we have considered the worst case of fig . 4 observed for a width = 1,500 ps and added an additional distribution centred at = 1,000 ps with a width = 300 ps .
four values for the amplitude of this additional peak have been considered : 100 , 50 , 25 and the 10 % of the main peak at = 5,000 ps . as before , a set of 20 fluorescence decay curves has been generated in each case for working out the errors in recovering the characteristic parameters of these bi - modal lifetime distributions through a bi - gaussian fitting procedure . in each panel of the fig .
5 the typical mem spectrum ( black points ) and the best fit ( red curve ) by two gaussian curves have been shown .
the average for each set of decay curves of the peak position ( center ) , the height ( amplitude ) and the width ( ) are reported in table 2 .
as it can be seen , the position and the width of the main peak are estimated with an accuracy that is not affected by the presence of the secondary peak .
similar results are observed for the retrieved parameters of the secondary peak showing that our algorithm resolves two distributions even when their amplitude are in the ratio 1:10 .
5the normalized lifetimes spectra ( ) reconstructed by the mem analysis ( black points ) for a bi - modal gaussian distribution with the main peak centred at = 5,000 ps and the secondary to = 1,000 ps .
four values for the amplitude of the additional peak have been considered and they represent 100 % a , 50 % b , 25 % c and the 10 % d of the main peak .
the results refer to fluorescence decay intensities with ~5 10 counts in the peak channel and have been obtained by using n = 400 points equally spaced in log between 40 ps and 10 ps .
the solid red line are the two gaussian fitted profiles used to estimate the characteristic parameters of the bi - modal distribution ( see table 2 ) the normalized lifetimes spectra ( ) reconstructed by the mem analysis ( black points ) for a bi - modal gaussian distribution with the main peak centred at = 5,000 ps and the secondary to = 1,000 ps .
four values for the amplitude of the additional peak have been considered and they represent 100 % a , 50 % b , 25 % c and the 10 % d of the main peak . both gaussians have size equals to the 30 % of their peak location .
the results refer to fluorescence decay intensities with ~5 10 counts in the peak channel and have been obtained by using n = 400 points equally spaced in log between 40 ps and 10 ps .
the solid red line are the two gaussian fitted profiles used to estimate the characteristic parameters of the bi - modal distribution ( see table 2 )
we have described a new algorithm for implementing a mem analysis of the time - resolved fluorescence decays .
the proposed procedure is based on seeking the desired lifetime distribution by solving the set of non linear equations \documentclass[12pt]{minimal }
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\begin{document}$\nabla \lambda = 0$\end{document } through iterative linear approximations , lu decomposition of the hessian matrix h and the golden section search for backtracking .
this algorithm has been tested on complex analytically simulated data that arise from multi - exponential decays and from broad lifetime distributions .
a typical inversion with m = 4,096 data points and n = 400 discretization of the lifetime spectrum takes about 60 s in total using an intel(r ) core(tm)i7 - 2600 cpu@3.40 ghz processor with 8 gb memory .
the computation time is about 150 s when the number of lifetimes considered is n = 1,000 .
the analysis of the multi - exponential decays with our computational approach has clearly shown that the sensitivity of the mem increases as the number n of discretization in log space increases .
an accuracy in retrieving the simulated parameters comparable to that of non linear regression can be achieved by considering n = 1,000 lifetimes .
particularly , our mem procedure has retrieved the widths that represent 10 % of the lifetime with a discrepancy lower than 3 % by using a typical value of 510 counts in the maximum peak .
this result clearly indicates that the procedure proposed generates mem lifetime distributions that can be used to quantify the real heterogeneity of lifetimes in a sample with no need for a time consuming high statistic .
moreover , the analysis of bi - modal distributions has demonstrated that our algorithm resolves a secondary peak even when its relative amplitude is 10 % of the amplitude of the neighbourhood peak .
it is also important to highlight that the mem algorithm proposed in this paper extends the analysis to datasets of up to 4,096 data points , thereby increasing the limit currently set at about 1,000 .
this increases the information that can be achieved from the data thus improving the accuracy in recovering the fast decay times ; in fact , short lifetimes affect the leading edge that only contains few points . on the other hand , a larger density ( n 1,000 ) is beneficial also for larger lifetimes since their spectrum can be determined with higher resolution .
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:
: a new algorithm for the maximum entropy method ( mem ) is proposed for recovering the lifetime distribution in time - resolved fluorescence decays . the procedure is based on seeking the distribution that maximizes the skilling entropy function subjected to the chi - squared constraint 2 ~ 1 through iterative linear approximations , lu decomposition of the hessian matrix of the lagrangian problem and the golden section search for backtracking .
the accuracy of this algorithm has been investigated through comparisons with simulated fluorescence decays both of narrow and broad lifetime distributions .
the proposed approach is capable to analyse datasets of up to 4,096 points with a discretization ranging from 100 to 1,000 lifetimes .
a good agreement with non linear fitting estimates has been observed when the method has been applied to multi - exponential decays .
remarkable results have been also obtained for the broad lifetime distributions where the position is recovered with high accuracy and the distribution width is estimated within 3 % .
these results indicate that the procedure proposed generates mem lifetime distributions that can be used to quantify the real heterogeneity of lifetimes in a sample .
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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:
: cancer refers to a group of maladies characterized by uncontrolled cell proliferation in normal tissue of the body .
three proprieties can distinguish between malignant and benign tumors : 1 ) uncontrolled growth , 2 ) invasion , and 3 ) metastasis ( 1 ) . according to previous research , the risk factors of cancer include the use of tobacco and alcohol ( 2 , 3 ) , obesity and inactivity ( 4 , 5 ) , nutritional insufficiencies , such as low intake of fruits and vegetables ( 6 ) , pollution ( including indoor smoke from household use of solid fuels ) ( 7 ) , and some sexually - transmitted infections , such as human papillomavirus ( hpv ) ( 8 , 9 ) .
research also has proven that the risk of cancer increases with age ( 10 ) .
cancer caused about 8.2 million human deaths in 2012 , with breast cancer accounting for 521,000 of the deaths ( 11 ) .
the prognosis of breast cancer is a multi - disciplinary research domain that involves several specialities , including medicine , biology , psychology , and computer science .
also , some clinical techniques can be used for making diagnoses , e.g. , microarray ( 12 , 13 ) , mammography ( 12 , 14 , and 15 ) , and cytology ( 16 , 17 ) . several computational techniques are used for computer - aided detection of breast cancer , e.g. , artificial neural networks anns ( 14 , 16 , and 18 ) , bayes network ( 12 , 18 ) , genetic algorithms ( 19 ) , fuzzy logic ( 14 ) , linear programing ( lp ) ( 20 ) , support vector machine ( svm ) ( 18 , 21 ) , and k - nearest neighbors ( knn ) ( 17 ) .
a promising result was generated by the intensive knowledge - distributed case - based reasoning classifier ( ik - dcbrc ) ( 22 ) , which implements fuzzy sets theory ( 23 ) and the case - based reasoning and distributed approach for the automatic detection of the class of malignancies from cytological images .
to date , uncertainty , which is caused by several natural and technical factors , remains an important obstacle in obtaining an accurate diagnosis .
these factors include faults in the measures that are taken and the uncertainty of reasoning systems . in the interest of overcoming these issues ,
some computational techniques have been introduced , including fuzzy sets theory ( 23 , 24 ) , probability reasoning ( 12 , 24 ) , and explanation - aware computing ( 25 ) . in this work
, we presented an intelligent agent , supported by ik - dcbrc , for explaining the prognosis of breast cancer .
the agent that was developed uses a rule - based system that explains the reasoning trace , the strategy that was used , justification for the choice , and the terms that are used .
the rest of this paper presents the ik - dcbrc system , explanation - aware computing , breast cancer prognosis and computer - aided detection , the explanation agent that was developed , and a discussion of the effectiveness of the proposed approach .
the case - based reasoning paradigm was implemented in several computer - aided medical diagnoses , some of which were reviewed in ( 26 ) .
also , the system used in this survey , i.e. , ik - dcbrc , was mentioned in ( 22 , 27 ) , and it has shown promising results for use in the diagnosis of cardiac arrhythmia ( 27 ) and breast cancer ( 22 ) .
ik - dcbrc uses distributed , case - based reasoning by integrating a set of agents and a set of case bases , each of which contains cases from the same class ( disease ) , and just one agent , called the similarity agent , can inferred from this case base . an adaptation agent is integrated for selecting the class from the responses of the other agents .
a knowledge base that contains the physician s rules also is inferred by the adaptation agent .
the log files generated by the system contains all needed information for explanations since the agents messages and the computed similarity measures of each similarity agent are included , as well as the uncertainty of the responses provided by adaptation rules and similarity parameters that were used .
the breast cancer dataset used for machine learning and testing was collected and tested by o. l. mangasarian and w. h. wolberg ( 17 , 20 ) .
they did so by applying linear programming and the k - nearest neighbor algorithm and achieved rates of correct classification results of 91.5 and 93.5% , respectively .
using ik - dcbrc and several different strategies ( 26 ) , the precision of the various approaches were determined , ranging from 98 to 100% .
the concept of explanation is a common area of interest in several related domains , such as didactics , physics , cognitive systems , philosophy .
intelligent systems , as an applied science of cognitive systems , are complex systems that are used by a wide variety of critical applications in which uncertainty represents an important risk . under these circumstances ,
the explanation of the behaviors of intelligent systems becomes a necessity for a trusted interaction between the users and these complex systems .
several researchers have introduced the explanation concept in their intelligent systems , which are used to generate a variety of extensions for ensuring pragmatism in the human - machine interaction process .
the uncertainty in medical applications is an important issue that has been considered by several of the systems that have been developed .
the meaningful interaction proposed by explanation systems impacts the uncertainty and can reduce the risks in the medical applications .
explanation - aware computing in computer - aided diagnosis is a complex task in which machine learning can be used as discussed in ( 28 ) . in the existing systems that support the explanation ,
there are four forms :
reasoning traces as in ( 29 ) in which the explainer generates the trace of reasoning processesjustifications as in ( 30 ) in which the explainer provides justifications for a reasoning to be reused in future judgmentsreasoning strategy as in the use of neomycin ( 30)terminology identified in ( 31 ) for explaining the terms and concepts of the domain reasoning traces as in ( 29 ) in which the explainer generates the trace of reasoning processes justifications as in ( 30 ) in which the explainer provides justifications for a reasoning to be reused in future judgments reasoning strategy as in the use of neomycin ( 30 ) terminology identified in ( 31 ) for explaining the terms and concepts of the domain explanation - aware computing becomes a necessity for all complex medical applications in which uncertainty and risks are the first preoccupation , and they are seriously considered because human life is at stake .
several researchers contribute the explanation in their medical applications as well as , e.g. , mycin in bacterial diagnosis and therapy ( 29 ) , ztrk and aamodt ( 32 ) in hypothesis and test strategies for diagnosis in electronic medical record , and processing mr images ( 33 ) .
breast cancer prognosis research refers to many techniques , including microarray ( 25 ) , cytology ( 1813 ) and mammography ( 19 ) .
cytology analysis is an indispensable test before any surgical intervention for distinguishing between malignant and benign tumors .
figure 2 shows two samples of tumors cells with benign on the left and malignant on the right . in the literature
, there are several computational techniques that have been used for the computer - aided detection and diagnosis of breast cancer .
these techniques include artificial neural networks anns ( 14 , 16 , and 18 ) , bayes network ( 12 , 18 ) , genetic algorithms ( 19 ) , fuzzy logic ( 14 ) , linear programing ( 20 ) , svm ( 18 , 21 ) , and knn ( 17 ) . and
the different sources of information include microarray ( 12 , 13 ) , mammography ( 12 , 14 , and 15 ) , and cytology ( 16 , 17 , and 20 ) .
a promising result was generated by ik - cbrc cited in ( 22 ) and described in section 2.1 , which used the hybrid and distributed approach in the automatic detection of malignant cancer class from the cytological images .
the case - based reasoning paradigm was implemented in several computer - aided medical diagnoses , some of which were reviewed in ( 26 ) .
also , the system used in this survey , i.e. , ik - dcbrc , was mentioned in ( 22 , 27 ) , and it has shown promising results for use in the diagnosis of cardiac arrhythmia ( 27 ) and breast cancer ( 22 ) .
ik - dcbrc uses distributed , case - based reasoning by integrating a set of agents and a set of case bases , each of which contains cases from the same class ( disease ) , and just one agent , called the similarity agent , can inferred from this case base . an adaptation agent is integrated for selecting the class from the responses of the other agents .
a knowledge base that contains the physician s rules also is inferred by the adaptation agent .
the log files generated by the system contains all needed information for explanations since the agents messages and the computed similarity measures of each similarity agent are included , as well as the uncertainty of the responses provided by adaptation rules and similarity parameters that were used .
the breast cancer dataset used for machine learning and testing was collected and tested by o. l. mangasarian and w. h. wolberg ( 17 , 20 ) .
they did so by applying linear programming and the k - nearest neighbor algorithm and achieved rates of correct classification results of 91.5 and 93.5% , respectively .
using ik - dcbrc and several different strategies ( 26 ) , the precision of the various approaches were determined , ranging from 98 to 100% .
the concept of explanation is a common area of interest in several related domains , such as didactics , physics , cognitive systems , philosophy .
intelligent systems , as an applied science of cognitive systems , are complex systems that are used by a wide variety of critical applications in which uncertainty represents an important risk . under these circumstances ,
the explanation of the behaviors of intelligent systems becomes a necessity for a trusted interaction between the users and these complex systems .
several researchers have introduced the explanation concept in their intelligent systems , which are used to generate a variety of extensions for ensuring pragmatism in the human - machine interaction process .
the uncertainty in medical applications is an important issue that has been considered by several of the systems that have been developed .
the meaningful interaction proposed by explanation systems impacts the uncertainty and can reduce the risks in the medical applications .
explanation - aware computing in computer - aided diagnosis is a complex task in which machine learning can be used as discussed in ( 28 ) . in the existing systems that support the explanation , there are four forms :
reasoning traces as in ( 29 ) in which the explainer generates the trace of reasoning processesjustifications as in ( 30 ) in which the explainer provides justifications for a reasoning to be reused in future judgmentsreasoning strategy as in the use of neomycin ( 30)terminology identified in ( 31 ) for explaining the terms and concepts of the domain reasoning traces as in ( 29 ) in which the explainer generates the trace of reasoning processes justifications as in ( 30 ) in which the explainer provides justifications for a reasoning to be reused in future judgments reasoning strategy as in the use of neomycin ( 30 ) terminology identified in ( 31 ) for explaining the terms and concepts of the domain explanation - aware computing becomes a necessity for all complex medical applications in which uncertainty and risks are the first preoccupation , and they are seriously considered because human life is at stake .
several researchers contribute the explanation in their medical applications as well as , e.g. , mycin in bacterial diagnosis and therapy ( 29 ) , ztrk and aamodt ( 32 ) in hypothesis and test strategies for diagnosis in electronic medical record , and processing mr images ( 33 ) .
breast cancer prognosis research refers to many techniques , including microarray ( 25 ) , cytology ( 1813 ) and mammography ( 19 ) .
cytology analysis is an indispensable test before any surgical intervention for distinguishing between malignant and benign tumors .
figure 2 shows two samples of tumors cells with benign on the left and malignant on the right . in the literature
, there are several computational techniques that have been used for the computer - aided detection and diagnosis of breast cancer .
these techniques include artificial neural networks anns ( 14 , 16 , and 18 ) , bayes network ( 12 , 18 ) , genetic algorithms ( 19 ) , fuzzy logic ( 14 ) , linear programing ( 20 ) , svm ( 18 , 21 ) , and knn ( 17 ) . and the different sources of information include microarray ( 12 , 13 ) , mammography ( 12 , 14 , and 15 ) , and cytology ( 16 , 17 , and 20 ) .
a promising result was generated by ik - cbrc cited in ( 22 ) and described in section 2.1 , which used the hybrid and distributed approach in the automatic detection of malignant cancer class from the cytological images .
first , the cytological images should be analyzed by xcyt ( 34 ) , which is a remote cytological image analyzer , to create a query .
the ik - dcbrc classifies the generated query to distinguish between the malignant and benign classes .
the explanation agent explains the results of the previous diagnosis according to the rules of the explanation knowledge base and the logged information . via the explanation agent s user interface , shown in figure 5 ,
the user selects the demanded level of abstraction for the explanation . as in ( 2931 ) , the explanation agent visualizes the trace of reasoning , justification , the terminology , and the applied strategy according to the selected level of abstraction .
the cognitive agent for explanation defines the following three levels of abstraction :
level 1 : ordinary explanations . in this level
, the agent presents just the information that is needed about the class of the query , the disease , associated with the terminological explanations , the indexed links of useful wiki documents , and the cytological image.level 2 : deep explanations . in this level
the agent adds the justification , the reasoning trace , and the strategy to the explanation presented in the prior level.level 3 : maintaining explanations .
this level contains all kinds of explanations plus the professional information that can help developers understand the abnormality of the reasoning system in the case of errors .
, the agent presents just the information that is needed about the class of the query , the disease , associated with the terminological explanations , the indexed links of useful wiki documents , and the cytological image .
the agent adds the justification , the reasoning trace , and the strategy to the explanation presented in the prior level .
this level contains all kinds of explanations plus the professional information that can help developers understand the abnormality of the reasoning system in the case of errors .
figure 5 shows an example of explanation in which the user selects level 3 and the log file of the breast cancer diagnosis case . after visualizing the explanation , in the reasoning trace ,
the first agent associated with the benign class generates that the diagnosed case is not similar with a rate of 17% and 83% unknown ; the response of the second agent associated with the malignant class is 1% similar and 99% unknown .
the response of the adaptation agent is malignant by using rule number 2 , and no rule was used by the rule - based system .
the terminological explanation also is presented with the wiki doc and the localization of the abnormality in the breast cancer pattern .
the strategic explanation is ensured by visualizing the similarity function that was used and the weights of the features for each class .
first , the cytological images should be analyzed by xcyt ( 34 ) , which is a remote cytological image analyzer , to create a query .
the ik - dcbrc classifies the generated query to distinguish between the malignant and benign classes .
the explanation agent explains the results of the previous diagnosis according to the rules of the explanation knowledge base and the logged information . via the explanation agent s user interface , shown in figure 5 ,
the user selects the demanded level of abstraction for the explanation . as in ( 2931 ) , the explanation agent visualizes the trace of reasoning , justification , the terminology , and the applied strategy according to the selected level of abstraction .
the cognitive agent for explanation defines the following three levels of abstraction :
level 1 : ordinary explanations . in this level
, the agent presents just the information that is needed about the class of the query , the disease , associated with the terminological explanations , the indexed links of useful wiki documents , and the cytological image.level 2 : deep explanations . in this level
the agent adds the justification , the reasoning trace , and the strategy to the explanation presented in the prior level.level 3 : maintaining explanations .
this level contains all kinds of explanations plus the professional information that can help developers understand the abnormality of the reasoning system in the case of errors .
, the agent presents just the information that is needed about the class of the query , the disease , associated with the terminological explanations , the indexed links of useful wiki documents , and the cytological image .
the agent adds the justification , the reasoning trace , and the strategy to the explanation presented in the prior level .
this level contains all kinds of explanations plus the professional information that can help developers understand the abnormality of the reasoning system in the case of errors .
figure 5 shows an example of explanation in which the user selects level 3 and the log file of the breast cancer diagnosis case . after visualizing the explanation , in the reasoning trace ,
the first agent associated with the benign class generates that the diagnosed case is not similar with a rate of 17% and 83% unknown ; the response of the second agent associated with the malignant class is 1% similar and 99% unknown .
the response of the adaptation agent is malignant by using rule number 2 , and no rule was used by the rule - based system .
the terminological explanation also is presented with the wiki doc and the localization of the abnormality in the breast cancer pattern .
the strategic explanation is ensured by visualizing the similarity function that was used and the weights of the features for each class .
as described in the comparative diagram in figure 3 , in which the accuracy was between 86.5 and 98.5% and error rate was between 1.5 and 13.5% , the existence of risks in the automatic detection of breast cancer was proven .
this risk changes from one computational technique to another . but researchers should detect and prevent doubts about decreasing these risks , and this is the aim of this contribution . in this paper ,
a cognitive agent was described for medical explanation by reusing the trace of reasoning , the case bases , and the adaptation knowledge base of ik - dcbrc .
the interaction between the agent and the users is personalized and made meaningful via a graphical interface with the user .
the multi - level of abstraction in the explanation process ensures an appropriate assignment of explanation according to the context of the uses of the application . in figure 5 ,
the explained case is well classified , but the decision was deduced with just 1% of membership in the malignant case base , which increases the doubts , but the explanation rule explains that the decision was deduced also by considering the membership of the case in the non - similar set of the benign class , i.e. , 17% , which decreases the doubts about this diagnosis .
although the proposed solution decreases the risks of breast cancer prognosis , there are other sources of risks that are not considered as faults of measures , conflicts in the knowledge bases , and others .
but the visualization of the reasoning trace can guide the detection of conflicts and faults .
this study makes an original contribution for the resolution of the problem of uncertainty in breast cancer prognosis supported by ik - cbrc .
this contribution consists of introducing an explanation - aware computing process after the automatic detection of the class of breast cancer . the proposed solution impacts breast cancer diagnosis by sensitizing physicians to the entire context of the computer - aided diagnosis .
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### Summary:
: background : active research is being conducted to determine the prognosis for breast cancer .
however , the uncertainty is a major obstacle in this domain of medical research . in that context
, explanation - aware computing has the potential for providing meaningful interactions between complex medical applications and users , which would ensure a significant reduction of uncertainty and risks .
this paper presents an explanation - aware agent , supported by intensive knowledge - distributed case - based reasoning classifier ( ik - dcbrc ) , to reduce the uncertainty and risks associated with the diagnosis of breast cancer.methods:a meaningful explanation is generated by inferring from a rule - based system according to the level of abstraction and the reasoning traces .
the computer - aided detection is conducted by ik - dcbrc , which is a multi - agent system that applies the case - based reasoning paradigm and a fuzzy similarity function for the automatic prognosis by the class of breast tumors , i.e. malignant or benign , from a pattern of cytological images.results:a meaningful interaction between the physician and the computer - aided diagnosis system , ik - dcbrc , is achieved via an intelligent agent .
the physician can observe the trace of reasoning , terms , justifications , and the strategy to be used to decrease the risks and doubts associated with the automatic diagnosis .
the capability of the system we have developed was proven by an example in which conflicts were clarified and transparency was ensured.conclusion:the explanation agent ensures the transparency of the automatic diagnosis of breast cancer supported by ik - dcbrc , which decreases uncertainty and risks and detects some conflicts .
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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:
: orbital decompression surgery in graves ' orbitopathy ( go ) represents an established treatment for rehabilitative exophthalmos reduction and for restoration of visual function in dysthyroid optic neuropathy ( don ) .
a vast number of surgical techniques with regard to orbital decompression are described in the literature .
each orbital surgeon usually favors a particular technique either tailored to the individual patient 's needs or the surgeon 's preference .
the problem in comparing different techniques for orbital decompression is the lack of randomized controlled trials ( rcts ) .
boboridis and bunce systematically reviewed the data from all rcts addressing the issue of orbital decompression surgery .
after searching electronic databases , oculoplastic surgery textbooks , conference proceedings , and personal communications from researchers , they found just one rct comparing different decompression techniques and a second trial comparing medical versus surgical decompression .
furthermore , analysis of data after decompression surgery or comparison of results from different studies is often hampered by the pool of patients , which is highly heterogeneous in terms of both preoperative clinical characteristics and methodological backgrounds and outcome measures .
hence , our knowledge concerning surgical treatment of disfiguring exophthalmos or compressive neuropathy in go patients frequently derives from case series involving small patient numbers .
overall there seems to be a trend in favor of lateral wall decompression surgery , as advocated by different authors with excellent track record [ 48 ] .
this technique , in which the rim of the orbital wall is usually preserved or repositioned at the end of surgery , offers the advantage of effective decompression of the orbit combined with a low complication rate . for
more than 15 years we successfully used a modified technique with en bloc resection of the lateral wall , including removal of the orbital rim , in order to better visualize the deep lateral orbit and therefore facilitate deep resection towards the greater wing of the sphenoid .
the aim of the present study was to evaluate outcomes with this en bloc technique in our patients over a 12-year period .
a retrospective case record analysis of go patients after complete ( en bloc ) resection of the lateral orbital wall , including the lateral rim , with additional orbital fat resection was performed .
the study was approved by the ethics committee of the medical faculty of the university of rostock and all investigations were performed according to the current version of the helsinki declaration . during the period from june 1999 to june 2011
a single surgeon ( rfg ) performed a total of 201 lateral wall decompression procedures in 130 patients with go .
patients with a minimum follow - up of 3 months were considered eligible for analysis , and the charts of 111 patients ( 87 females , 24 males ; 164 orbits ) were reviewed in detail .
the indication for surgery was disfiguring exophthalmos with or without retrobulbar pressure sensation in inactive eye disease in 146 orbits .
an additional subset of 18 orbits was found to have mild don . in 53 patients in whom
bilateral decompression was planned , surgery was usually performed in a two - step procedure with a minimum interval of 4 weeks between the two surgical sessions .
the mean age of the patients at the time of surgery was 48.8 11.7 years ( range : 2476 years ) .
patients who had a surgical orbital intervention before the first consultation were not included in the study .
one patient who needed a further medial wall decompression 4 weeks after lateral wall decompression and therefore within the defined follow - up of at least 3 months was not excluded from the study because this shows the importance of a careful and critical preselection of the patients . in this case
the results of clinical examination before and after surgery concerning visual acuity , exophthalmometer readings , diplopia ( gorman score ) , and retrobulbar pressure sensation were extracted from the case records .
the last follow - up was either the last consultation in our clinic in those patients without further surgical interventions or the last consultation before the next surgical step in rehabilitative surgery ( e.g. , extraocular muscle surgery or lid surgery ) .
conventional lateral rim - supported hertel exophthalmometers were not suitable for postoperative exophthalmos assessment because our surgical technique involves complete en bloc resection of the lateral orbital wall , including the orbital rim .
therefore we used the superior and inferior orbital rim - based exophthalmometers developed by naugle jr . and
couvillion and the measurements were done by multiple examiners . a comparative study by cole iii et al .
has concluded that accuracy was comparable for the naugle and hertel instruments , justifying our use of the naugle exophthalmometer for pre- and postoperative measurements .
extraocular muscle involvement was assessed using the gorman score for classification of diplopia : 1 = no diplopia , 2 = intermittent diplopia ( when tired ) , 3 = inconstant diplopia ( depending on direction of gaze ) , and 4 = constant diplopia in primary or reading position ( with or without prism ) .
information concerning the presence of retrobulbar pressure sensation before and after surgery was also reviewed and documented in a qualitative manner ( yes / no ) . we diagnosed don if two or more of the following features were present : visual acuity less than 6/6 ( decimals ) , visual field defects in the automated visual field analyser ( humphrey 24 - 2 ) , impaired color vision ( lanthony panel - d15 : > 2 minor errors or > 1 major error ) , pathologic visual evoked responses with a prolongation of latency and/or reduction of amplitude , presence of a relative afferent pupillary defect ( rapd ) , presence of optic disc swelling , or apical crowding in orbital imaging .
patients were led to orbital decompression surgery if there was no adequate response to the medical pretreatment with systemic steroids or steroids were contraindicated .
reported complications and subsequent need for further ( rehabilitative ) surgical interventions were analyzed in detail .
surgery was performed under general anesthesia and started with an upper eyelid crease incision in the lateral third of the upper lid crease that was extended down to the zygomatic bone about 2 cm lateral to the orbital rim and blunt exposure of the lateral orbital rim .
the temporalis muscle was carefully detached from the temporal surface of the lateral orbital wall , followed by incision of the periosteum along the lateral orbital rim . after preparation of the lateral orbital wall with the periosteal elevator the superior osteotomy was marked above the frontozygomatic suture , and the inferior osteotomy was marked just above the zygomatic arch .
the osteotomies were performed with an oscillating saw and the fragment of the lateral orbital wall was outfractured using a hammer and osteotome .
the amount of bone resection was increased towards the height of the greater wing of the sphenoid using the bone nibbler and burr down to the level of bone marrow .
the landmark for the lower border of resection was the inferior orbital fissure . during this procedure
the globe and its soft - tissue contents were protected and carefully pulled nasally with malleable retractors . after removing the deep parts of the lateral wall
the periorbit was opened superiorly and inferiorly to the lateral rectus muscle and carefully excised .
this procedure is usually accompanied by a variable degree of orbital fat prolapse , which is resected mainly from the inferolateral orbit .
additional fat prolapse can be achieved with only minimal risk of orbital bleeding by exerting slight axial pressure on the globe .
finally a suction drainage system was placed into the fossa temporalis and the wound incision was accurately closed in layers .
a temporary compression bandage was used for the first 24 hours in order to maintain axial retropositioning of the globe in the newly created space .
the volume of blood in the suction balloon was monitored every 6 hours in order to be aware of possible postoperative orbital bleeding .
spearman 's rho coefficient was calculated for nonparametric correlations , and p values were analyzed using the wilcoxon nonparametric test .
p values < 0.05 were accepted as statistically significant , with p < 0.01 being regarded as highly significant .
calculations were done using spss version 15 for windows ( spss inc . , chicago , il , usa ) .
mean follow - up was 16.4 20.4 months ( range : 3 months to 10.5 years ; median : 8 months ) .
mean exophthalmos improved significantly from 21.40 2.3 mm preoperatively to 18.32 2.6 mm postoperatively ( p < 0.001 ) , resulting in a mean exophthalmos reduction of 3.05 1.45 mm .
. the greater the degree of exophthalmos before surgery , the greater the reduction achieved ( r = 0.431 ; p < 0.001 ) . for some exemplary pre
mean visual acuity ( va ) in patients being operated for rehabilitative purposes was 0.91 0.22 preoperatively , increasing to 0.93 0.23 postoperatively ( p = 0.03 ) .
those patients undergoing surgery because of suspected mild don initially presented with a mean va of 0.73 0.21 that increased significantly to 0.83 0.22 ( p = 0.02 ) after decompression surgery .
interestingly , the increase was significantly greater in patients with preoperative signs of don compared to patients without preoperative suspicion of don ( p = 0.015 ) .
the don group included one 52-year - old euthyroid female smoker with inadequate recovery and slowly progressing visual impairment postoperatively , necessitating an additional medial wall decompression .
furthermore one female nonsmoking , euthyroid patient who was treated before for don on the contralateral eye had no clinical evidence of don at the time of surgery .
she required an additional medial wall decompression 4 weeks after lateral wall decompression because of new - onset visual loss , visual field defects , and prolonged latency in visual evoked responses due to a compressive optic neuropathy with increased extraocular muscle volume .
the patient received intravenous high - dose steroids and immediately underwent additional medial wall decompression .
both patients showed a rapid restoration of visual acuity within one week after additional endonasal medial wall decompression surgery .
a disturbing retrobulbar pressure sensation was reported in 98 out of 164 orbits preoperatively ; for 9 orbits the chart records contained no information concerning this symptom .
postoperatively , retrobulbar pressure sensation was reported to be completely resolved in 71 orbits and markedly improved in 3 orbits .
preoperatively about one - third of our patients presented without diplopia ( gorman score : 1 ) .
postoperatively , overall distribution within the four gorman categories showed a slight improvement , that is , a shift to a lower gorman score , although not statistically significant ( table 1 ) .
postoperatively , unchanged gorman scores were observed in 88 patients ( 87.1% , 135 orbits ) , diplopia improved in 10 patients ( 9.0% , 14 orbits ) , but new - onset diplopia was also noted in 5 patients ( 4.5% , 6 orbits ) ( tables 2(a ) and 2(b ) )
. detailed analysis of patients with an improved diplopia score revealed that preexisting vertical squint improved in 5 of the 10 patients and horizontal squint improved in 3 patients , while 2 patients improved in the sense of resolved intermittent diplopia .
one patient ( listed as number 4 in table 2(b ) ) moved from no diplopia to inconstant diplopia 2 months after surgery because of impaired elevation presented with signs of recurrent go activity in conjunction with recurrent hyperthyroid function and a persisting smoking habit .
while worsening of extraocular muscle function was probably not the result of decompression surgery , correction was subsequently done by inferior rectus recession .
one patient had a satisfactory field of binocular single vision without impairment of routine daily activities and did not require any further treatment .
the deterioration in the second patient who moved from gorman 1 to gorman 4 could not be accounted for from the chart record ( no intraoperative anomalies ; inactive eye disease 5 years after orbital irradiation prior to surgery ) .
worsening of horizontal motility occurred in two patients ( adduction in one patient and abduction in the other ) with diplopia at the extremes of lateral gaze .
the patient with worsened adduction required surgical correction in order to increase the field of binocular single vision .
altogether 5 out of 111 patients ( 4.5% ) showed worsening of extraocular muscle motility presumably due to lateral wall decompression ; surgical correction was required in 3 of these patients ( 2.7% ) , resulting in a favorable outcome in all of them .
the remaining 100 orbits ( 60.9% ) required one or more additional surgical procedures ( figure 3 ) . in detail ,
lid surgery included 58 upper lid lengthening procedures , 16 lower lid lengthening procedures , 10 upper / lower lid blepharoplasties , 4 lateral tarsal sling procedures , 3 lateral tarsorrhaphies , 1 ptosis repair , and 4 wound revisions .
strabismus surgery included 62 rectus muscle recessions ( inferior 33 , medial 23 , lateral 5 , and superior 1 ) , 3 faden procedures ( lateral rectus muscle ) , 1 lateral rectus resection , and 1 inferior oblique muscle recession .
further decompression surgery with additional removal of the medial orbital wall was required in two orbits , as mentioned previously .
further complications related to wound healing , scar formation , infection , hyperesthesia , and oscillopsia .
furthermore one female patient undergoing bilateral decompression experienced a slight hollowing of the temporal fossa region that did not require any further intervention ( figure 4 ) .
oscillopsia when chewing was noticed by one patient but did not affect her related quality of life .
expulsive orbital bleeding shortly after wound closure occurred in one patient ; immediate revision with hemostasis led to complete restitution without any functional deficits .
to our knowledge this study represents the largest retrospective case series after en bloc resection of the lateral orbital wall in conjunction with orbital fat resection .
the first results regarding this technique were published in 1966 by long and ellis who described a series of 45 decompression procedures . in 1989
et al . combined this technique with an additional medial wall decompression using sewall 's external approach . in 1991 matton
presented data on 56 decompression procedures in 29 patients following en bloc resection of the lateral wall and lateral floor .
exophthalmos improved in all patients , complications encompassed postoperative bleeding and hypesthesia of the infraorbital nerve , and there was no flattening of the malar contour .
most recently , describing their results after two - wall inferolateral decompression in 44 patients , schaaf et al . reported an average exophthalmos reduction of 3.8 mm , with one patient developing new - onset diplopia after surgery that required surgical correction . in the present study we found an average exophthalmos reduction of 3.05 mm , ranging up to 7 mm , after en bloc lateral wall decompression with orbital fat resection .
these results are in accordance with our data in an earlier and smaller patient series .
either data do not clarify the extent to which orbital fat resection contributed to exophthalmos reduction , but a review of the literature suggests an additional effect on proptosis reduction to be assumed [ 1618 ] . to achieve this goal
our practise is to resect a moderate amount of intraconal fat mainly from the inferolateral orbit as this location is associated with the lowest risk of injury to vulnerable orbital structures [ 19 , 20 ] .
mourits et al . from the eugogo working group found a mean exophthalmos reduction after two - wall decompression of 4.3 mm independent of the surgical approach .
thus , exophthalmos reduction after single wall decompression combined with moderate orbital fat resection appears to be slightly less effective than a two - wall decompression technique
. however , nal et al . postulated that orbital fat resection allows an additional wall to be spared from decompression , thereby reducing the risk of postoperative diplopia .
these findings underline the ongoing controversy concerning the role of orbital fat resection in orbital decompression surgery .
additional factors potentially influencing the amount of orbital volume expansion relate to the anatomical variability of the bony orbit , variations in the fat - to - muscle volume ratio , the elastic capacity / amount of fibrosis of the orbital contents that determines the ability to fill the newly created space , the orbital opening angle between medial and lateral walls , and the axial lengths of orbit and globe and their relation to each other [ 22 , 23 ] .
interestingly , orbital irradiation has been shown not to influence the outcome after orbital decompression surgery .
but from our personal experience and considering the pathophysiological processes and morphological changes of the orbital soft tissues after irradiation , these results need to be clarified by further studies . in our study
lateral wall decompression surgery produced significant improvement in visual functions in patients with and without don .
the results showed a significantly greater improvement of visual acuity in don patients compared to patients without preoperative signs of compressive neuropathy , showing that lateral wall decompression can be a sufficient treatment in selected patients with don .
we presume that the improvement of visual functioning in these patients was probably due to a relief of orbital pressure in the sense of an orbital compartment syndrome , and in patients without don this presumably reflected an improvement in ocular surface conditions .
only one of the don patients ( 1/18 orbits ) was not sufficiently cured and needed further medial wall decompression .
this patient was a severe smoker who showed recurrent inflammatory signs in repeated orbital imaging but again without compression of the nerve in the deep orbital apex .
published their results after decompression of the deep lateral orbit and recommend this technique also for use in don , but not for cases in the acute inflammatory stage where they advocate additional apical decompression of the medial orbital wall .
one comparative study found no difference between lateral and medial walls ' decompression in terms of efficacy in treating don , although lateral wall decompression resulted in greater exophthalmos reduction .
our approach to orbital decompression in don is to restrict lateral wall decompression to cases with mild don without signs of optic nerve compression in the deep orbital apex . in patients with a crowded orbital apex
we prefer a combined lateral and ( endonasal ) medial wall decompression to sufficiently decompress the optic nerve and to restore visual functions .
in the present study about one - third of our patients were preoperatively unaffected by diplopia in their routine daily activities and this number did not change significantly after surgery .
detailed scrutiny of the data revealed that some patients ( 9% ) had an improved gorman score , while a smaller number ( 4.5% ) became worse . the latter underwent surgery between 2003 and 2008 , indicating that this complication was probably not related to the surgeon 's experience .
interestingly , none of the don patients showed worsening of preexisting diplopia or new - onset diplopia after surgery .
the fact that vertical deviation was equally affected as horizontal deviation indicates that the underlying mechanism relates more to the vulnerability of extraocular muscle balance than possible direct damage to the lateral rectus muscle itself . in line with our findings and using the same surgical technique , schaaf et al . found an improvement in preexisting strabismus in 14% of their patients and new - onset diplopia in 4.7% ( one out of 21 patients ) .
they found a slight worsening of eye motility on average by 2.4 on upgaze and 0.5 on lateral gaze .
though the authors give no detailed information about the orthoptic assessment these postoperative changes in eye motility do not seem to influence binocular functions and therefore do not seem to influence the patients ' quality of life .
. nevertheless , the reported incidence rates of induced diplopia or worsening of motility after different other than lateral wall approaches for orbital decompression are generally higher than those with our technique .
a literature review reveals worsening of binocular functions in 1674% after inferomedial decompression [ 27 , 28 ] , in up to 45% after balanced decompression [ 5 , 29 ] , in 2.68% after rim - sparing ( deep ) lateral wall decompression [ 5 , 30 , 31 ] , and in 05% after en blocresection of the lateral wall [ 13 , 14 ] .
these latter reports reflect our finding of a low risk for worsening or new - onset diplopia after lateral wall decompression .
some authors have raised concerns about the potential creation of disfiguring hollowing of the temporal fossa after lateral wall decompression and about complications due to periorbital incisions ( e.g. , retracted scars or lid retraction ) or increased postoperative morbidity as a result of orbital rim removal .
reported temporal bossing in 3 out of 46 patients after coronal 3-wall decompression involving a rim - sparing lateral wall resection that required surgical correction in one of the patients .
bailey described temporalis muscle atrophy after lateral wall decompression via a swinging eyelid approach in 1 out of 55 patients though the lateral rim was repositioned at the end of surgery . in our study
one patient had slight hollowing of the temporalis region around the scar that did not require any intervention and was probably due to circumscribed atrophy of the temporalis muscle , such as is known also to occur with the above - mentioned procedures , where the lateral rim was preserved or reconstructed .
hence , the postoperative phenomenon of temporalis wasting does not seem to be caused by the removal of the lateral rim itself rather than by intraoperative temporalis muscle trauma or scarring of the periorbital incision , respectively .
the same applies to our patient with a retracted scar and the lady who reported oscillopsia when chewing ; both phenomena were probably caused by deep cicatricial adhesions .
while the circumscribed retraction of the scar was sufficiently treated by scar revision , mild oscillopsia when chewing remained until the last follow - up at 1 year after surgery but did not affect the patients quality of life .
this coincides with a recently published retrospective study which showed the incidence of postoperative oscillopsia after rim - sparing lateral wall decompression to be surprisingly high ( 35% ) , but showed it to resolve or improve spontaneously in all but one out of 34 affected patients within 2 years . in summary , these fortunately rare observations underline the importance of an appropriate surgical technique when detaching the temporalis muscle and of a precisely layered wound closure .
in addition to our observations in this retrospective study on postoperative temporalis fossa appearance we found no significant influence of the lateral rim removal technique on canthus formation and stability in a prospective study published recently .
furthermore none of the patients ever reported any kind of eye injury after orbital trauma though this could be possible in theory considering the surgical technique removing the lateral orbital rim .
one way to completely avoid these potential problems would be to perform a lateral wall decompression ab interno , though this is offset according to some authors by the disadvantage of a more difficult access to the deep lateral orbit with a higher risk for severe complications like csf leaks and lesser exophthalmos reduction [ 8 , 37 , 38 ] .
on the other hand , rocchi et al . from the sellari - franceschini working group who published their results after rim - sparing lateral wall decompression via
the internal approach found comparable results for exophthalmos reduction with a negligible risk for new - onset diplopia in primary gaze if patients were free of diplopia preoperatively , while 26.1% of the patients with preoperative inconstant diplopia developed constant diplopia in primary gaze position . in conclusion ,
en bloc resection of the lateral orbital wall offers the advantage of good visualization of the surgical field that facilitates resection of the deep lateral wall with a lower risk for severe complications like csf leaks .
though the limitation of the study is its retrospective , noncontrolled , and noncomparative design the analysis of a huge number of patients supports the recent trend towards lateral wall decompression : the technique has proved to be effective and safe in terms of exophthalmos reduction , postoperative motility disturbances , overall morbidity , and lowest incidence of induced diplopia compared with other orbital decompression techniques . in our opinion , repositioning of the orbital rim does not seem to be necessary with regard to scar retraction and circumscribed hollowing of the temporalis fossa .
. found comparable results to our technique with a modified internal approach to the lateral orbital wall sparing the anterior orbital rim .
lateral wall decompression with orbital fat resection is our preferred first choice in patients without disturbance of binocular functions and where moderate exophthalmos reduction is required .
additional medial wall decompression is reserved for patients in whom a lateral wall decompression with or without fat resection might not be sufficient , that is , patients with thickening of the extraocular muscles predominantly in the orbital apex that places the patient at risk to optic nerve compression or in patients where more than 3 mm exophthalmos reduction is needed .
the surgical approach therefore has to be customized for each patient according to individual characteristics and the clinical situation .
it therefore seems reasonable to compare our technique with stellaris ' ab interno technique in randomized controlled trials .
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### Summary:
: purpose . to evaluate the effect of en bloc lateral wall decompression with additional orbital fat resection in terms of exophthalmos reduction and complications
. methods .
a retrospective , noncomparative case series study from 1999 to 2011 ( chart review ) in graves ' orbitopathy ( go ) patients .
the standardized surgical technique involved removal of the lateral orbital wall including the orbital rim via a lid crease approach combined with additional orbital fat resection .
exophthalmos , diplopia , retrobulbar pressure sensation , and complications were analyzed pre- and postoperatively .
results .
a total of 111 patients ( 164 orbits ) with follow - up > 3 months were analysed .
mean exophthalmos reduction was 3.05 mm and preoperative orbital pressure sensation resolved or improved in all patients .
visual acuity improved significantly in patients undergoing surgery for rehabilitative or vision threatening purposes .
preoperative diplopia improved in 10 patients ( 9.0% ) but worsened in 5 patients ( 4.5% ) , necessitating surgical correction in 3 patients .
there were no significant complications ; however , one patient had slight hollowing of the temporalis muscle around the scar that did not necessitate revision , and another patient with a circumscribed retraction of the scar itself underwent surgical correction . conclusions .
the study confirms the efficiency of en bloc lateral wall decompression in go in a large series of patients , highlighting the low risk of disturbance of binocular functions and of cosmetic blemish in the temporal midface region .
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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:
: ameloblastomas are benign but locally invasive tumors of odontogenic epithelial origin and generally without induction in the connective tissue
. rare cases of ameloblastoma associated with an odontome have been reported and are known as odontoameloblastoma . in 1992 , the first case of an ameloblastoma showing evidence of induction of dentinoid which diagnosed as a
the term adenoid ameloblastoma with dentinoid was first introduced by evans et al . in 2004 .
they described a neoplasm showing histopathological features similar to ameloblastoma and adenomatoid odontogenic tumor ( aot ) along with hard tissue formation .
histopathologically , ameloblastoma exhibits follicular , plexiform , acanthomatous , granular cell , desmoplastic , and basal cell patterns .
granular cell ameloblastoma is rare to occur and accounts for only 5% of all ameloblastomas .
based on current knowledge , there is no reported case of granular cell ameloblastoma with dentinoid in the literature . in this paper , we present a case of a rare histological subtype of ameloblastoma with large amounts of granular cells , glandular pattern , and dentinoid areas in the right mandible of a 31-year - old male .
final histopathological diagnosis of adenoid granular cell ameloblastoma with dentinoid was made for this entity .
a 31-year - old man was referred to us with a chief complaint of a swelling on the left side of the mandible , which had been presented for nearly 1 month .
clinical examination revealed a localized expansion of the left mandible covered by normal oral mucosa .
the swelling was painful with palpation , soft in consistency , and fluctuant in nature .
the tumor caused mobility and displacement of left mandibular canine , first and second premolars .
radiographically , panoramic view showed a unilocular radiolucency with well - defined borders extending from the left canine to the left mandibular second molar .
there was root divergence , but no root resorption and the lamina dura of the affected teeth were destroyed [ figure 1a ] .
cone beam computed tomography scan showed a radiolucent lesion in the left mandibular area with buccal and lingual cortices destruction [ figure 1b ] .
radiographic differential diagnosis includes central giant cell granuloma , ameloblastoma , odontogenic myxoma , and keratocystic odontogenic tumor was given .
the sections showed a combination of follicular , plexiform , and desmoplastic patterns of ameloblastoma [ figure 2a and b ] with wide areas of granular cells and fibrous stroma [ figure 2c and d ] .
dentinoid calcified [ figure 3a and b ] and occasionally glandular area were observed in some sections [ figure 3c and d ] .
( a and b ) combination of follicular , plexiform , and desmoplastic patterns of ameloblastoma .
( c and d ) zone of follicular pattern of ameloblastoma demonstrating peripheral ameloblastic cells and duct - like pattern .
the central zone exhibiting granular cells and foci of cystic degeneration . considering these features ,
the patient was submitted for left partial hemimandibulectomy from left central incisor to left third molar area .
histopathological examination of the last specimen showed neoplastic proliferation of odontogenic epithelial cells in follicular and plexiform patterns and large amounts of granular cells .
considering the histopathological features of present and previous tissue sections , the diagnosis of adenoid granular cell ameloblastoma with dentinoid was confirmed .
the patient is under close follow - up and shows no evidence of recurrence 18 months after the operation .
granular cell ameloblastoma is a rare subtype of ameloblastoma in which granular cells located in the center of the follicles .
its median age is 35-year - old with no distinct gender predilection in the literature .
granular cell ameloblastoma should be differentiated from other odontogenic and nonodontogenic lesions along with granular cells , including granular cell tumor , congenital epulis , and granular cell odontogenic tumor .
the granular cell tumor is a soft tissue tumor and should be distinguished from ameloblastomas that cause cortical perforation and soft tissue extension .
congenital epulis is also a soft tissue tumor and with regards to its age outbreak , there is no need to distinguish it from a granular cell ameloblastoma .
granular cell odontogenic tumors exhibit a proliferation of large cells with eosinophilic granular cytoplasm and may show dystrophic calcifications .
granules of granular cells in granular cell ameloblastoma are positive for cytokeratin , cd68 , lysozyme , and alpha-1-antichymotrypsin , and in granular cell odontogenic tumor are positive for vimentin , cd68 , lysozyme , muscle - specific actin , alpha - smooth muscle actin , calponin , neuron - specific enolase , cd138 , and bcl-2 in immunohistochemistry ( ihc ) staining .
granular cell lesions are easy to rule out with observing follicular , plexiform , and desmoplastic patterns of ameloblastoma in the specimens . in this case ,
this is due to the presence of glandular pattern and dentinoid areas in the histopathological assessment .
duct - like structures are the characteristic of the aots , and dystrophic calcifications are usually seen in these lesions . considering that granular cell is not exist in aots , distinction between the present case and aot was performed without ihc .
bone formation was only reported in one neoplasm , two polycystic ameloblastomas showed diffuse interstitial ossification and enamel formation were described in few reports . in most other reported cases , the hard tissue had been construed as dentin or dentinoid .
consequently , hard tissue in these unusual cases of ameloblastoma has a wide variety of nature . finally ,
because of an existing neoplastic proliferation of odontogenic epithelial cells in follicular , plexiform and glandular patterns , dentinoid areas , and abundant granular cells , we concluded the present tumor to be a rare case of adenoid granular cell ameloblastoma with dentinoid . to make accurate diagnosis , it is essential that all the oral and maxillofacial pathologist to be aware of this entity . the authors of this manuscript
declare that they have no conflicts of interest , real or perceived , financial or non - financial in this article .
the authors of this manuscript declare that they have no conflicts of interest , real or perceived , financial or non - financial in this article .
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### Summary:
: adenoid ameloblastoma with dentinoid is a rare odontogenic tumor .
granular cell ameloblastoma also is a less common histological subtype of ameloblastoma . in this report ,
the patient was a 31-year - old male .
the lesion was located in the right mandible and was unicystic with well - defined borders .
the tumor tissue was showing a combination of follicular , plexiform , and desmoplastic patterns of ameloblastoma with wide areas of granular cells , fibrous stroma , glandular pattern , and dentinoid calcified .
very few cases of distinct forms of ameloblastoma that show the formation of dentinoid has been reported .
however , there are no cases of adenoid granular cell ameloblastoma with dentinoid 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:
: ureteral obstruction , resulting in impaired graft function , is a well - known problem following renal transplantation .
management of ureteral complications includes percutaneous nephrostomy , which is considered to be a safe and effective measure .
here , we demonstrate a case of a 35-year old renal allograft recipient with primary graft function but stagnating serum creatinine following extraction of the double - j catheter .
ureteral stenosis was suspected by ultrasound imaging and magnetic resonance tomography , and urinary flow was preserved with a percutaneous nephrostomy . however , early displacement of the percutaneous nephrostomy catheter resulted in distinct clinical discomfort .
ct imaging suggested an intra - abdominal position of the catheter 's tip , requiring immediate surgical action .
percutaneous nephrostomy ( pcn ) is an established procedure following ureteral complications after renal transplantation .
insertion of a pcn catheter for decompression of the collecting system in cases of obstruction is considered to be an easy and safe procedure .
however , early or delayed catheter displacement is a frequent event . even with optimal imaging and choice of the puncture site , this complication can not reliably be prevented .
we here report the case of a renal allograft recipient with unexpected intra - abdominal position of a nephrostomy catheter .
a 35-year old woman with end - stage renal disease due to chronic glomerulonephritis received a first cadaveric renal transplant from a living - related donor .
doppler ultrasound imaging showed homogenous perfusion of the graft with excellent systolic and diastolic flow , and the double - j catheter could be removed on day 14 .
thereafter , serum creatinine levels did not develop as expected ( table 1 ) , but routine renal ultrasound was unremarkable .
thus , a renal biopsy was performed on day 16 , revealing moderate cellular rejection .
however , serum creatinine remained unchanged despite treatment with high - dose methylprednisolone . at this time point ,
magnetic resonance tomography confirmed the findings and suggested the presence of a distal ureteral stenosis , while results obtained using renal scintigraphy were not conclusive . since retrograde imaging of the ureter and re - insertion of a double - j catheter was not feasible , a pcn was performed .
1 ) demonstrated an unexpected position of the catheter ( arrows ) , far away from the renal allograft ( asterisk ) and suggested adherence of the catheter tip to the ileum or within the small bowels ( arrowhead ) .
urgent surgery confirmed the intra - abdominal position but fortunately did neither reveal any injured intestine nor signs of intra - abdominal fluid or peritonitis .
a few days later , the patient was dismissed symptom - free with a serum creatinine level of 131
course of serum creatinine levels and estimated glomerular filtration rate , using the mdrd formula ct imaging with digital reconstruction showing the course of the nephrostomy catheter ( a ) and its unexpected position ( b and c ; arrows ) far away from the renal allograft ( asterisk ) and its tip likely adherent to or within the ileum ( arrowhead ) .
ureteral complications in renal transplantation occur in approximately 8% of renal transplant recipients , diagnosed at a mean of 18 days after renal transplantation , and occasionally leading to graft loss .
initial treatment often consists of pcn , followed by other procedures such as surgical repair of the ureter or placement of a nephroureteral stent .
percutaneous therapy has also been successfully used after renal transplantation as sole therapy in treatment of ureteral obstruction and leakage . of note ,
patient and graft survival rates are not different in patients undergoing pcn when compared to other kidney recipients . we here demonstrate a rare complication of pcn in a renal transplant recipient . while displacement of a pcn catheter is a common problem not only in native but also transplanted kidneys , intra - abdominal position is rare , but requires immediate attention and action to prevent further damage .
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### Summary:
: context : ureteral obstruction , resulting in impaired graft function , is a well - known problem following renal transplantation .
management of ureteral complications includes percutaneous nephrostomy , which is considered to be a safe and effective measure.case report : here , we demonstrate a case of a 35-year old renal allograft recipient with primary graft function but stagnating serum creatinine following extraction of the double - j catheter .
ureteral stenosis was suspected by ultrasound imaging and magnetic resonance tomography , and urinary flow was preserved with a percutaneous nephrostomy . however , early displacement of the percutaneous nephrostomy catheter resulted in distinct clinical discomfort .
ct imaging suggested an intra - abdominal position of the catheter 's tip , requiring immediate surgical action.conclusion:the present case demonstrates that performing pcn following renal transplantation may have unexpected risks .
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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:
: intracerebral hemorrhage ( ich ) , characterized by its high morbidity and mortality , is still an tough public health problem throughout the world . despite the progress of ich diagnostic techniques , knowledge of the pathophysiologic mechanism of ich
volume of hematoma has been generally recognized as a predictor of prognosis and a number of observational studies have revealed that hematoma enlargement ( he ) occurs commonly within the first 24 h and independently predicts early neurological deterioration and poor outcome .
thus , it is essentially important to stable the hematoma and prevent he . elevated blood pressure ( bp ) , an independent predictor for poor prognosis for ich , was deemed to increase the risk of he . in a retrospective analysis of 76 patients with ich , target systolic bp ( sbp ) of 160 mmhg
were significantly associated with he compared with those of 150 mmhg ( p = 0.025 < 0.05 ) .
antihypertensive therapy has been widely practiced and conservative target levels were prevalently achieved due to concerning about decreasing cerebral blood flow ( cbf ) in the past years .
the american heart association ( aha ) guidelines for spontaneous ich has recommended a target sbp level of < 180 mmhg or mean artery pressure ( map ) < 110 mmhg .
different from ischemic stroke , in ich patients , neuroimaging studies have proved that there exists no so - called an ischemic penumbra in the peri - hematoma brain tissues .
therefore , this enlightened researchers to intervene high bp more aggressively . based on these findings , several relevant clinical trials were performed in recent years . in this study
, we attempted to make a systematic review and meta - analysis assessing the safety and efficacy of aggressive bp lowering compared with conservative antihypertensive levels recommended by the aha guidelines .
randomized controlled trials ( rcts ) of antihypertensive drugs interventions that aimed at lowering bp in patients with acute ich were identified by searching pubmed , embase , the cochrane library , china national knowledge infrastructure , and vip database up to july 2014 with different combinations of the following key words : intracerebral hemorrhage or cerebral hemorrhage or antihypertensive or blood pressure lowering or hematoma enlargement or hematoma expansion or hematoma growth .
inclusion criteria were as follows : ( 1 ) patients with acute spontaneous ich diagnosed by computed tomography ( ct ) scan ; ( 2 ) rcts on bp management comparing conservative levels and intensive or rapid or aggressive protocols ; ( 3 ) studies scoring 3 using the cochrane criteria .
exclusion criteria were as follows : ( 1 ) low quality studies ; ( 2 ) hemorrhage secondary to brain injury , ischemic stroke , tumor , intracranial vascular malformation , and aneurysm ; ( 3 ) therapies combining with other interventions such as craniotomy or minimally invasive surgery . aggressive or intensive or rapid bp reduction protocols ( target sbp 140 mmhg or map
< 110 mmhg ) were compared with conservative bp treatment strategy ( target sbp 180 mmhg or map < 130 mmhg ) recommended by the guidelines .
two researchers ( chao pan and yang hu ) independently identified the articles following the inclusion and exclusion criteria and assessed the articles qualities .
any discrepancies were resolved by discussion or consultation with a third reviewer ( zhou - ping tang , an expert in neurology ) .
the secondary outcomes were he at 24 h after onset , mortality , and favorable clinical outcome at 90 days ( a modified rankin scale [ mrs ] score 2 at 90 days ) .
he was defined as a substantially increase in volume above 33% or an absolute change in hematoma volume of 12.520 ml on repeated ct scan ( 24 h after ictus ) .
we used review manager version 5.1.2 software ( cochrane collaboration , denmark ) for data analysis and calculated the i to describe the heterogeneity .
a fixed - effects model was employed in the absence of significant heterogeneity ( i < 50% ) ; otherwise , a random - effects model was used as an alternative .
the pooled results were presented as odds ratio ( or ) , 95% confidence interval ( 95% ci ) and p value .
randomized controlled trials ( rcts ) of antihypertensive drugs interventions that aimed at lowering bp in patients with acute ich were identified by searching pubmed , embase , the cochrane library , china national knowledge infrastructure , and vip database up to july 2014 with different combinations of the following key words : intracerebral hemorrhage or cerebral hemorrhage or antihypertensive or blood pressure lowering or hematoma enlargement or hematoma expansion or hematoma growth .
inclusion criteria were as follows : ( 1 ) patients with acute spontaneous ich diagnosed by computed tomography ( ct ) scan ; ( 2 ) rcts on bp management comparing conservative levels and intensive or rapid or aggressive protocols ; ( 3 ) studies scoring 3 using the cochrane criteria .
exclusion criteria were as follows : ( 1 ) low quality studies ; ( 2 ) hemorrhage secondary to brain injury , ischemic stroke , tumor , intracranial vascular malformation , and aneurysm ; ( 3 ) therapies combining with other interventions such as craniotomy or minimally invasive surgery . aggressive or intensive or rapid bp reduction protocols ( target sbp 140 mmhg or map
< 110 mmhg ) were compared with conservative bp treatment strategy ( target sbp 180 mmhg or map < 130 mmhg ) recommended by the guidelines .
two researchers ( chao pan and yang hu ) independently identified the articles following the inclusion and exclusion criteria and assessed the articles qualities .
any discrepancies were resolved by discussion or consultation with a third reviewer ( zhou - ping tang , an expert in neurology ) .
the secondary outcomes were he at 24 h after onset , mortality , and favorable clinical outcome at 90 days ( a modified rankin scale [ mrs ] score 2 at 90 days ) .
he was defined as a substantially increase in volume above 33% or an absolute change in hematoma volume of 12.520 ml on repeated ct scan ( 24 h after ictus ) .
we used review manager version 5.1.2 software ( cochrane collaboration , denmark ) for data analysis and calculated the i to describe the heterogeneity .
a fixed - effects model was employed in the absence of significant heterogeneity ( i < 50% ) ; otherwise , a random - effects model was used as an alternative .
the pooled results were presented as odds ratio ( or ) , 95% confidence interval ( 95% ci ) and p value .
, 2474 articles did not meet the inclusion criteria after reading the titles , abstracts , and full - text [ figure 1 ] .
after quality assessment , four high - quality trials were eligible for further pooling analysis [ table 1 ] .
study quality assessment 2 : yes ; 1 : unclear ; adapt : acutely decreasing arterial pressure trial ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial ; bp : blood pressure
. characteristics of the four included studies adapt : acutely decreasing arterial pressure trial ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial ; map : mean artery pressure ; sbp : systolic blood pressure ; cbf : cerebral blood flow ; bp : blood pressure ; he : hematoma enlargement ; nihss : national institutes of health stroke scale ; mrs : modified rankin scale .
koch et al . conducted the rapid bp reduction trial aimed at evaluating the feasibility and safety of rapid bp reduction to lower than previously recommended levels in acute ich from 2004 to 2006 . in this study
, subjects satisfying the criteria were randomized into one of two bp lowering groups : a standard bp management group with a target map 110130 mmhg according to the 2007 aha guidelines or an aggressive bp management group with a target map < 110 mmhg .
there were no significant differences in early neurological deterioration , hematoma and edema growth , and clinical outcome at 90 days .
the first and second intensive blood pressure reduction in acute intracerebral hemorrhage trial ( interact1 and 2 ) study assessed the feasibility , safety and effectiveness of intensive bp lowering protocol ( target sbp < 140 mmhg ) comparing with conservative bp lowering group ( target sbp < 180 mmhg ) . the results of interact1 and 2 have showed that intensive and early bp management did decrease hematoma volume modestly but not to the extent of a substantial degree .
interact2 failed to show significant improvement in the rate of functionally independence , with early aggressive bp lowering .
however , in an ordinal analysis of the distribution of mrs scores , there was a significant shift in favor of those patients who received aggressive bp therapy .
the ich acutely decreasing arterial pressure trial ( ich adapt ) was conducted to observe the cbf changes secondary to aggressive bp reduction in patients with ich .
subjects with sbp > 150 mmhg were randomized into one of two treatment regimens receiving intravenous antihypertensive therapy : a targeted sbp < 150 mmhg or < 180 mmhg .
a noncontrast ct was performed at 24 h. the images and statistics of the results dispelled the long - existing concern that lowering bp aggressively may induce cerebral ischemia .
saes were defined as ischemic or undifferentiated stroke , acute coronary event , severe hypotension , or others according to the interact trials .
a low heterogeneity ( i = 0% , p = 0.49 ) was observed , thus we used a fixed - effect model to identify the pooled or ( 0.96 ) , 95% ci ( 0.821.13 ) and p ( p = 0.61 ) [ figure 2 ] .
this result demonstrated no statistically significant difference between these two bp management protocols in saes , indicating that aggressive bp protocol is safety enough and would not bring more adverse effects .
forest plots depicting safety of aggressive blood pressure reduction ( serious adverse effect ) in aggressive versus guideline protocol .
ci : confidence interval ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial .
this founding would dispel the long - existing doubt that further bp management may induce more unexpected bad results on ich patients .
hematoma enlargement at 24 h the relevant data of these four studies involving 1427 patients ( 725 in the aggressive bp lowering group , 702 in the guideline recommended group ) were presented in figure 3 .
the heterogeneity among these trials were quite low ( i = 41% , p = 0.16 ) .
the value of or was 0.91 ( 95% ci : 0.721.17 ) , indicated that reducing bp intensively or aggressively , maintaining sbp < 140 mmhg or map < 110 mmhg , demonstrated a moderate tendency toward preventing he compared with guideline group , but was not significant different according to the p value ( p = 0.47 ) and 95% ci .
ci : confidence interval ; adapt : acutely decreasing arterial pressure trial ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial .
three studies presented data on 90 days mortality shown in figure 4 . according to our analysis , no heterogeneity ( p = 0.83 , i = 0% ) was found among the trials , thus a fixed - effect model was chosen for the pooling analysis .
the mortality rate was slightly greater in the guideline group than in the intensive group but did not reach significant values with a pooled or of 0.97 ( 95% ci : 0.791.20 ) .
these results demonstrated that intensive bp lowering brought small effects on improving mortality rates at 90 days .
ci : confidence interval ; adapt : intracerebral hemorrhage acutely decreasing arterial pressure trial ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial
. favorable clinical outcome at 90 days ( a modified rankin scale score 2 at 90 days ) data on favorable clinical outcome ( mrs 2 ) were available in 3 trials [ figure 5 ] .
there existed no heterogeneity ( i = 0% , p = 0.60 ) and the pooled or were identified using a fixed - effect model ( or : 1.13 ; 95% ci : 0.981.30 ) . although no significant difference were achieved between the aggressive bp group and the guideline group ( 95% ci : 0.981.30 , p = 0.09 ) , a tendency that lowering bp aggressively may benefit the ich patients through promoting their operational abilities in everyday life
forest plots depicting favorable clinical outcome at 90 days ( a modified rankin scale score 2 at 90 days ) in aggressive versus guideline protocol .
ci : confidence interval ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial
, 2474 articles did not meet the inclusion criteria after reading the titles , abstracts , and full - text [ figure 1 ] .
after quality assessment , four high - quality trials were eligible for further pooling analysis [ table 1 ] .
study quality assessment 2 : yes ; 1 : unclear ; adapt : acutely decreasing arterial pressure trial ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial ; bp : blood pressure
. characteristics of the four included studies adapt : acutely decreasing arterial pressure trial ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial ; map : mean artery pressure ; sbp : systolic blood pressure ; cbf : cerebral blood flow ; bp : blood pressure ; he : hematoma enlargement ; nihss : national institutes of health stroke scale ; mrs : modified rankin scale .
koch et al . conducted the rapid bp reduction trial aimed at evaluating the feasibility and safety of rapid bp reduction to lower than previously recommended levels in acute ich from 2004 to 2006 . in this study
, subjects satisfying the criteria were randomized into one of two bp lowering groups : a standard bp management group with a target map 110130 mmhg according to the 2007 aha guidelines or an aggressive bp management group with a target map < 110 mmhg .
there were no significant differences in early neurological deterioration , hematoma and edema growth , and clinical outcome at 90 days .
the first and second intensive blood pressure reduction in acute intracerebral hemorrhage trial ( interact1 and 2 ) study assessed the feasibility , safety and effectiveness of intensive bp lowering protocol ( target sbp < 140 mmhg ) comparing with conservative bp lowering group ( target sbp < 180 mmhg ) . the results of interact1 and 2 have showed that intensive and early bp management did decrease hematoma volume modestly but not to the extent of a substantial degree .
interact2 failed to show significant improvement in the rate of functionally independence , with early aggressive bp lowering .
however , in an ordinal analysis of the distribution of mrs scores , there was a significant shift in favor of those patients who received aggressive bp therapy .
the ich acutely decreasing arterial pressure trial ( ich adapt ) was conducted to observe the cbf changes secondary to aggressive bp reduction in patients with ich .
subjects with sbp > 150 mmhg were randomized into one of two treatment regimens receiving intravenous antihypertensive therapy : a targeted sbp < 150 mmhg or < 180 mmhg .
a noncontrast ct was performed at 24 h. the images and statistics of the results dispelled the long - existing concern that lowering bp aggressively may induce cerebral ischemia .
saes were defined as ischemic or undifferentiated stroke , acute coronary event , severe hypotension , or others according to the interact trials .
a low heterogeneity ( i = 0% , p = 0.49 ) was observed , thus we used a fixed - effect model to identify the pooled or ( 0.96 ) , 95% ci ( 0.821.13 ) and p ( p = 0.61 ) [ figure 2 ] .
this result demonstrated no statistically significant difference between these two bp management protocols in saes , indicating that aggressive bp protocol is safety enough and would not bring more adverse effects .
forest plots depicting safety of aggressive blood pressure reduction ( serious adverse effect ) in aggressive versus guideline protocol .
ci : confidence interval ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial .
this founding would dispel the long - existing doubt that further bp management may induce more unexpected bad results on ich patients .
hematoma enlargement at 24 h the relevant data of these four studies involving 1427 patients ( 725 in the aggressive bp lowering group , 702 in the guideline recommended group ) were presented in figure 3 .
the heterogeneity among these trials were quite low ( i = 41% , p = 0.16 ) .
the value of or was 0.91 ( 95% ci : 0.721.17 ) , indicated that reducing bp intensively or aggressively , maintaining sbp < 140 mmhg or map < 110 mmhg , demonstrated a moderate tendency toward preventing he compared with guideline group , but was not significant different according to the p value ( p = 0.47 ) and 95% ci . forest plots depicting hematoma enlargement at 24 h in aggressive versus guideline protocol .
ci : confidence interval ; adapt : acutely decreasing arterial pressure trial ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial .
three studies presented data on 90 days mortality shown in figure 4 . according to our analysis , no heterogeneity ( p = 0.83 , i = 0% ) was found among the trials , thus a fixed - effect model was chosen for the pooling analysis .
the mortality rate was slightly greater in the guideline group than in the intensive group but did not reach significant values with a pooled or of 0.97 ( 95% ci : 0.791.20 ) .
these results demonstrated that intensive bp lowering brought small effects on improving mortality rates at 90 days .
ci : confidence interval ; adapt : intracerebral hemorrhage acutely decreasing arterial pressure trial ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial
. favorable clinical outcome at 90 days ( a modified rankin scale score 2 at 90 days ) data on favorable clinical outcome ( mrs 2 ) were available in 3 trials [ figure 5 ] .
there existed no heterogeneity ( i = 0% , p = 0.60 ) and the pooled or were identified using a fixed - effect model ( or : 1.13 ; 95% ci : 0.981.30 ) . although no significant difference were achieved between the aggressive bp group and the guideline group ( 95% ci : 0.981.30 , p = 0.09 ) , a tendency that lowering bp aggressively may benefit the ich patients through promoting their operational abilities in everyday life
forest plots depicting favorable clinical outcome at 90 days ( a modified rankin scale score 2 at 90 days ) in aggressive versus guideline protocol .
ci : confidence interval ; interact : intensive blood pressure reduction in acute cerebral hemorrhage trial
treatment of high bp was a crucial question , which directly affects early outcome and long - time prognosis of patients , whereas there was too much disagreement , especially with regard to targeted bp levels .
consensuses that hypertensive response should be handled deliberately , based on relatively deficient and inferior evidences , were temporarily reached in consideration of preserving cerebral blood supply .
we systematically evaluated the safety and effectiveness of aggressive bp treatment protocols compared with conservative bp lowering levels and made a review on antihypertensive studies on ich . on the basis of low heterogeneity , we pooled these trials and expanded the sample size for a meta - analysis .
our results suggested that aggressive bp treatment policies are quite safe and tend to show a potential to reduce he in acute ich patients with elevated bp , though the difference was not significant .
results of mortality and favorable clinical outcome , in accordance with that of he , indicated that for ich patients with rising bp , to reduce bp aggressively and early might benefit patients through restrict he .
the 95% ci was narrowed compared with that of interact2 , the largest rcts among these trials , containing 2839 ich subjects .
interestingly , in the rapid bp reduction trial , patients assigned into the aggressive bp management group with a target map < 110 mmhg demonstrated no more saes than patients assigned into conservative level group , indicating that this map level may be safe .
similarly , the ich adapt trial used ct perfusion to observe the cbf and the results dispelled the concern that lowering bp aggressively may induce cerebral ischemia .
most of the observational studies found a tight association between bp and he , while the results did not reach statistically significances strictly .
the inconformity may be explained as follow : he is a complicated process with multiple factors involved in apart from bp , such as liver diseases , hyperglycemia , history of stroke , alcohol consumption , hematoma volume , locations of hematoma , and irritability .
different antihypertensive agents and other therapies besides bp lowering , for example , hemostasis medication , therapeutic hypothermia , abuse of mannitol may influence the results .
moreover , however , there is a noteworthy fact that opinions differ on whether bp plays an important role in he . in an analysis of recombinant activated factor vii ict ( fast ) , he was found not associated with baseline bp . theoretically speaking ,
even a modest decrease of hematoma would ameliorate recovery and in this regard , an aggressive bp management was worth implementing .
indeed , in interact2 , the ordinal analysis of mrs demonstrated a significantly lower score in intensive treatment group ( or : 0.87 ; 95% ci : 0.771.00 ; p = 0.04 ) .
for example , the antihypertensive treatment of acute cerebral hemorrhage trial was excluded for nonrandomization .
three levels of sbp reduction in patients suffering ich were achieved using intravenous nicardipine within 6 h after bleeding : 170200 , 140170 , or 110140 mmhg . what 's more , most cases were provided by interact2 , leading to a larger weight of interact2 .
in ich adapt study , the relatively aggressive sbp reduction level was 150 mmhg , instead of 140 mmhg in other trials .
bp management was supposed to be beneficial through reducing cerebral edema , but the impact of antihypertensive therapy on peri - hematomal edema was not discussed for a lack of materials .
the absolute increase of hematoma volume was not within the scope of analysis because of limited original data .
since the number of included studies was < 10 , it was improper to draw a funnel plot to explore the publication bias . in conclusion
, we hold that aggressive bp management was safe enough and show its promising potential compared with a more conservative bp policy previously recommended for acute ich patients .
it might be worth implementing aggressive bp lowing therapy for ich patients presenting with sbp between 150 and 220 mmhg .
more rcts were desperately needed to further investigate optimal bp reduction levels , drug selection and the most likely candidates that will benefit from aggressive bp management .
this research was supported by grants from the national natural science foundation of china ( no .
81171089 ; 81471201 ) and the key clinical program of the ministry of health of china ( 2010 ) .
this research was supported by grants from the national natural science foundation of china ( no . 81171089 ; 81471201 ) and the key clinical program of the ministry of health of china ( 2010 ) .
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### Summary:
: background : the influence of blood pressure ( bp ) lowering on intracerebral hemorrhage ( ich ) patients is unclear . to assess the safety and efficacy of aggressive antihypertensive therapies in acute ich patients
, we carried out a systematic review and meta-analysis.methods:pubmed , embase , cochrane library , china national knowledge infrastructure , and vip database up to july 2014 were searched .
high - quality randomized controlled trials were included .
low - quality trials were excluded .
serious adverse events were defined as the primary outcome .
the secondary outcomes were hematoma enlargement ( he ) at 24 h after onset , mortality , and favorable clinical outcome at 90 days.results:four high - quality trials involving a total of 1427 patients met the inclusion criteria and were analyzed .
odds ratios ( ors ) of primary outcome was 0.96 ( 95% confidence interval [ ci ] : 0.821.13 , p = 0.61 ) .
ors of he at 24 h after onset , mortality and favorable clinical outcome at 90 days were 0.91 ( 95% ci : 0.721.17 , p = 0.47 ) , 0.97 ( 95% ci : 0.791.20 , p = 0.81 ) , 1.13 ( 95% ci : 0.981.30 , p = 0.09 ) respectively.conclusions:aggressive bp management policies are safe and might have a potency of reducing he and improving clinical 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:
: . it may be of open variety caused by primary neurulation failure , leading to neural tissue getting exposed without skin covering and usually associated with external discharge of cerebrospinal fluid , while another being closed category is caused by faulty secondary neurulation and in resultant defect , the neural tissue being not exposed and usually covered with intact skin .
the anterior and posterior neuropore used to close in the last , so these sites are most likely to remain vulnerable for occurrence of such congenital defects .
occurrence of lipomyelomeningocele with type ii split cord malformation , low - lying tethered cord with anomaly of cervical vertebrae fusion in the form of block klippel feil syndrome and sacral
agenesis plays a challenge to the clinician in the search and early diagnosis for multiple neural tube defects , and further , management of such cases also possesses challenge to the neurosurgical , urologist , orthopedician , and rehabilitatory team .
a 23-year - old male presented with low backache for the last 2-years , with a history of surgery for repair of lumbosacral lipomeningocoele at the age of 1 year .
he was asymptomatic after surgery for almost 20-years , and later on , he noticed wasting and weakness of lower limbs associated with difficulty in walking ; however , he had no bowel or bladder disturbances . clinical examination revealed an healthy male , wasting of bilateral calf muscle , and power of grade 4/5 at bilateral hip , knee , and ankle joints and rest of the neurological examination were essentially within normal limits .
x - ray of the lumbosacral spine revealed the presence of spina bifida with agenesis of lower sacral and coccygeal segments [ figure 1 ] .
x - ray of the cervical spine showed fusion of c2 and c3 spinous process [ figure 2 ] , and lumbosacral spine magnetic resonance imaging sagittal section , t1-weighted image showed the presence of the low - lying conus lying at the l4 vertebra level with tethering with lipoma and associated agenesis of the lower sacral and coccygeal segments [ figure 3 ] .
x - ray lumbar spine , anteroposterior view showing spina bifida with partial sacral agenesis x - ray cervical spine , lateral view showing c2-c3 block vertebrae magnetic resonance imaging , t2-weighted image showing low - lying tethered cord at l4 vertebra with sacral agenesis t2-weighted coronal section magnetic resonance image revealed type ii split cord malformation with split extending from d11 vertebrae to l4 vertebrae [ figures 4 and 5 ] .
he underwent surgical repair of lipomyelomeningocele with the resection of residual lipoma ; conus was freed and reconstructed , with meticulous dural closure being carried out . in the postoperative period , he had temporary mild worsening in the neurological status , which recovered over next 2 months ; however , wasting of calf muscles was still persisting at the last follow - up at 2-years , following the second surgery . magnetic resonance imaging lumbosacral spine ,
axial section , t1-weighted image showing conus tethering at the previous surgical exploration site magnetic resonance imaging axial section , t2-weighted image showing presence of type - ii split cord malformation with two neural tubes lying in the single dural sheath
neural tube defects are congenital development anomaly and commonly observed at these potential sites , which includes posterior and anterior neuropore , as these sites used to close in the last during the embryonic life and remain most vulnerable for congenital defect .
divergent views are existing regarding etiogenesis of multiple neural tube defects , and two most important theories are postulated .
another theory is multiple neural tube defect closure theory , which was postulated by van allen et al . in 1993 ,
described , and advocated five sites of initiation for the neural tube closure process and the multiple tube defect commonly used to occur at the these collision sites of neural tube closure and as such can produce a spectrum of combinations of associated developmental anomaly , which are developing simultaneously in an individual .
the occurrence of two or more meningomyelocele , or meningocele in combination with encephaloceles or even triple meningoceles , can be lying dispersed along the entire neuraxis ; however , such occurrence of two or three defects combinations occurring along the entire vertebral axis is extremely rare although reported in the form of isolated case reports .
authors observed simultaneous occurrence of pentad of congenital defects , spread along the whole spinal axis , not reported previously , who presented with tethered cord in the literature , the current case report represents the first case of its kind .
exact mechanism of dichotomy about the age of onset clinical presentation is still debated being symptomatic either in the infancy age or later life . as majority
may get symptomatic in infancy or early childhood , a few cases only get symptomatic in adult age .
the spectrum of amount of the traction applied on the conus is incriminated to be related to the age of onset of clinical manifestation . in those cases , who have thick filum terminale or very firm causing tethering and
severely stretched conus , it leads to early onset of neurological disturbances even appearing in infancy or toddler age . while lesser degree of tethering may cause only minimal or nonprogressive neurological deficits in childhood , making subclinical in childhood until aggravated factors
however , other postulates hypothesized that the mechanism of late onset of tethered cord syndrome is due to progression of tightening of conus ; as a child grows older , the cumulative effect of repeated cord traction over many years , during natural movement of spine , could ultimately leads to the to development of the conus injury .
reported direct trauma to the back can precipitate the neurological deficit manifestations by causing deformation of the remaining merely functioning neuronal elements of the involved stretched cord .
reported neurological dysfunction in patient with tethered cord correlating well with the anoxia of mitochondria , which is energy powerhouse within the conus developmental stenosis of lower spinal cord and disc prolapse are also other known precipitate factors .
the closed spinal dysraphism with lipoma called as lipomyeloschisis and it can be of lipomyelomeningocele or lipomyelocele when associated with meningomyelocele or myelocele .
lipomyelocele is one of the more common than lipomyelomeningocele , usually presents as a fatty subcutaneous mass and commonly located in the thoracolumbar spinal region . with the growth of spinal canal , lipomas cause distortion of nerve roots attached to the lipoma , leading to neurological deficits .
posterior spinal defect is commonly observed in these patients , which is covered with skin and shows interspersed lipomatous tissue .
the interface of neural placode - lipoma junction lies inside or just at dural edge within the spinal canal in the lipomyelocele , while in the lipomyelomeningocele , it lies outside the spinal canal with resultant enlargement of anterior subarachnoid space .
it can clearly delineate posterior spinal elements defect with the presence of intact skin cover and interspersed lipomatous tissue . in lipomyelocele ,
the lipoma - neural placed interface lies within the spinal canal or at its edge while in lipomyelomeningocele it lies outside the spinal canal due to enlargement of subarachnoid space and commonly associated with low lying conus .
clinically , it may present with low backache , weakness of both lower limbs , foot deformity , spinal deformity , or failure of sphincter control of bowel and urinary bladder ; these can lead to significant progressive disability and psychological trauma to the patients as well as family and associated economic loss to the society .
the diagnosis of based on high degree of clinical suspicion and findings of various neuroimaging modalities includes x - ray and mri to evaluate the whole spine is must to exclude other associated lesion .
however , management includes surgical detethering with careful intradural dissection of lipoma to avoid fresh neurological deficit and meticulous dural and wound closure . however , any case who had associated with sacral agenesis is another indicator for imaging screening of the entire spine .
early diagnosis and prompt surgical management can be helpful in at least halting neurological deterioration , and some cases may get neurological improvement with almost negligible surgical complication rate .
authors analyzed 147 cases , having spinal lipomas , out of which 93 had conus lipomas , 26 had filum lipomas , and remaining 28 had only lipomeningomyelocele .
management of such cases was challenging , especially in the groups of the patients with no neurological deficits .
the neurological deficits were observed in the older age group patients in comparison to those neurologically intact were relatively younger .
authors also reported a rare occurrence of thoracic myelocystocele associated with multiple neural tube defects including presence of type-1 split cord malformation with low - lying tethered conus , dorsal syringomyelia in the dorsal region along with the presence of sacral agenesis , who underwent successful surgical repair .
in a few cases , spinal dysraphism may have additional presence of two or multiple neural tube defect located at far from conus region along the spinal axis , so screening of the whole spine is highly imperative to look for the search for the presence of additional defect and accordingly surgical planning should be tailor made with aim to improve the neurological outcome and providing proper care in the future as many of additional anomaly currently might be asymptomatic , may get symptomatic later on , warranting neurosurgical therapeutic intervention .
hence , authors advise that mri screening of the whole spine is highly essential along with screening of craniovertebral junction and scout film of brain to exclude hydrocephalus for holistic management planning of spinal dysraphism cases .
hence , high degree of clinical suspicion of existence of multiple defects , detailed clinical evaluation and appropriate neuroimaging is prerequisite for proper diagnosis of such rare multiple neural tube closure defects .
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### Summary:
: neural tube defects are congenital development anomaly of the central nervous system and usually have relatively more predilection to affect at anterior and posterior neuropore embryological development sites , so usually one or two defects are commonly encountered .
however , occurrence of simultaneous multiple neural tube defects is very rare , presence of constellation of five neural defects is extremely rare , and all defects add up together to produce gross neurological deficit .
we present an interesting case of a 23-year - old male who presented with history of lower backache and noticed wasting and weakness of lower limbs associated with difficulty in walking for the last 2 years but had no associated sphincter disturbances .
he was operated for lumbosacral lipomeningocoele repair at the age of 1 year .
he was asymptomatic , following the first surgical intervention . at the current admission
, he underwent re - exploration of surgical wound with surgical repair although suffered mild - temporary neurological worsening in the immediate postoperative period . imaging feature and management of such rare constellation of five embryological anomalies and its significance and brief literature
are 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:
: the incidence of intertrochanteric femoral fracture has been estimated to be more than 250,000 patients each year in the united states , with the reported mortality ranging from 15 to 20%.12 the reverse oblique trochanteric fracture of proximal part of femur is a distinct fracture pattern which is mechanically different and accounts for 2% of all the hip fractures and 5% of all the intertrochanteric and subtrochanteric fractures.3 a sliding hip screw is not indicated for stabilization of these fractures because the large diameter lag screw does not cross the primary fracture line and telescoping of implant may promote fracture separation rather than its impaction.4 this leads to an unacceptably high rate of failure when a conventional sliding hip screw is used to treat such fracture patterns .
to overcome this problem , the 95 dynamic condylar screw ( dcs ) was introduced to stabilize this fracture pattern.356 though its use involves a relatively simple operative procedure , various modes of failure of dcs were observed in reverse oblique trochanteric fractures like cutting out of screw , breakage of the plate , and screw or plate pull off from the bone.67 in an attempt to overcome some of these limitations , intramedullary devices like proximal femoral nails ( pfns ) were used for these fractures.8 with the use of intramedullary devices , the shaft fixation is nearer to the center of rotation of the hip , which gives a shorter lever arm and a lower sliding moment or tensile strain on the implant .
the intramedullary location provides buttress against lateral displacement and reduces bending strain on the implant .
the clinical relevance of these presumed biomechanical advantages and less complication rates of pfn are yet to be established .
this study aims to biomechanically compare the cutout resistance as well as modes of failure of dcs and pfn in reverse oblique trochanteric fractures .
dual energy x - ray absorptiometry ( dexa ) was used to determine the quality of specimens and these were classified into three groups based on the bone mineral density ( bmd ) : group a < 0.5 g / cm ; group b 0.51.0 g / cm ; and group c > 1.0 g / cm .
each group was further randomized into two intervention methods , i.e. pfn and dcs made up of stainless steel ( yogeshwar pvt . ltd , mumbai , india ) .
eight specimens were implanted with dcs and the rest with pfn ( with single screw in the neck ) under image intensifier control . during instrumentation , the tip apex distance ( tad ) was kept constant to 25 mm for each specimen .
the constructs were made unstable after putting the implant to resemble a reverse oblique trochanteric fracture by removing a standard - sized ( 1 cm ) posteromedial wedge .
these constructs were tested with a cyclic compressive load of 200 kg to mimic the joint reaction force of an adult hip.459 the tests were conducted at a cyclic frequency of 1 hz for 50,000 cycles or till failure ( defined as more than 5 mm of vertical displacement during cyclical loading ) , whichever was earlier .
fatigue tests were conducted using computer controlled servohydraulic materials testing system ( mts model 810 , mn , usa ) of 50 kn capacity .
the tested constructs were examined by naked eye as well as by radiographs to look for implant bending or breakage / backout / or screw fracture .
the deformations in the original structure of implant which were clearly visible on clinical examination were classified as macroscopic failure and those detected only on radiographs were labeled as microscopic failures [ appendix 1 ] .
the bending moment ( bm ) or the moment arm of a construct is the vector of force exerted at the confluence of the axial and the angular forces which can be mathematically calculated using the formula : where f is the bm force , p is the load applied ( 200 kg ) , and l is the length of lag screw from the base of barrel of dcs or medial edge of the pfn nail . for pfn , is the angle subtended to the normal and it is 45 ( 13590 = 45 ) : for dcs , is the angle subtended to the normal and it is 5 ( 9590 = 5 ) : all the statistical analyses were performed using instat software for windows ( graphpad version 3.00 , sandiego , ca , usa ) .
student 's t - test was used to analyze the difference of mean for bmd , number of cycles sustained , and bm of the constructs .
mean , standard deviation , and standard error of mean for these variables were also calculated .
the test was referenced for two - tailed p value and 95% confidence interval was constructed around sensitivity proportion using normal approximation method .
fisher 's exact test was used to comparatively evaluate the component failure in each group .
it is a statistical test used to determine if there is nonrandom association ( contingency ) present between two kinds of interventions .
the test was referenced for two - tailed p value and a value of < 0.05 was considered statistically significant .
all the statistical analyses were performed using instat software for windows ( graphpad version 3.00 , sandiego , ca , usa ) .
student 's t - test was used to analyze the difference of mean for bmd , number of cycles sustained , and bm of the constructs .
mean , standard deviation , and standard error of mean for these variables were also calculated .
the test was referenced for two - tailed p value and 95% confidence interval was constructed around sensitivity proportion using normal approximation method .
fisher 's exact test was used to comparatively evaluate the component failure in each group .
it is a statistical test used to determine if there is nonrandom association ( contingency ) present between two kinds of interventions .
the test was referenced for two - tailed p value and a value of < 0.05 was considered statistically significant .
the detailed test data of both the groups were duly registered [ tables 1 and 2 ] and comparisons were made in construct characteristics ( bmd , bm , and number of cycles sustained ) and component failures .
correlation of bone mineral density , bending moment , and number of cycles sustained with mode of failure in pfn specimens correlation of bone mineral density , bending moment , and number of cycles sustained with mode of failure in dcs specimens the difference in bmd of the specimens of both the groups was statistically not significant ( p=0.51 ) , which implies that the quality of the specimen bones was comparable in both the groups [ table 3 ] .
average bm of dcs group was found to be approximately 50% higher than that of pfn group .
mean bm of pfn group was 10.01 , while the value was 15.32 for dcs group , and this difference was found to be statistically significant ( p<0.0001 ) .
similarly , mean numbers of cycles sustained by pfn and dcs groups were 42,000 and 19,329 respectively , and the difference was found to attain sufficient statistical significance ( p=0.03 ) [ table 3 ] .
detailed analysis of bone mineral density of specimens , bending moment of implants , and number of cycles sustained in the pfn group , there were four failures ( three macroscopic and one microscopic ) .
all the failures were present in screw component [ figure 1 ] , and no failures were noticed in nail component . there was no failure in group c ( bmd>1.0 g / cm ) .
one specimen from group a ( bmd<0.5 g / cm ) failed at 10,000 cycles and this was the earliest failure seen in pfn constructs .
five out of eight constructs completed 50,000 cycles successfully without any gross failure [ figure 2 ] .
no failure of any implant was seen in the initial 10,000 cycles . in the dcs group
, we noticed plate barrel angle deformation [ figure 3 ] in 5 constructs , screw bending [ figures 3 and 4 ] in 6 constructs , and plate bending [ figures 3 and 4 ] in 7 constructs ( 18 component failures out of total 24 components ) .
only two specimens completed 50,000 cycles successfully , out of which one showed microscopic deformation .
thus , there were 4 component failures ( out of total 16 components ) in the pfn group and 18 component failures ( out of total 24 components ) in the dcs group .
the difference in component failures in both the groups was found to be statistically significant ( p=0.003 ) .
x - rays of cadaveric femoral specimen ( a ) with unstable reverse oblique trochanteric fracture with posteromedial defect implanted with proximal femoral nail and it was subjected to cyclical compression load . screw component failed ( b ) to compression load after 36,000 cycles x - rays of cadaveric femoral specimen ( a ) with unstable reverse oblique trochanteric fracture with posteromedial defect implanted with proximal femoral nail and it was subjected to cyclical compressive load .
it remained stable ( b ) after 50,000 cycles x - rays of cadaveric femoral specimen ( a ) with unstable reverse oblique trochanteric fracture with posteromedial defect implanted with 95 dynamic hip screw and it was subjected to cyclical compression load .
( b ) it failed after 4482 cycles . plate bending of 15 , plate barrel junction deformation of 2.5 , and screw bending of 1.5 were observed at the end of cyclical loading x - rays of cadaveric femoral specimen ( a ) with unstable reverse oblique trochanteric fracture with posteromedial defect implanted with 95 dynamic hip screw and it was subjected to cyclical compression load .
( b ) it failed after 1962cycles . plate bending of 10 , and screw bending of 1 were observed at the end of cyclical loading it was also observed that bends of 2 or less could be detected only by radiography .
the difference in bmd of the specimens of both the groups was statistically not significant ( p=0.51 ) , which implies that the quality of the specimen bones was comparable in both the groups [ table 3 ] .
average bm of dcs group was found to be approximately 50% higher than that of pfn group .
mean bm of pfn group was 10.01 , while the value was 15.32 for dcs group , and this difference was found to be statistically significant ( p<0.0001 ) .
similarly , mean numbers of cycles sustained by pfn and dcs groups were 42,000 and 19,329 respectively , and the difference was found to attain sufficient statistical significance ( p=0.03 ) [ table 3 ] .
detailed analysis of bone mineral density of specimens , bending moment of implants , and number of cycles sustained
in the pfn group , there were four failures ( three macroscopic and one microscopic ) .
all the failures were present in screw component [ figure 1 ] , and no failures were noticed in nail component .
one specimen from group a ( bmd<0.5 g / cm ) failed at 10,000 cycles and this was the earliest failure seen in pfn constructs .
five out of eight constructs completed 50,000 cycles successfully without any gross failure [ figure 2 ] .
no failure of any implant was seen in the initial 10,000 cycles . in the dcs group
, we noticed plate barrel angle deformation [ figure 3 ] in 5 constructs , screw bending [ figures 3 and 4 ] in 6 constructs , and plate bending [ figures 3 and 4 ] in 7 constructs ( 18 component failures out of total 24 components ) .
only two specimens completed 50,000 cycles successfully , out of which one showed microscopic deformation .
thus , there were 4 component failures ( out of total 16 components ) in the pfn group and 18 component failures ( out of total 24 components ) in the dcs group .
the difference in component failures in both the groups was found to be statistically significant ( p=0.003 ) .
x - rays of cadaveric femoral specimen ( a ) with unstable reverse oblique trochanteric fracture with posteromedial defect implanted with proximal femoral nail and it was subjected to cyclical compression load . screw component failed ( b ) to compression load after 36,000 cycles x - rays of cadaveric femoral specimen ( a ) with unstable reverse oblique trochanteric fracture with posteromedial defect implanted with proximal femoral nail and it was subjected to cyclical compressive load .
it remained stable ( b ) after 50,000 cycles x - rays of cadaveric femoral specimen ( a ) with unstable reverse oblique trochanteric fracture with posteromedial defect implanted with 95 dynamic hip screw and it was subjected to cyclical compression load .
( b ) it failed after 4482 cycles . plate bending of 15 , plate barrel junction deformation of 2.5 , and screw bending of 1.5 were observed at the end of cyclical loading x - rays of cadaveric femoral specimen ( a ) with unstable reverse oblique trochanteric fracture with posteromedial defect implanted with 95 dynamic hip screw and it was subjected to cyclical compression load .
( b ) it failed after 1962cycles . plate bending of 10 , and screw bending of 1 were observed at the end of cyclical loading it was also observed that bends of 2 or less could be detected only by radiography .
historically , unstable reverse oblique trochanteric fractures have spurred the development of various implants ranging from extramedullary to intramedullary devices.481027 the sliding hip screw is the most widely used extramedullary implant for stabilization of both stable and unstable intertrochanteric fractures . however
, a number of investigators have reported unsatisfactory results with the use of a sliding hip screw for fixation of these unstable fractures.32830 the overall failure rate associated with the sliding hip screw was higher when the device was used for a3 fractures as compared to that for standard ( a1 and a2 ) fractures .
it was recommended that a 95 fixed angle implant was a better alternative for the treatment of reverse oblique trochanteric fractures.356 on the basis of biomechanical analysis , fixed angle devices were preferred for the treatment of reverse oblique fractures against sliding hip screw.56 intramedullary devices offer several theoretical advantages like more efficient loading because of their location and less tensile strain on the implant due to shorter lever arm of the intramedullary device and the consequent decrease in the risk of implant failure .
it also incorporates a sliding hip screw which provides the advantage of controlled fracture impaction in addition to limited surgical exposure and leads to preservation of fracture hematoma and less periosteal stripping.7 it is postulated that this superiority of pfn may be directly attributed to its biomechanical advantage due to its less bm .
we prospectively sought to determine whether there is any difference in the biomechanical performance of dcs and pfn in cadaveric proximal femoral specimens for a specific subset of unstable intertrochanteric fractures , namely , ao / ota 31-a3 fractures
. the possible limitations of the study were its small sample size and in vitro study design .
the constructs were cyclically loaded with compressive forces at a single point uniaxially in contrast to the multipoint and multiaxial nature of joint reaction forces in vivo .
a single screw was used in the nail proximally in contrast to the standard pfn where two screws are used .
detailed examination of the dcs constructs in our study revealed 18 failures of three types : plate bending in 7 , screw bending in 6 , and plate barrel angle change in 5 specimens . on the other hand
, there were four failures of two types seen in the pfn group , i.e. bending of screws in three and breakage of screw in one specimen .
it may be pertinent to mention that shaft diameters of lag screws were identical in both the dcs and pfn groups ( 8 mm ) .
failure of the screw was the only mode of failure noted in the pfn constructs , whereas in the dcs group , additional modes of failure were also observed like proximal bending of the plate and deformation of plate - barrel junction .
obviously the bm in the dcs constructs was more than that of the pfn specimens .
it may be relevant to mention that the plastic deformation would be inversely proportional to the diameter of the screw shaft , provided the properties of the material are constant .
thus , an increase in the bm explains the higher rate of failure in the dcs specimens .
one could validate this hypothesis by correlating the bm , which was approximately 50% higher in the dcs group , as the diameter of the screw shaft was constant in both the groups .
it may be noted that only one dcs specimen in contrast to four pfn specimens actually remained stable at the end point of cyclical loading .
cut through of any screw from bone can be attributed to the design of screw and the quality of the bone .
. however , dexa results in the present study do not strongly correlate with the observed failure .
loading in the mts machine was at a single point and it was uniaxial in contrast to multipoint and multiaxial loading in vivo .
although no frank cut out was observed in the implants mounted in the osteoporotic bones , the radiological evidence of screw migration was observed in four pfn and four dcs specimens , all having dexa less than 1 g / cm .
it may be suggested that on continuous cyclic loading , this radiological migration would ultimately proceed to frank cut out in vitro
. clinical extrapolation of the scenario leads to believe that continuous screw migration superolaterally in the head leads to varus collapse of the fracture , decreasing the gap present posteriomedially in the unstable reverse oblique trochanteric fractures .
it would lead to union of the fracture in some cases , while in other cases , it would lead to implant cut through requiring consequent revision . hence , loss of position i.e. varus drift of fracture , should be taken as a clear evidence of impending construct failure and early corrective steps should be taken , including conversion of surface devices to intramedullary devices . a complex implant , i.e. made up of an assembly of multiple components , will have higher probability of failure because failure tendency of each component will add up . in the dcs group , multiple component failure to various degrees was seen in different combinations .
for example , the combination of plate bending , plate barrel angle deformation , and screw bending was seen in four specimens ; plate bending and screw bending was seen in two specimens ; and plate barrel angle deformation and screw bending was seen in one specimen .
these complex types of failure were observed in the dcs group and not in the pfn group .
future studies may be directed to comparatively evaluate these implants in vivo on a larger sample size .
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### Summary:
: background : reverse oblique trochanteric fracture of femur is a distinct fracture pattern .
95 dynamic condylar screw ( dcs ) and proximal femoral nail ( pfn ) are currently the most commonly used implants for its fixation .
this study aims to biomechanically compare the cutout resistance as well as modes of failure of dcs and pfn in reverse oblique trochanteric fractures.materials and methods : sixteen freshly harvested cadaveric proximal femoral specimens were randomly assigned to three mean bone mineral density matched groups , eight of which were implanted with 95 dcs and the other eight with pfn .
the constructs were made unstable to resemble a reverse oblique trochanteric fracture by removing a standard size posteromedial wedge .
these constructs were subjected to computer controlled cyclic compressive loading with 200 kg at a frequency of 1 cycle / second ( 1 hz ) and end points of both the groups were analyzed.results:the bending moment of the pfn group was approximately 50% less than that of the dcs group ( p<0.0001 ) .
the pfn group resisted more number of cycles than the dcs group ( p=0.03 ) and showed lesser number of component failures as compared with the dcs group ( p=0.003).conclusions : the pfn is biomechanically superior to dcs for the fixation of reverse oblique trochanteric fractures of femur .
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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:
: cellular fate is predominantly determined by the processes of division , differentiation , and death .
a cell is considered dead when the plasma membrane has lost its integrity or when it is fragmented into so - called apoptotic bodies ( kroemer et al . , 2005 ) , but a plethora of definitions based on morphological parameters tries to capture the manifold types of mammalian cell death and the routes toward it .
originally , apoptosis was described as the type of cell death characterized by rounding and shrinking of the cell , chromatin condensation ( pyknosis ) , nuclear fragmentation ( karyorrhexis ) , and budding of discrete plasma membrane lined portions of cytoplasm ( blebbing ; kerr et al . , 1972 ) .
during apoptosis in mammalian tissues , the plasma membrane remains intact until late stages , thereby preventing an unwanted inflammatory response ( krysko et al . , 2006 ) .
autophagic vacuoles have two membranes and contain degenerating organelles and cytosolic content ( gozuacik and kimchi , 2007 ) .
the third main type of cell death , necrosis , is characterized by cell swelling ( oncosis ) , organelle dilation , and subsequent rupture of the plasma membrane ( festjens et al . , 2006 ) .
the acquisition of apoptotic morphology is , in most cases , associated with and depends on the activation of cys - dependent asp - specific peptidases ( caspases ; alnemri et al . ,
1996 ; leist and jttel , 2001 ) . caspases ( clan cd , family c14 ) cleave their substrates after asp , are synthesized as inactive zymogens , and can be divided into two types based on their overall structure and activation modes .
effectors or executioner caspases are activated by proteolytic separation of the large ( p20 ) and small ( p10 ) subunits , resulting in active ( p20)2(p10)2 heterotetramers .
initiator caspases have an n - terminal extension , the prodomain , that is needed to recruit them into protein complexes that function as activation platforms , called apoptosomes ( riedl and salvesen , 2007 ) .
their activation does not require proteolytic cleavage but relies on conformational changes after oligomerization ( fuentes - prior and salvesen , 2004 ) .
once triggered , initiator caspases can ignite a cascade by the proteolytic activation of effector caspase zymogens .
the effector caspases ultimately cleave numerous substrates , thereby causing the typical morphological features of apoptosis ( kumar , 2007 ; timmer and salvesen , 2007 ) .
members of the cd clan of proteases are characterized by their specificity for the residue at the n - terminal side of the scissile bond , the p1 residue , in their substrates . for caspases ,
based on the optimal substrate oligopeptide sequence , caspase activity can be specifically measured by synthetic peptides c - terminally coupled to a fluorogenic moiety , such as 7-amido-4-methylcoumarin ( amc ) . upon cleavage by caspases ,
, caspases are also involved in nonapoptotic events , including inflammation , cell proliferation , and cell differentiation .
therefore , the reciprocal conclusion that caspase activities are strictly correlated with apoptosis is invalid ( lamkanfi et al . , 2007 ) .
as in animals , cell death is an essential part of the life cycle of plants . from seed germination until seed production , developmental cell death is manifested .
a few well known examples are cell death during terminal differentiation of the vascular tracheary elements , leaf and flower senescence , elimination of reproductive organs in unisexual flowers , pollen rejection in the self - incompatibility response , fruit dehiscence , or pod shattering ( van doorn and woltering , 2005 ) . in addition , plants attempt to block the invasion of biotrophic pathogens via the hypersensitive response , leading to localized cell death at the site of infection ( jones and dangl , 2006 ) .
typical animal apoptotic features such as pyknosis , karyorrhexis , internucleosomal dna cleavage , cell shrinkage , and the formation of apoptotic bodies have been observed in dying plant cells ( van doorn and woltering , 2005 ) .
importantly , during cell death , caspaselike activities are easily detected by synthetic fluorogenic oligopeptide substrates , and cell death can often be attenuated by synthetic caspase - specific inhibitors ( woltering , 2004 ) . with the sequencing of the complete genome of the model plant arabidopsis thaliana ( arabidopsis genome initiative , 2000 ) ,
these caspaselike activities have steered an intensive but frustrating search for caspase genes within plants .
at the end of 2000 , distant caspase relatives were discovered in silico in plants , fungi , and protozoa and were designated metacaspases ( uren et al . , 2000 ) .
the sequences of previously found caspaselike proteins ( paracaspases ) in metazoans and in the slime mold dictyostelium discoideum had been used in an iterative psi - blast search of plant - expressed sequence tags ( aravind et al . , 1999 ) .
paracaspases contain a prodomain consisting of a death domain and one or two ig domains , whereas two types of metacaspases can be distinguished ( fig .
1 a ) . type i metacaspases have an n - terminal extension reminiscent of the prodomain in initiator and inflammatory caspases .
type ii metacaspases lack such a prodomain but harbor a linker region between the putative large and small subunits ( uren et al . , 2000 ;
contain a conserved catalytic his / cys dyad , and structure predictions show that they bear the core of the caspase / hemoglobinase fold ( fig .
1 b ) , which is the determining structural feature of all clan cd cys proteases ( rawlings and barrett , 1993 ; aravind and koonin , 2002 ) .
( a ) schematic representation of the domains of caspases ( c ) , metacaspases ( mc ) , and paracaspases ( pc ) . the catalytic domains consist of a large p20 ( red ) and small p10 subunit ( green )
the n - terminal domain of paracaspases contains a death domain ( black ) and one or two ig domains ( blue ) .
the c - terminal region of paracaspases , which is involved in ubiquitination , is shown in pink .
( b ) topological diagram of the structure of human caspase 8 and metacaspase 9 of arabidopsis thaliana .
catalytic his and cys residues are labeled in red , ( putative ) s1 pocket forming residues are in blue , and maturation sites are in green .
figure layout is adapted from the diagram for human caspase 8 in fuentes - prior and salvesen ( 2004 ) .
the secondary structure of atmc9 was predicted using the protein structure prediction server ( mcguffin et al . , 2000 ) .
in eukaryota , paracaspases and caspases are restricted to animal genomes ( kingdom animalia ) , and metacaspases are present in the kingdoms protozoa , fungi , plantae , and chromista , whereas in prokaryota , meta-/paracaspase - like proteins are found in both archaea and eubacteria ( fig .
2 ) . previous phylogenetic analysis of eukaryotic caspases , metacaspases , and paracaspases has suggested that these groups are about equally distant from each other .
these findings have led to the hypothesis that eukaryotic metacaspases originate from a horizontal gene transfer ( hgt ) between the mitochondrial endosymbionts , -proteobacteria , and the early eukaryotes ( koonin and aravind , 2002 ) .
furthermore , meta-/paracaspase - like proteins can be found not only in -proteobacteria but also in all groups of bacteria , including cyanobacteria , the ancestors of chloroplasts in plants .
also , it is striking that only type i metacaspases can be found in protozoa , fungi , and chromista , whereas both type i and ii are present in plantae , including green plants , glaucophyta , and rhodophyta .
therefore , an alternative hypothesis would be that caspases , paracaspases , and type i metacaspases have a common ancestor originating from hgt between mitochondrial endosymbionts and host eukaryotic cells .
type ii metacaspases might possibly be derived from a second hgt event during the establishment of plastids from endosymbiotic cyanobacteria .
phylogenic distribution of caspases , metacaspases , paracaspases , and bacterial para-/metacaspase - like proteins .
c , caspase ; mc , metacaspase ; pc , paracaspase ; protopc / mc , bacterial para-/metacaspase - like proteins .
classification of cellular life into one prokaryotic ( bacteria , including archaebacteria ) and five eukaryotic kingdoms ( fungi , protozoa , chromista , animalia , and plantae ) as described in cavalier - smith ( 2004 ) .
the alleged paracaspase of d. discoideum is a surprising element in this phylogenetic distribution because slime molds belong to the protozoa kingdom .
phylogenetic analysis of the sequence of its putative catalytic p20 subunit reveals that it is almost equally related to that of caspases , metacaspases , paracaspases , and their bacterial homologues , making its classification as a separate paracaspase not well founded ( our unpublished data ) .
also , its prodomain lacks a death domain and ig domains , which is typical of animal paracaspases .
therefore , it is tempting to classify the d. discoideum protease as a metacaspase rather than a paracaspase .
in the arabidopsis genome , nine metacaspase genes are present : three of type i ( arabidopsis thaliana metacaspase 1 [ atmc1 ] to atmc3 ) and six of type ii ( atmc4 to atmc9 ; vercammen et al . , 2004 ) .
upon overproduction in escherichia coli , type ii metacaspases autoprocess and display a cys - dependent proteolytic activity against synthetic p1-arg substrates , whereas atmc9 also cleaves p1-lys substrates , albeit with low efficiency ( vercammen et al . , 2004 , 2006 ;
type i metacaspases from arabidopsis do not autoprocess upon recombinant overproduction and , like mammalian initiator caspases , possibly require induced oligomerization within an activation platform ( fuentes - prior and salvesen , 2004 ) .
a positional scanning synthetic combinatorial library screening with purified recombinant atmc9 confirmed the preference for p1-arg .
the optimized tetrapeptide substrate ac - val - arg - pro - arg - amc had a kcat / km of 4.6 10 m s and , thus , can be considered a very efficient substrate for atmc9 ( vercammen et al . , 2006 ) .
the p1 preference of clan cd proteases is dictated by conserved amino acids distributed throughout the mature protease that together form the s1 pocket ( fuentes - prior and salvesen , 2004 ) . in caspases ,
arg , gln , and arg ( according to caspase-1 residue numbering ) form a basic s1 pocket for optimal binding of the acidic p1-asp within their substrates ( fuentes - prior and salvesen , 2004 ) .
when the available sequences of eukaryotic metacaspases , paracaspases , and bacterial meta-/paracaspase homologues are aligned to those of animal caspases , gln is replaced by an asp , and arg is replaced by asp or glu in both para- and metacaspases .
six residues more c terminal , a highly conserved asp is present that aligns with asp of bacterial gingipain r , which is known to coordinate binding of the p1-arg of substrates of this peptidase ( eichinger et al . , 1999 ) .
together , these residues are ideally positioned to create a highly acidic s1 pocket that is perfectly suited to accept the basic p1 residues arg and lys ( fig .
1 b ) . as the predicted s1 pocket forming residues are strictly conserved in all known sequences of para- and metacaspases , the arg / lys specificity is very probably shared by all of them .
the determined p1 specificity of metacaspases of other plants and of yeast and protozoa confirmed this hypothesis ( bozhkov et al . , 2005 ; watanabe and lam , 2005 ; gonzlez et al . , 2007 ) .
the fact that no close bacterial caspase homologues have been identified yet would reflect an animal - specific evolutionary process of gene duplications and progression of the caspases from arg / lys toward asp specificity .
until now , attempts to detect the protease activity of paracaspases have been unsuccessful ( snipas et al . ,
2004 ) , but paracaspases may have retained their preference for basic p1 residues in their substrates .
a biochemical particularity of atmc9 is the presence of a second catalytic cys , cys .
mutation analysis revealed that the primary cys is necessary for autocatalytic processing and concomitant activation of atmc9 .
however , once activated either autocatalytically or by exogenous atmc9 , proteolytic activity almost completely depends on cys because replacement of this residue by ala reduces protease activity by 99% . furthermore , cys but not cys can be inactivated by s - nitrosylation .
thus , in the presence of nitric oxide , atmc9 remains inactive until s - nitrosylation is reversed or until upstream proteases convert pro - atmc9 into its mature form ( belenghi et al .
the identification of metacaspase genes prompted the assessment of their potential involvement in cell death events in fungi , protozoa , and plants .
overproduction of the single metacaspase yca1 resulted in autocatalytic processing and rendered cells more sensitive to exogenous or aging - related oxidative stress , as determined by reduced clonogenicity ( madeo et al . ,
2002 ) . however , it may not be surprising that overproduction of an active protease , causing endogenous stress , resulted in a higher sensitivity to exogenous stress .
a yeast strain with a disrupted yca1 gene ( yca1 ) was also shown to be threefold less sensitive to h2o2 , and 5% of the cells escaped from aging - related cell death ( madeo et al . , 2002 ) .
whether this observation reflects a direct involvement of yca1 in cell death or this desensitization is caused by indirect effects , such as an altered protein turnover disturbing the balance of pro and anti cell death mediators , remains unclear .
indeed , after treatment of yca1 cells with h2o2 , levels of oxidized proteins were much higher than those of wild - type cells ( khan et al . ,
concomitantly , the proteasome activity of yca1 cells increased and apoptosis decreased upon h2o2 treatment , as measured by phosphatidylserine ( ps ) externalization and dna fragmentation .
the reduced capability of yca1 cells compared with wild - type cells to cope with damaged proteins might explain the considerable decrease in cell viability after extended culture ( i.e. , > 30 d ; herker et al . , 2004 ) .
whereas ps exposure and dna fragmentation are genuine apoptotic markers , clonogenicity assays might also reflect other cellular states such as cell cycle arrest or metabolic deficiencies .
therefore , the clonogenicity results themselves do not exclude functions of metacaspases other than cell death involvement . in animal cells , ps exposure by dying cells functions as an eat - me signal for phagocytotic cells .
however , the physiological function of ps exposure by yeast and plant cells remains intriguing because they possess a rigid cell wall and , thus , are incapable of phagocytosis . extracts of h2o2-treated yca1-overproducing yeast were highly active toward the synthetic caspase substrates val - glu - ile - asp - amc and ile - glu - thr - asp - amc , suggesting that the yca1 metacaspase behaved as a bona fide caspase ( madeo et al . ,
these results were later contradicted : lysates from bacteria and h2o2-stimulated yeast overproducing yca1 were not active against synthetic caspase substrates but cleaved p1-arg and , to a lesser extent , p1-lys substrates similarly to plant metacaspases ( watanabe and lam , 2005 ) .
thus , yca1 involvement can not be determined by using synthetic caspase substrates or inhibitors .
because yca1-independent cell death ( bttner et al . , 2007 ; for review see vchov and palkov , 2007 ) and yca1-independent caspaselike activities ( vchov and palkov , 2005 ; hauptmann et al . , 2006 ) have been reported , the involvement of metacaspase activity in yeast cell death remains debatable ( for review see vchov and palkov , 2007 ) .
the identification of endogenous yca1 substrates will be crucial in unraveling the signaling pathways regulated by this metacaspase .
the genome of the pathogenic filamentous fungus aspergillus fumigatus contains two type i metacaspases , casa and casb . with double knockout mutants ,
in addition , stress - induced cell death did not depend on metacaspases despite the abrogation of apoptosis - related membrane ps exposure in casa and casb double knockout stationary - phase cultures .
interestingly , both casa and casb were required for growth in the presence of agents inducing endoplasmic reticulum stress , suggesting a prosurvival role for metacaspases rather than an involvement in cell death processes ( richie et al . , 2007 ) .
of the five type i metacaspases of trypanosoma brucei , only tbmca4 caused retardation in growth , loss of respiratory competence , and subsequent decrease in clonogenicity when overproduced in baker 's yeast ( szallies et al .
surprisingly , tbmca4 , like tbmca1 , lacks a catalytic cys at the canonical location , although an adjacent cys is present .
nevertheless , using different synthetic tetrapeptides with asn , asp , arg , or lys at the p1 position , no proteolytic activity in lysates of e. coli or yeast overproducing tbmca4 could be demonstrated .
triple - null trypanosomes for tbmca2 , tbmca3 , and tbmca5 had no altered cell death or enhanced susceptibility to stresses , but the rapid down - regulation of all three genes with induced rnai resulted in an in vitro growth arrest ( helms et al . ,
2006 ) . in trypanosoma cruzi , two metacaspase genes , tcmca3 and tcmca5 , have been reported . in untreated epimastigotes ,
the encoded proteins were distributed in the whole cell , but , after exposure to fresh human serum , which induces rapid apoptosis - like cell death , relocalization to the nucleus was observed . upon overproduction of tcmca5 ,
overproduction in yeast of the single type i metacaspase from leishmania major , lmjmca , slightly enhanced sensitivity toward h2o2 , as measured by ps exposure .
interestingly , extracts of lmjmca - overproducing yeast cells were proteolytically active toward p1-arg synthetic substrates , demonstrating the probably universal preference for basic p1 residues of metacaspases ( gonzlez et al . , 2007 ) .
plasmodium berghei has three type i metacaspases , of which pbmc2 and pbmc3 lack one or both of the catalytic site residues , but knockout mutants of the pbmc1 gene did not display any obvious phenotype ( le chat et al . , 2007 ) .
as discussed in the section phylogeny of the caspases , metacaspases , and paracaspases , we propose to classify the slime mold paracaspase as a metacaspase . upon starvation ,
d. discoideum differentiates into multicellular fruiting bodies consisting of a spore mass supported by a stalk . during this process ,
stalk cells die in a caspase - independent autophagic cell death ( cornillon et al . , 1994 ; olie et al . ,
both differentiation and cell death were demonstrated to be independent of meta-/paracaspase action ( roisin - bouffay et al . , 2004 ) .
in norway spruce ( picea abies ) , metacaspases were studied in the context of developmental cell death during in vitro somatic embryogenesis . in this process ,
dying embryo suspensor cells contained elevated activity against the synthetic fluorogenic caspase-6 substrate val - glu - ile - asp - amc .
accordingly , treatment with the synthetic inhibitor val - glu - ile - asp - fmk prevented differentiation of the suspensor and subsequent suspensor cell death ( bozhkov et al . , 2004 ) .
disruption of the type ii metacaspase gene mcii - pa abrogated the terminal differentiation and death of the suspensor cells and drastically reduced caspaselike activity , suggesting that mcii - pa had caspase activity and was involved in cell death ( suarez et al . ,
later in vitro experiments have shown that mcii - pa had arg but not asp specificity ( bozhkov et al . , 2005 ) . because knocking down mcii - pa not only disrupted cell death but also blocked embryonic differentiation , we speculate that mcii - pa might be primarily involved in suspensor differentiation rather than in suspensor cell death .
possibly , mcii - pa regulates the actin reorganization observed during suspensor differentiation ( smertenko et al . , 2003 ) , like mammalian caspases do in the cytoskeletal rearrangements during apoptosis ( mashima et al .
, 1999 ) . in arabidopsis , mere constitutive overexpression or disruption of metacaspase genes does not lead to an obvious phenotype ( vercammen et al . , 2006 ; belenghi et al . , 2007 ;
our unpublished data ) , and , thus , a role for metacaspases in cell death or other processes has not been identified yet .
redundancy may exist between the various members of this family , or additional factors may be necessary to activate ectopically expressed metacaspases .
a large amount of microarray data is available ( http://www.arabidopsis.org/info/expression/atgenexpress.jsp ) describing the expression of > 20,000 arabidopsis genes ( zimmermann et al . , 2004 ) .
analysis of these data for the nine metacaspase genes could at least give a hint to their functional roles .
several metacaspase genes are strongly induced in senescing flowers , in response to various pathogens and elicitors , and during various abiotic stresses ( sanmartn et al . , 2005 ; our unpublished data ) . as a prominent role for cell death
has been demonstrated in responses to biotic and abiotic stresses , it might be tempting to deduce from these expression profiles that metacaspases play a role in cell death signaling .
alternatively , plants might first try to cope with stresses by rapid adaptation before sacrifice . in vivo reporter systems
for example , the activity of atmc9 is regulated by autoprocessing , ph , a protease inhibitor ( atserpin1 ) , and s - nitrosylation ( vercammen et al . , 2004 , 2006 ;
likewise , atmc4 and atmc5 activity depends on calcium ( vercammen et al . , 2004 ;
therefore , specific in vivo activity assays would strongly contribute to our understanding of the role of individual metacaspases in plant development and stress response .
to date , metacaspases of plants , fungi , and protozoa have been shown to have arg / lys - specific activity ( vercammen et al . , 2004 , 2006 ;
, 2005 ; watanabe and lam , 2005 ; gonzlez et al . , 2007 ) .
based on the available sequences , we speculate that all metacaspases and possibly also paracaspases share this specificity . as a consequence , the caspaselike activities reported to be involved in plant and fungal cell death most probably differ from the metacaspases . other plant proteases exhibiting
caspaselike activity and suggested to be involved in cell death include the legumains ( also called vacuolar processing enzymes ) and some subtilisins ( coffeen and wolpert , 2004 ; hara - nishimura et al . , 2005 ; hatsugai et al . ,
until now , the role of metacaspases in cell death still remained enigmatic , and both up- and down - regulation of metacaspases have yielded conflicting data . however , such approaches bear the risk that a constitutive perturbation of genes that are essential for normal cellular homeostasis leads to overinterpretation .
alternative routes toward unraveling the function of metacaspases could involve the identification of their substrates by using technologies that allow direct characterization of in vivo protein processing on a proteome - wide scale ( gevaert et al . , 2006 ) . knowing the degradome specificity of metacaspases could reveal their role in cellular and developmental processes , including cell death .
overproduction of the cleavage fragments and/or of uncleavable mutant proteins would help elucidate the functional consequences of substrate cleavage by metacaspases .
we conclude that although metacaspases , paracaspases , and caspases contain a caspase fold and probably originated from a common ancestor gene , metacaspases and paracaspases are clearly distinct from caspases for the following reasons .
first , the fact that these different proteases contain a caspase fold might not be a valid argument to group them together in the caspase family ( clan cd , family c14 ; http://merops.sanger.ac.uk/ ) .
legumains ( clan cd , family c13 ) and gingipains ( clan cd , family c25 ) constitute separate families that also contain a caspase fold ( chen et al . , 1998 ; eichinger et al . , 1999 ) .
second , the p1 preference of metacaspases is basic , whereas that of caspases is acidic .
if metacaspases and caspases shared similar functions , we assume that both the proteases and their specific degradome would have coevolved . in view of the crucial functions of many of their substrates ,
third , previous phylogenetic analyses of clan cd peptidases have shown that caspases constitute a separate group distinct from other clan cd peptidases , including metacaspases and paracaspases ( koonin and aravind , 2002 ) .
therefore , we believe that it might be expedient to regroup metacaspases and paracaspases into a separate family in the cd clan of cys peptidases .
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### Summary:
: the identification of caspases as major regulators of apoptotic cell death in animals initiated a quest for homologous peptidases in other kingdoms . with the discovery of metacaspases in plants , fungi , and protozoa
, this search had apparently reached its goal . however , there is compelling evidence that metacaspases lack caspase activity and that they are not responsible for the caspaselike activities detected during plant and fungal cell death . in this paper
, we attempt to broaden the discussion of these peptidases to biological functions beyond apoptosis and cell death .
we further suggest that metacaspases and paracaspases , although sharing structural and mechanistic features with the metazoan caspases , form a distinct family of clan cd cysteine peptidases .
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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:
: intraradicular posts are recommended in the rehabilitation of endodontically treated teeth where the clinical crown has been partially or totally destroyed and requires prosthetic treatment .
their use promote the union and retention between the prosthetic crown and the remaining radicular structure16,18 and also prevent the passage of microorganisms and organic liquids to the interior of the root canals19,28 .
retention and stability of intraradicular posts in relation to the roots that house them are fundamentally dependent on their anatomic characteristics , post space preparation and the physicochemical properties of the luting agents6 .
cementation is defined as the use of a modelable substance to seal or cement two parts , keeping them together , promoting retention and sealing of the space between them , minimizing microleakage4 .
the capacity of different cements to retain posts is related to their mechanical properties , their capacity of interlocking to metal and dentin , and their durability3 .
zinc phosphate cement has been widely used in the cementation of intraradicular posts ; however , it does not form a chemical union ( adhesion ) with the dentin and the metal4 .
the resistance of posts cemented with zinc phosphate to removal by traction is related to their mechanical retention to irregularities of the dentin or the metal18 . according to some authors9,2 , zinc phosphate cement is friable , which may lead to failures such as post loosening and subsequent root fracture , when subjected to horizontal forces . with the development of adhesive materials , such as glass ionomer and resin cements , a new perspective has arisen in relation to the increase of post retention , due to the adhesion potential of these materials both to the metal alloy and to the dentin18 .
resin cements , unfilled resins and adhesive systems have been recommended for the cementation of metal parts due to their good performance in tests evaluating adhesion , resistance to removal by traction and decrease of coronal leakage4,5,22 .
furthermore , saupe , et al.21 ( 1996 ) have reported that resin cements are able to reinforce the weakened root structure , making it more resistant to fracture .
it has been demonstrated that , among other factors , the force required for post removal depends on the type of cement used for post fixation9,17,18 .
posts cemented with resin agents require greater force for removal when compared to those cemented with zinc phosphate . according to gomes , et al.12 ( 2006 )
, the adhesion of resin compounds to the root canal and post retention can be affected by the type of endodontic sealer and certain irrigation solutions used in the biomechanical preparation .
many studies have evaluated the effect of endodontic sealers and their compounds in the retention of intraradicular posts , and the results have shown a decrease in the retention of posts cemented fixed with resin cements , in canals obturated with cements containing eugenol2,8,11,12,13,14,25,27 .
some authors have reported that eugenol interferes in the polymerization of resin compounds , altering different physical and mechanical properties1,10,12,27 . according to hagge , et al.14 ( 2002 ) , a longer interval between canal obturation with a zinc oxide and eugenol- based cement and post cementation had a negative effect on retention , probably because of the penetration of eugenol into the dental tubules due to the longer contact time of the endodontic sealer with the root canal walls .
thus , it is possible that the period between root canal obturation with zinc oxide and eugenol - based cement and post space preparation may cause adverse effects in the resin cements used for post cementation , inhibiting its retention27 . considering that zinc oxide and eugenol - based sealers are the most widely used by endodontists worldwide , the purpose of this study was to evaluate in vitro the influence of a zinc oxide and eugenol - based endodontic sealer on the retention of intraradicular posts fixed with resin and zinc phosphate cements after different periods of root canal obturation , using the pull - out test .
the null hypothesis was that there is no difference in the retention of posts cemented with different cements in endodontically treated teeth .
sixty non - restored caries - free human maxillary canines with roots of similar shape were selected .
the clinical crowns were sectioned transversally close to the cementoenamel junction leaving a root length of 14 mm .
the roots were placed in aluminum molds ( 16 x 16 x 32 mm ) and embedded in acrylic resin ( jet ; clssico , so paulo , sp , brazil ) to maintain 2 mm of root length extending beyond the top of the acrylic resin .
the specimens were randomly distributed into 3 groups ( n=20 ) , according to the period between obturation and post cementation : gi - immediately , gii - 72 h and giii - 4 months .
each group was divided into two subgroups ( n=10 ) , according to the luting agent used for fixation of the intraradicular posts : a - zinc phosphate cement ( ss white , rio de janeiro , rj , brazil ) and b - panavia f dual - cured resin cement ( kuraray co ltd , osaka , japan ) .
the cervical and middle thirds were prepared using largo drills ( dentsply / maillefer , ballaigues , switzerland ) sizes 1 ( 0.70 diameter mm ) , 2 ( 0.90 mm ) and 3 ( 1.10 mm).the root canals were explored with a size 25 k - file ( dentsply / maillefer ) to select specimens with a working length of 13 mm ( 1 mm short of the apical foramen ) and anatomic diameter of 250 m .
instrumentation was performed at the working length with hand files up to a size 45 master apical file .
the canals were irrigated with 2 ml of 1% sodium hypochlorite during instrumentation followed by a final irrigation with 10 ml of distilled water .
after aspiration of liquid content , the canals were dried with absorbent paper points ( dentsply / herpo , petrpolis , rj , brazil ) and obturated with gutta - percha cones ( dentsply / herpol ) and an eugenol - based endodontic sealer ( endofill ; dentsply indstria e comrcio ltda . ,
vertical condensation was done with the same instruments and the pulp chamber was sealed with a noneugenol , self - setting , single - component temporary coronal filling material ( coltosol ; coltene - whaledent , cuyahoga falls , oh , usa ) .
specimens were stored in distilled water at 37 2c for 72 h , except for gi 's specimens . in gi ,
the preparation of the canals was done immediately after obturation , while in gii and giii the canals were prepared after 72 h and 4 months , respectively .
post spaces were prepared to a length of 8 mm with a size 4 largo drill ( figure 1 ) mounted at a low - speed handpiece ( dabi atlante ; ribeiro preto , sp , brazil ) coupled to a surveyor ( bioart , so carlos , sp , brazil ) . in all groups , cylindrical stainless steel prefabricated posts measuring 1.5 mm in diameter and 11 mm in length ( reforpost ii # 4 ; ngelus , londrina , pr , brazil ) were used . in the specimens of gia , giia and giiia ,
the posts were cemented with the zinc phosphate cement prepared with at a ratio of 2.0 g of powder and 0.5 ml of liquid .
the posts were coated with cement , inserted into the post space and constant finger pressure was applied for 60 s. after 10 min , cement excess was removed with an explorer . in the specimens of gib , giib and giiib ,
the posts were cemented with panavia f. first , the primer ( alloy primer ; kuraray co ltd . ) was applied to the post .
then , each canal surface was acid etched ( ivoclar / vivadent ; so paulo , sp , brazil ) for 30 s , rinsed and dried with paper points ( dentsply / herpo ) .
two coats of the adhesive system ( kuraray co ltd . ) were applied , air dried for 20 s and photoactivated for 30 s with a halogen light source ( ultralux electronic ; dabi atlante , ribeiro preto , sp , brazil ) with a wavelength of 350 to 500 nm and a light intensity of 350 to 500 mv / cm .
the light guide tip was positioned perpendicular to the root long axis at a distance of 2.0 mm from the specimen surface .
the cement ( panavia f ; kuraray co ltd ) was applied according to the manufacturer 's instructions . a lentulo spiral instrument ( lentulo ; dentsply / maillefer )
was used for the application of the cement inside the prepared canals , and , to avoid any difficulty resulting from premature polymerization of the resin cement in the canal , the post was inserted immediately after cement placement .
any excess cement was removed , and the core was maintained under constant finger pressure for 60 s. the halogen light ( ultralux eletronic ; dabi atlante ) was activated for 60 s , in the same way as described for photoactivation of the adhesive layer . a waiting period of 6 min was used to allow complete polymerization of the cement . an oxygen barrier ( oxyguard ii gel
; kuraray co ltd ) was applied to the superficial margins for 10 min and then removed with cotton rolls and water spray .
after storage at 37 2c for 72 , the specimens were subjected to the pull - out test .
each specimen was fixed to a custom device to be a held in a vertical position to minimize the incidence of non - axial forces , so that traction forces could be applied parallel to their long axis .
the core of the post was grasped by the mandrill apparatus in a universal testing machine ( instron 4444 ; instron corporation , canton , ma , usa ) and the force was applied on the post at a crosshead speed of 0.5 mm / min until the post was dislodged from the root ( figure 2 ) . since normal distribution of data was observed , the tensile force values ( kn ) required for post dislodgment were analyzed statistically by 2-way anova and tukey - kramer test with = 0.001 .
the tensile force values ( kn ) required for post dislodgment after different periods between root canal obturation and post space preparation / post cementation with the two cements are presented in table 1 .
groups with same superscript letter were not significantly different ( tukey 's test ; p>0.05 ) . regarding the luting agent
, there was no statistically significant difference between the posts fixed with zinc phosphate cement and those fixed with panavia f ( p>0.05 ) .
for the interaction cement x cementation period , there was statistically significant difference ( p<0.001 ) between the posts fixed with zinc phosphate cement immediately , 72 h and 4 months after obturation compared to the posts fixed with panavia f after the same periods .
the loss of retention of an intraradicular post is a frequent failure in dental rehabilitation and is an important factor that influences the success of the treatment .
the major factors affecting post retention are : post dimensions ( length , diameter ) , shape ( conical , cylindrical ) and type of surface ( serrated , threaded and smooth ) ; intracanal space preparation ; and type of cement used for post fixation6,10,19,18,24,27 . in the present study , higher mean
tensile force values were needed for vertical dislodgment of the intraradicular posts fixed with zinc phosphate cement compared to those fixed with panavia f. these results indicate that the eugenol- containing sealer used for root canal obturation ( endofill ) might have altered the polymerization of the resin cement but did not influence the properties of the zinc phosphate cement , which produced higher retention values .
accordingly , dilts , et al.11 ( 1986 ) observed that the zinc phosphate cement was the least altered luting agent by the eugenol present in endodontic sealers .
schwartz , et al.22 ( 1998 ) who found higher retention for prefabricated posts fixed with zinc phosphate cement compared to panavia 21 resin cement , and alfredo , et al.2 ( 2006 ) reported that zinc phosphate cement produced greater retention than enforce resin cement . the greater resistance to traction of the posts fixed with zinc phosphate cement
may be explained by the physical characteristics of this cement . according to anusavice4 ( 2005 )
, the adherence with zinc phosphate cement does not involve any reaction with the surrounding mineralized tissue or other restoration materials .
its adhesion is mainly due to mechanical interlocking at the interfaces rather than to chemical interactions .
addition , it has been demonstrated that zinc phosphate cement application technique can also influence post retention , and thus post surface and root canal walls should be coated by a uniform cement layer26 .
there are divergent opinions from authors who have investigated the possible influence of the eugenol contained in some endodontic sealers on the polymerization of resin cements used for fixation of intraradicular posts . according to some authors11,13,23,25 , eugenol has harmful effects on resin compounds since its phenolic components influence the polymerization and thus adversely affects their adhesive properties .
the phenolic components are free radical collectors and delay the polymerization reaction when interact with resin materials .
carvalho , et al.8 ( 2007 ) observed that temporary sealing cement containing eugenol reduced the bonding strength of adhesive systems . on the other hand ,
hagge , et al.14 ( 2002 ) concluded that the chemical formulation of endodontic sealers did not affect significantly the retention of posts cemented with resin cements .
schwartz , et al.22 ( 1998 ) observed that the type of endodontic sealer used ( with or without eugenol ) did not affect the retention of resin cement used for the fixation of intraradicular posts .
the results obtained in this study in relation to the different preparation and post cementation times ( immediately , 72 h and 4 months after obturation ) did not show a significant difference ( p>0.05 ) between the groups , regardless of the cement used for post fixation .
although mean tensile force values needed for dislodgment of the posts fixed with panavia f were lower than those fixed with zinc phosphate cement , the different time periods between root canal obturation and post cementation in this group did not lead to different results .
the group where post preparation and cementation were done immediately after obturation showed a slightly higher value ( 0.07 kn ) than those in which these procedures occurred after 72 h and 4 months ( 0.04 kn and 0.04 kn , respectively ) .
the fact that the retention of the posts fixed with resin cement did not change with the different time periods , may be explained by the fact that the diffusion of eugenol through dentin occurs rapidly within the first 24 h , decreasing slowly and reaching a concentration of 10
mol / l in the zone immediately adjacent to the material , where it remains constant for more than 1 week12,15 .
the occurrence of this phenomenon has been supported by some studies6,7,25 that stated that irrigating solutions , acid etching and post space preparation may demineralize and remove part of dentin surface , which would be sufficient for eliminating cement excess from the dentinal tubules . according to those authors6,7,25 , these mechanical and chemical processes
may limit the amount of free eugenol , reducing its interference in resin cement polymerization , regardless of the contact time of the cement with the dentin surface .
nevertheless , hagge , et al.13 ( 2002 ) found that the longer the obturation time of the root canal with zinc oxide and eugenol - based cement , the greater the negative influence on the retention of intraradicular posts , probably due to the greater penetration of eugenol in the dental tubules . in this way , some questions related to the behavior of resin compounds when in contact with eugenol - based materials remain unclear , mainly with respect to the time interval between canal obturation and its preparation to receive an intraradicular post .
further research is needed since these materials are widely used and the time elapsed between endodontic and prosthetic procedures varies considerably in clinical practice , possibly leading to implications that may culminate in unsuccessful treatment .
based on the methodology used and the obtained results , it may be concluded that : 1 . regarding the cementing agent , the posts fixed with zinc phosphate cement showed higher retention values than those fixed with resin cement ; 2 . regarding the different periods between obturation and post space preparation / post cementation ( immediately , 72 h and 4 months )
, there was no significant difference between the groups , regardless of the cementing agent used .
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### Summary:
: objective : this study evaluated in vitro the influence of an eugenol - based sealer ( endofill ) on the retention of stainless steel prefabricated posts cemented with zinc phosphate and resin - based ( panavia f ) cements after different periods of root canal obturation , using the pull - out test.material and methods : sixty upper canines were decoronated and the roots were embedded in resin blocks . the specimens were distributed into 3 groups , according to the period elapsed between canal obturation and post cementation : group i - immediately ; group ii - 72 h and group iii - 4 months .
the groups were subdivided according to the type of cement used for post cementation : a - zinc phosphate and b - panavia f. following the experimental periods , specimens were subjected to pull- out test in an instron machine with application of tensile force at a crosshead speed of 0.5 mm / min until post dislodgement .
the maximum forces required for post removal were recorded ( kn ) and means were subjected to statistical analysis by 2-way anova and tukey - kramer test ( =0.001)results : there were statistically significant differences ( p<0.01 ) between the posts cemented with zinc phosphate cement ( 0.2112 kn ) and panavia f ( 0.0501 kn ) .
however , no statistically significant differences ( p>0.05 ) were found between the three post cementation periods , regardless of the cement.conclusions:it was concluded that the eugenol - based sealer influenced the tensile strength of the posts cemented with the resin cement , but had no influence on the time waited between root canal obturation and post space preparation / post cementation .
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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 50-year - old woman presenting with back pain was referred to our center with a 2.5-cm nodule in the right middle lung field on a chest x - ray .
the patient had a past history of surgical excision of an odontogenic tumor at a local dental clinic 17 years previously . a chest computed tomography ( ct ) scan revealed a 2.6-cm lobulated , heterogeneous enhancing nodule and a 1.5-cm satellite nodule in the anterior segment of the right upper lobe ( rul ) ( fig .
1 ) . therefore , we performed ct - guided percutaneous needle biopsy for the tissue diagnosis of the main nodule .
the specimen showed a cohesive tumor island composed of squamoid cells , with central keratin pearl - like material .
bronchoscopy , brain magnetic resonance imaging , and positron emission tomography scanning were performed for further evaluation and staging , based on the impression of primary lung cancer .
then , we performed a planned rul lobectomy and mediastinal lymph node dissection through thoracotomy upon the diagnosis of clinical stage ia ( t1bn0 ) or iib ( t3n0 ) lung cancer .
however , the histopathological diagnosis after the operation was different from that of preoperative biopsy .
these tumor islands showed peripheral palisading and loosely arranged central cells , which resembled stellate reticulum .
we contacted the patient 's former dentist and requested her medical records , but we could not obtain any information related to the odontogenic tumor . finally , the diagnosis of metastasizing ameloblastoma was made based on the patient 's past history and histopathological studies .
although the patient had no associated symptoms , panoramic radiography and facial ct were performed after consulting a dentist to identify local recurrence at the oral cavity .
there was fibrotic scar formation but no evidence of recurrence at previous odontogenic tumor site .
the patient was doing well without any evidence of recurrence or metastasis during regular follow - up .
ameloblastomas are rare odontogenic epithelial tumors and account for 1% of all tumors and cysts of the jaws .
they are classified as benign and characterized by slow growth , local invasiveness , and a high rate of recurrence .
in contrast with its high recurrence rate ( up to 50% to 72% ) , the metastasizing ameloblastoma ( ma ) is uncommon .
the incidence of malignancy / metastasis in relation to ameloblastoma has been reported to be only 2% . to our knowledge , this is the first report of a patient who was diagnosed with metastasizing pulmonary ameloblastoma in south korea .
the odontogenic tumors are classified according to the current world health organization histological classification published in 2005 .
ma is defined as an ameloblastoma that metastasizes despite a benign histological appearance and shows no specific features different from those of ameloblastomas that do not metastasize .
thus , the diagnosis of metastasizing ameloblastoma can only be made in retrospect , after the event of metastasis .
ameloblastic carcinoma is defined as a rare odontogenic malignancy that combines the histological features of ameloblastoma with cytological atypia , even in the absence of metastases .
mas mostly occur in the lungs , although there are some reports of ma arising in the regional lymph nodes , bones , liver , and brain .
van dam et al . reported a summary of clinical findings of mas after reviewing 27 previously published reports and 3 of their cases .
there are 74% of primary tumors with purely plexiform , follicular , or mixed patterns .
the lungs ( 78% ) are the most common site of metastasis , of which 71% are bilateral .
the average interval from the diagnosis of a primary tumor to the diagnosis of metastasis is 18 years , with a range of 3 to 45 years .
because of the rare occurrence of mas , the clinical course and the appropriate treatment are not yet well established . in most of the reported cases ,
close observation , surgical resection , and chemo / radiotherapy can be considered treatment options .
scannell et al . also suggested radiofrequency ablation as a possible treatment option for mas .
however , most authors recommend a complete surgical resection as the treatment of choice , particularly in the cases of operable pulmonary lesions .
chemo / radiotherapy can be reserved to relieve symptoms and to offer palliative care for inoperable lesions . of course
, meticulous follow - up for recurrence after adequate resection of primary tumors should take precedence . in summary
the diagnosis was made on the basis of the patient 's past history of surgical excision for an odontogenic tumor and the histopathological features of ameloblastoma .
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### Summary:
: ameloblastomas are rare odontogenic epithelial tumors that occur mainly in the mandible . despite their benign histologic appearance , they are locally aggressive with a high recurrence rate . however , a metastasizing ameloblastoma has been rarely reported .
according to the current world health organization classification system , the definitive diagnosis of metastasizing ameloblastoma can only be carried out in retrospect , after the event of metastasis .
this case report describes a patient with metastatic pulmonary ameloblastoma , 17 years after the surgical excision of an odontogenic tumor , preoperatively misdiagnosed as primary squamous cell carcinoma .
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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:
: an undescended testis is one of the most common clinical disorders of childhood , occurring in approximately 3% of full - term newborns , 21% of premature newborns , and 0.8 - 1.8% of 1-year - old boys [ 1 - 3 ] . in 80% of these boys ,
a testis is palpable in the groin , and in 90% of these boys , it is associated with hernia . in these cases , conventional open orchiopexy has been accepted as a standard treatment . in 20% of cases of an undescended testis ,
a testis is nonpalpable , however , and in 20 - 50% of nonpalpable testis , the testis is absent .
currently , diagnostic laparoscopy followed by laparoscopic orchiopexy has been accepted as the diagnostic tool of choice to confirm the existence of the nonpalpable testis and to identify the size and location of the testis [ 3 - 5 ] . since 1976 when cortesi and associates first described laparoscopic diagnosis of a nonpalpable testis , this method for diagnosing a nonpalpable testis has been established as the most reliable method . since 1992 when the first laparoscopic orchiopexy was reported by jordan et al , laparoscopic orchiopexy has obtained wide popularity with technologic advances in laparoscopic devices .
the final goals of orchiopexy are to keep the testis viable and to optimally position the testis .
we aimed to evaluate the efficacy and the availability of laparoscopic orchiopexy to manage a nonpalpable intra - abdominal testis by performing a retrospective review of patients ' records concerning testicular viability and orchiopexed positioning .
we reviewed the medical records including postoperative clinical results and complications of 67 patients ( 86 testicular units ) who underwent laparoscopic orchiopexy for a nonpalpable intra - abdominal testis between september 1996 and april 2008 .
the age of the children when undergoing the laparoscopic orchiopexy ranged from 0.5 to 9 years .
the mean age of the patients was 2.42.2 years and the median age was 1 year .
the mean period of clinical follow - up was 21.820 months , ranging from 0.3 to 138.4 months . by analyzing the diagnostic laparoscopy , we could classify 67 patients ( 86 testicular units ) who underwent laparoscopic orchiopexy for a nonpalpable intra - abdominal viable testis according to the laterality of the intra - abdominal testis : 48 patients ( 48 testicular units ) had a unilateral nonpalpable intra - abdominal testis , 32 testicular units ( 37.2% ) demonstrated right - sided , 16 testicular units ( 18.6% ) showed left - sided , and 38 testicular units ( 44.2% ) were bilateral nonpalpable intra - abdominal testes ( table 1 ) .
of 86 testicular units , 69 testicular units ( 80.2% ) were treated by primary laparoscopic orchiopexy ( plo ) .
the diagnostic laparoscopy showed that 58 testicular units were located within 3 cm of the internal inguinal ring , 2 testicular units were more than 3 cm from the internal inguinal ring , and 9 testicular units were peeping testes .
of 86 testicular units , 17 testicular units ( 19.8% ) were treated by fowler - stephens laparoscopic orchiopexy ( fslo ) .
one - stage fslo was performed in 14 testicular units ( 16.3% ) and two - stage fslo in 3 testicular units ( 3.5% ) for which the nonpalpable testis was located more than 3 cm from the internal inguinal ring .
a patient was placed supine in the frog - leg position and in the 30 degrees trendelenburg position .
after general anesthesia was administered , the bladder was emptied with a nlaton catheter and a nasogastric tube was not inserted .
intra - abdominal co2 was injected by a veress needle and intra - abdominal pressure was maintained at 10 - 12 mmhg .
a 5 mm port was inserted for the diagnostic laparoscopy and two additional sets of 5 mm working ports were placed symmetrically on the bilateral lower abdomen . the laparoscopic grasper and scissor were used to make up enough lengths of the spermatic cord for a testis to be fixed in the scrotum , and a transverse incision was made on the scrotum , making a subdartos pouch .
looking into the abdominal cavity through the laparoscopy , we perforated the peritoneum on the lateral side of the umbilical ligament and the medial side of the anterior inferior epigastric vessel .
the intra - abdominal testis was pulled down into the lowest part of scrotum and fixed there .
the clinical results were evaluated within 1 month after the laparoscopic orchiopexy on the basis of the complications that occurred during the operation and the clinical features at the first postoperative clinical follow - up .
all of the 67 patients ( 86 testicular units ) were examined within 1 month .
their clinical results were re - evaluated based on follow - ups that took place at 3 three months after the operation .
of 67 patients ( 86 testicular units ) , 48 patients ( 63 testicular units ) were re - examined , excluding 19 patients who did not make the second visit for the postoperative clinical follow - up .
success of the laparoscopic orchiopexy was defined when the orchiopexed testis was palpable in the lower scrotum without evident volume loss during the physical examination by a single surgeon or when no apparent volume loss was shown in the additional ultrasonography compared with the preoperative volume of the testis .
the patients were classified into two different groups according to the testicular location in the scrotum after the laparoscopic orchiopexy , and the spss computer software program ( version 12.0k for window ) was used to compile statistics on the ages of these two groups .
student 's t test was conducted , and p - values of less than 0.05 were considered statistically significant .
the clinical results within 1 month after the laparoscopic orchiopexy showed that 84 of 86 testicular units survived , giving a testicular survival rate ( tsr ) within 1 month of 97.7% .
of two testicular units that failed to survive , one testicular unit atrophied within one month and the other testicular unit underwent laparoscopic orchiectomy because of an intra - operative complication .
clinical results beyond 3 months after the laparoscopic orchiopexy were available for only 63 out of 86 testicular units , excluding 19 patients ( 23 testicular units ) who did not make the second visit for the postoperative clinical follow - up . of these 63 testicular units
, 59 testicular units survived , resulting in a tsr beyond 3 months of 93.7% . among four testicular units that did not survive , two testicular units were the ones that did not survive 1 one month as stated earlier and one testicular unit receiving one - stage fslo and another receiving two - stage fslo underwent atrophy ( table 2 ) .
physical examination of the location of the viable testis within 1 month after the laparoscopic orchiopexy demonstrated that 83.7% were located in the lower scrotum and 14.0% in the upper scrotum ; however , when the location was examined beyond 3 months , upward migration of the viable testis was found in some cases .
consequently , we confirmed that 76.2% were located in the lower scrotum and 17.5% in the upper scrotum ; therefore , the success rate of the laparoscopic orchiopexy for a nonpalpable intra - abdominal testis was 76.2% ( table 3 ) .
with the patient under general anesthesia , we analyzed 86 testicular units that were not palpable by a single surgeon in the physical examination .
we examined the diagnostic laparoscopy before the laparoscopic orchiopexy and chose cases of viable testes with well - developed internal spermatic vessels and vas deferens to actually undergo the laparoscopic orchiopexy .
first , we excluded testicular units that had received conventional open orchiopexy by an inguinal incision instead of laparoscopic orchiopexy . in some cases ,
such units were initially diagnosed as nonpalpable intra - abdominal testes in the physical examination but were palpable under the general anesthesia .
second , some testes did not undergo the orchiopexy or underwent laparoscopic orchiectomy instead of the laparoscopic orchiopexy because they were diagnosed as nubbin testes or vanishing testes in the diagnostic laparoscopy .
a total of 48 patients ( 48 testicular units ) had a unilateral nonpalpable intra - abdominal testis and 19 patients ( 38 testicular units ) had bilateral nonpalpable intra - abdominal testes . in the physical examination performed under general anesthesia , however , we found that 7 of the cases of bilateral intra - abdominal testes were actually unilateral ones that were palpable in the inguinal area .
therefore , in these 7 cases , laparoscopy was not used and unilateral conventional open orchiopexy via an inguinal incision was performed .
the choice of laparoscopic technique mostly depended on the distance from the internal inguinal ring to the nonpalpable intra - abdominal testis , which could be determined for 67 patients ( 86 testicular units ) .
a total of 63 testicular units were located within 3 cm of the internal inguinal ring , 14 testicular units were more than 3 cm from the internal inguinal ring , and 9 testicular units showed peeping .
samadi et al conducted plo in 70.5% and fslo in 29.5% of a total of 203 testicular units and reported a success rate of 95% , which was higher than the 76% success rate of open surgery .
lindgren et al did a 6-month clinical follow - up after laparoscopic orchiopexy and reported a success rate of 93% .
lintula et al reported a success rate of 88% for 19 testicular units undergoing laparoscopic orchiopexy and a success rate of 82% for 18 testicular units receiving open surgery , highlighting the excellent surgical outcomes of the laparoscopic orchiopexy .
we performed plo in 80.2% and fslo in 19.2% of 86 testicular units in this study . in our examination that took place 3 months after the laparoscopic orchiopexy ,
the tsr was 93.7% and the rate of fixation in the lower scrotum was 76.2% .
if classified on the basis of laparoscopic techniques , the plo showed a fixation rate in the lower scrotum of 79.6% , one - stage fslo showed a rate of 63.6% , and two - stage fslo showed a rate of 66.7% .
these outcomes were slightly lower than those reported in previous studies , but the successful results in this study confirm the clinical significance of laparoscopic orchiopexy for a nonpalpable intra - abdominal testis . chang and franco performed fslo in 48 testicular units and reported that the success rate of one - stage fslo was 94.3% and also proved that one - stage fslo and two - stage fslo in combination led to a success rate as high as 91.1% .
elder conducted two - stage fslo in 12 testicular units and reported a success rate of 92% .
when judged against these figures , the results of the fslo in the present study were relatively unsatisfactory , but the results were analyzed in only 17 testicular units .
we expect improved results in the near future after accumulating experience with fslo for nonpalpable intra - abdominal testis .
two cases developed complications within 1 month after the laparoscopic orchiopexy . in one case , we performed plo in a patient with bilateral nonpalpable intra - abdominal testes within 3 cm of the internal inguinal ring , but testicular atrophy was detected in the left testis in the physical examination at the 1 month clinical follow - up . in the other case ,
the patient had bilateral nonpalpable intra - abdominal testes more than 3 cm from the internal inguinal ring , and one - stage fslo was used to dissect the intra - abdominal testis fixed to the small intestine . however , the vas deferens was injured during the operation , which led to the laparoscopic unilateral orchiectomy . in one case of an intra - operative complication ,
transient hypercapnia and reactive tachycardia occurred during the plo ; therefore , we had to halt the procedure for 30 minutes and re - started the operation after the heart rate and arterial blood gas analysis were normalized through hyperventilation .
following are more detailed results of the laparoscopic orchiopexy performed by the authors , highlighting the postoperative location of the viable testis in the scrotum .
a total of 79.6% in the plo group were successfully fixed in the lower scrotum and 64.3% in the fslo group . when classifying the fslo into one - stage and two - stage fslo , the success rate of the one - stage fslo was 63.6% and that of the two - stage fslo was 66.7% .
when analyzing the ages of patients statistically in the spss software program by use of the student 's t test , we found that the mean age of the patients whose testes were fixed in the lower scrotum was 1.911.9 years and the mean age of the patients whose testes were fixed in the upper scrotum was 3.913.23 years .
the age of patients whose testes were located in the lower scrotum was therefore younger , but the difference was not significant statistically ( p=0.072 ) ( table 3 ) . when analyzing the postoperative location of the viable testis according to the period of clinical follow - up , 83.7% were fixed in the lower scrotum and 14.0% in the upper scrotum within 1 month ; however , 76.2% were located in the lower scrotum and 17.5% in the upper scrotum beyond 3 months .
we conclude that long - term clinical follow - up on the location of the fixed testis is required even if there is a satisfactory result right after or 1 month after the operation .
laparoscopic orchiopexy for a nonpalpable intra - abdominal testis shows a high success rate and high survival rate of the testes regardless of the distance from the internal inguinal ring to the nonpalpable intra - abdominal testis . in the follow - up after fixing the viable testes in the lower scrotum , however ,
therefore , long - term and vigilant clinical follow - up is recommended even after successful laparoscopic orchiopexy .
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### Summary:
: purposewe evaluated the efficacy and the availability of laparoscopic orchiopexy to manage a nonpalpable intra - abdominal testis and studied outcomes including the testicular survival rate and associated complications.materials and methodswe retrospectively reviewed the medical records of 67 children ( 86 testicular units ) who underwent laparoscopic orchiopexy for a nonpalpable intra - abdominal testis between 1996 and 2008 .
the mean patient age was 2.4 years ( median , 1 year ; range , 0.5 - 9 years ) , and the mean follow - up period was 21.8 months ( range , 0.3 - 138.4 months ) .
testicular viability and orchiopexed positioning were evaluated within 1 month and beyond 3 months.resultsof 86 testes , 69 testes were treated with primary laparoscopic orchiopexy ( plo ) sparing the internal spermatic vessel , 14 testes were treated with one - stage fowler - stephens laparoscopic orchiopexy 1 , and 3 testes were treated with two - stage fowler - stephens laparoscopic orchiopexy 2 .
the testicular survival rates were 97.7% ( 84/86 ) within 1 month and 93.7% ( 59/63 ) beyond 3 months .
of 59 viable testes followed up beyond 3 months , 48 ( 81.4% ) testes were positioned in the lower scrotum and 11 ( 18.6% ) testes in the mid to high scrotum.conclusionslaparoscopic orchiopexy was successful for a nonpalpable intra - abdominal testis with a high testicular survival rate irrespective of the location from the internal ring .
however , atrophy of the testis or upward migration of the testis can occur during follow - up , so we suggest watchful , periodic follow - up evaluating the viability and location of orchiopexed testes that are located in the lower scrotum in the immediate postoperative period or during short - term follow - 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:
: equity , irrespective of ethnicity , is a fundamental ethical principle for quality health care 1 .
it has risen up the policy agenda in recent years as modern health services are required to respond to increasing ethnic diversity within the populations they serve . in the uk , minority ethnic groups comprise 8 million people or 14% of the population , and this proportion is growing 2 .
a number of uk statutes over the past 50 years culminated in the equality act 2010 , requiring public and voluntary bodies to eliminate discrimination and promote equality of opportunity in service delivery 3 .
the national health service ( nhs ) , in response , has introduced guidance through its equality delivery system to ensure compliance with the equality act 2010 4 , 5 .
minority ethnic groups have different patterns of illness in the uk , including higher rates of coronary heart disease and type 2 diabetes in south asians ( patients from the indian subcontinent ) 6 , 7 , 8 , 9 as well as stroke in black caribbeans 10 .
although previous studies showed small and narrowing ethnic health disparities for cardiovascular diseases in primary 1 , 11 or secondary care settings 8 , few studies have focused on the quality of prehospital ambulance care for conditions including cardiovascular presentations in minority ethnic patients in the uk .
some south asian groups were more likely than white patients to seek immediate medical help for suspected cardiac pain 12 .
another study found that south asians experiencing chest pain were less likely to arrive by ambulance 13 .
's us study ( 2010 ) , which found that mexicanamericans who had suffered a stroke were 40% less likely to arrive by emergency medical services ( ems ) than nonhispanic whites 14 .
some minority ethnic groups are more likely to delay or even refuse seeking treatment . in the us , galea et al .
( 2007 ) 15 found two main reasons why africanamericans delayed seeking help for outofhospital cardiac arrests
previous negative , usually discriminatory , experiences of health care professionals and limited symptom awareness .
delaying or refusing treatment can lead to poorer health outcomes or excess morbidity and mortality 15 , 16 . owing to limited research in this area
, we aimed to investigate differences in prehospital ambulance care delivered to minority ethnic patients with suspected cardiac pain .
we conducted a crosssectional analysis of retrospective electronic clinical data extracted from a large single regional ambulance service for patients with suspected cardiac pain from august 2011 to july 2012 .
this study included patients recorded as having suspected cardiac pain attended by east midlands ambulance service nhs trust ( emas ) .
emas answers emergency 999 calls providing urgent and emergency services for 4.4 million people in derbyshire , leicestershire , rutland , lincolnshire , northamptonshire and nottinghamshire ( table 2 ) 17 .
the east midlands is a largely rural region in the uk , with the major cities being leicester , nottingham and derby , each of which have populations in excess of 200 000 .
the city of leicester local authority area has the highest minority ethnic population in the east midlands . according to the 2011 office for national statistics ( ons ) census ,
37% of its population of around 330 000 were asian , up from 30% in 2001 18 .
we accessed patient demographic data including ethnicity , age , sex , socioeconomic deprivation [ as measured by the index of multiple deprivation ( imd ) ] , and urban or rural place of residence .
clinical measurements usually undertaken for patients with suspected cardiac pain were extracted including rates of recording of blood pressure , respiratory rate , pain assessment , temperature , blood glucose , oxygen saturation and electrocardiogram .
we considered rates of drugs administered by paramedics , including aspirin , nitroglycerin , entonox and morphine for these patients .
finally , data on care outcomes , including rates of transportation to hospital ( termed see and convey ) , treatment at home followed by discharge ( see and treat ) or referral to primary care ( see and refer ) were also analysed .
we also compared ambulance data for patients attended to by the ambulance service from august 2011 to july 2012 with ons population estimates for east midlands in 2012 to investigate differences between rates of presentation to the ambulance service compared with ethnicity in the resident population 2 .
ambulance service staff are required to record ethnicity data for patients under the equality act 2010 .
we used multivariate regression to investigate differences in care by ethnicity comparing nonwhite with white patients adjusting for age , sex , socioeconomic and urban / rural status .
this study included patients recorded as having suspected cardiac pain attended by east midlands ambulance service nhs trust ( emas ) .
emas answers emergency 999 calls providing urgent and emergency services for 4.4 million people in derbyshire , leicestershire , rutland , lincolnshire , northamptonshire and nottinghamshire ( table 2 ) 17 .
the east midlands is a largely rural region in the uk , with the major cities being leicester , nottingham and derby , each of which have populations in excess of 200 000 .
the city of leicester local authority area has the highest minority ethnic population in the east midlands . according to the 2011 office for national statistics ( ons ) census ,
37% of its population of around 330 000 were asian , up from 30% in 2001 18 .
we accessed patient demographic data including ethnicity , age , sex , socioeconomic deprivation [ as measured by the index of multiple deprivation ( imd ) ] , and urban or rural place of residence .
clinical measurements usually undertaken for patients with suspected cardiac pain were extracted including rates of recording of blood pressure , respiratory rate , pain assessment , temperature , blood glucose , oxygen saturation and electrocardiogram .
we considered rates of drugs administered by paramedics , including aspirin , nitroglycerin , entonox and morphine for these patients .
finally , data on care outcomes , including rates of transportation to hospital ( termed see and convey ) , treatment at home followed by discharge ( see and treat ) or referral to primary care ( see and refer ) were also analysed .
we also compared ambulance data for patients attended to by the ambulance service from august 2011 to july 2012 with ons population estimates for east midlands in 2012 to investigate differences between rates of presentation to the ambulance service compared with ethnicity in the resident population 2 .
ambulance service staff are required to record ethnicity data for patients under the equality act 2010 .
we used multivariate regression to investigate differences in care by ethnicity comparing nonwhite with white patients adjusting for age , sex , socioeconomic and urban / rural status .
there were 7046 patients with suspected cardiac pain attended to by emas between august 2011 and july 2012 . of these , 4825 had ethnicity recorded , of whom 96.6% were white .
nonwhite patients were similar to white patients in relation to gender ( p = 0.63 ) and socioeconomic status ( p = 0.08 ) but were significantly younger ( p < 0.001 ) ( table 1 ) .
demographic information for white and nonwhite patients attended with cardiac chest pain
nonwhites are defined as all those who are noncaucasian .
of the 75 nonwhite patients for whom we had imd data for , 74 ( 98.7% ) lived in less sparse urban areas .
by contrast , the corresponding figure among the 1569 white patients for whom we had such data was 1273 ( 81.1% ) .
the ons population data for the east midlands 17 by ethnicity showed that ambulance services were proportionately more likely to attend white than nonwhite patients ( table 2 ) .
ambulance attendances by ethnic group compared with population estimate
office for national statistics ( 2012 ) census gives insights into characteristics of the east midlands ' population .
nonwhite patients were significantly more likely to have blood glucose ( 78.7% vs. 69.4% , p = 0.011 ) and temperature recorded ( 77.4% vs. 69.8% , p = 0.035 ) than white patients . for unadjusted drug administration ,
nonwhites were only significantly more likely to receive aspirin than whites ( 14.0% vs 8.7% , p = 0.018 ) .
there were no significant differences between nonwhite and white patients in those treated and discharged , referred to primary care , refused treatment , not treated and electrocardiogram ( ecg ) or cannulation performed. there were no significant differences in aspirin , nitroglycerin , entonox or morphine administration , adjusting for age , sex , socioeconomic status , urban / rural status , whether transported to hospital or treated and discharged ( table 3 ) .
assessment , drugs administered and treatment outcome comparing white and nonwhite patients with suspected cardiac chest pain attended by ambulance totals do not equal 4825 because of missing ethnicity data in some cases . additional multivariate logistic regression , adjusting for age , sex , socioeconomic status , imd , urban / rural status , whether transported to hospital or treated and discharged , showed that nonwhite patients were similar to white patients in recording of blood pressure , pain score , cannulation and ecg .
however , nonwhites were significantly more likely than whites to have their oxygen saturation [ odds ratio ( or ) 2.43 , p = 0.006 ] temperature ( or 2.96 , p = 0.007 ) , respiratory rate ( or 4.94 , p = 0.03 ) and blood glucose ( or 3.95 , p = 0.003 ) recorded ( table 4 ) .
multivariate logistic regression for clinical assessment comparing white and nonwhite patients attended by ambulance with suspected chest pain
adjusted for age , sex , treated and transported , treated and discharged , deprivation ( imd ) and rural / urban .
a multivariate logistic regression adjusting for ethnicity , age , sex , socioeconomic status and urban or rural status showed that nonwhites were 57% ( p = 0.03 ) less likely to be transported to hospital after adjusting for age , sex , imd and urban / rural setting .
men with suspected cardiac pain were 76% more likely to be transported to hospital than women ( table 5 ) .
multivariate regression for patients transported to hospital by ambulance with suspected cardiac chest pain
white was the reference group .
we found similarities in prehospital ambulance care for nonwhite compared with white patients with suspected cardiac pain .
however , nonwhite patients were more likely to have a number of clinical assessments recorded and less likely to be transported to hospital .
the finding that nonwhite patients were significantly more likely than white patients to have blood glucose recorded could be explained by higher levels of diabetes among the former .
delaying or refusing medical treatment may increase the risk of preventable morbidity and mortality in conditions such as cardiac disease 15 , 20 . in some minority ethnic groups ,
such delays or refusals can be because of a number of interrelated factors including , different cultural norms , perceived discrimination , language and communication problems and limited knowledge of how and when to appropriately use health care services .
cultural norms and beliefs can influence health and helpseeking behaviour , for example , in some minority ethnic groups , it is not considered masculine to seek help or express pain 20 , 21 .
there is also a greater reliance on the family to manage illness in some ethnic groups 22 .
for example , the family is a key agency in seeking medical help 20 , 23 in some south asian families in the uk who are more likely to live in large households with an extended family network to call upon 24 .
clinicians need to be aware of differences in how patients report their symptoms and to consider the impact of language , culture and gender on the assessment process 21 .
low levels of cultural understanding among staff can lead to discriminatory experiences that can reduce trust and lead to future reluctance to use services 14 , 16 , 25 .
people from minority ethnic groups who have lower levels of acculturation , that is , shorter residencies , limited language skills and awareness of the different health structures and systems , and so on , may also find it more difficult to access health care services 25 , 26 .
access to appropriate health care services may be reduced further by a lack of knowledge of symptoms 16 , 20 .
limited understanding of symptoms together with the complexity of a new health care system allied to lack of information about how health care works can lead to people using services that are inappropriate to their needs , which can lead to increased pressure on prehospital ambulance care 16 , 27 .
language and communication problems are another reason why there is underuse of prehospital ambulance care among some minority ethnic groups .
for example , language can be a significant barrier for patients when trying to communicate their symptoms over the telephone to emergency call handlers 26 .
interpreting services are available for ambulance staff but may be inaccessible at certain times or unable to provide necessary languages or dialects 28 .
this places a greater reliance on family members to translate , which also has its drawbacks 28 , 29 .
language barriers can also lead to miscommunication of diagnosis and treatment resulting in preventable morbidity and mortality 26 , 30 . while previous literature suggests that some ethnic groups are reluctant to seek help for medical conditions ,
evidence also suggests that they may be taken less seriously by health care professionals or perceived as inappropriately frequent users of health services . in the uk , gps sometimes perceive that their south asian patients take up more time in the surgery presenting with trivial disorders 31 .
the significant proportion of patients for whom ethnicity data was missing also raises issues for ambulance services , especially as they strive towards their statutory equality duties set out in the equality act 2010 .
paramedics are required to collect ethnicity data from patients , but ambulance services may not record such information accurately or at all .
for example , in 2013/2014 , one ambulance service reported recording only 47% of patient ethnicity data 32 .
there are a number of reasons for the incompleteness and inaccuracy of ethnicity data recording .
given the emergency nature of the situations , paramedics may focus on patients ' clinical conditions rather than recording ethnicity .
paramedics may also feel uncomfortable asking the patient their ethnicity as they are worried how this question may be perceived by the patient , who may be reluctant to disclose their ethnicity .
this problem is heightened by the lack of consistency of ethnicity coding between ambulance services 6 .
the incompleteness of ethnicity data is likely to hinder progress towards reducing ethnic health inequalities 33 .
these findings call for further studies utilizing larger and more complete data sets to explore ethnic differences in prehospital ambulance care .
qualitative studies could also be used to explore the experiences of minority ethnic patients and other groups of patients with suspected cardiac pain or other conditions where differences in prehospital management are found .
a better understanding of the cultural factors affecting expression and choice of treatment could improve the quality and equity of prehospital ambulance care for minority ethnic patients suffering from suspected cardiac pain or other conditions .
our analysis showed significant differences for ethnic groups in the way that some aspects of prehospital ambulance care were delivered to patients with suspected cardiac pain .
although we used a large data set , almost onethird of patients had missing ethnicity data .
this could be due to language barriers , time constraints , patient reluctance to disclose ethnicity and paramedics prioritizing the improvement of clinical conditions rather than ethnicity data recording .
the missing ethnicity data may have been a source of bias and led to overestimation or underestimation of the differences by ethnicity .
the low numbers of minority ethnic patients also prevented ethnic group analysis , which limits the extent to which our findings can be generalized . also , variation in diagnostic codes used by paramedics could have led to differences by ethnicity .
these findings call for further studies utilizing larger and more complete data sets to explore ethnic differences in prehospital ambulance care .
qualitative studies could also be used to explore the experiences of minority ethnic patients and other groups of patients with suspected cardiac pain or other conditions where differences in prehospital management are found
. a better understanding of the cultural factors affecting expression and choice of treatment could improve the quality and equity of prehospital ambulance care for minority ethnic patients suffering from suspected cardiac pain or other conditions .
our analysis showed significant differences for ethnic groups in the way that some aspects of prehospital ambulance care were delivered to patients with suspected cardiac pain . although we used a large data set , almost onethird of patients had missing ethnicity data .
this could be due to language barriers , time constraints , patient reluctance to disclose ethnicity and paramedics prioritizing the improvement of clinical conditions rather than ethnicity data recording .
the missing ethnicity data may have been a source of bias and led to overestimation or underestimation of the differences by ethnicity .
the low numbers of minority ethnic patients also prevented ethnic group analysis , which limits the extent to which our findings can be generalized . also , variation in diagnostic codes used by paramedics could have led to differences by ethnicity .
this is the first study showing differences in prehospital ambulance care for people with suspected cardiac pain according to ethnic status .
the ethnic differences in the treatment of suspected cardiac pain could be due to recording bias , differences in the clinical conditions presented or real disparities in clinical management .
ethnic differences in treatment for suspected cardiac pain may also arise through cultural differences , discriminatory experiences , language and communication problems and a limited patient awareness of symptoms and how to use health care services appropriately
. there may also be issues about local variations in ethnic classifications , which may lead to paramedics being unsure of how to record patient ethnicity data .
when attending emergency situations , paramedics may not prioritize the recording of patient ethnicity data as their primary focus will often be on trying to improve the patient 's clinical condition .
we also found that women with suspected cardiac pain were less likely to be transported to hospital compared with men .
if these differences are confirmed , qualitative exploration of reasons why they exist is needed .
approval for research management and governance was sought and gained from east midlands ambulance services nhs trust .
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### Summary:
: abstractobjectivesfew studies have investigated the quality of prehospital care by ethnicity .
we aimed to investigate ethnic differences in prehospital ambulance care of patients with suspected cardiac pain.methodswe conducted a crosssectional analysis of retrospective electronic clinical data for patients with suspected cardiac pain over one year ( august 2011 to july 2012 ) extracted from a single regional ambulance service .
this included patient demographic data , clinical measurements , drugs administered and outcomes , such as transportation to hospital or referral to primary care .
we used multivariate regression to investigate differences in care by ethnicity comparing nonwhite with white patients.resultsthere were 7046 patients with suspected cardiac pain , with 4825 who had ethnicity recorded including 4661 ( 96.6% ) white and 164 ( 3.4% ) nonwhite .
after correcting for age , sex , socioeconomic status and whether transported to hospital , nonwhite patients were significantly more likely to have temperature [ odds ratio ( or ) 2.96 , p = 0.007 ] , blood glucose ( or 3.95 , p = 0.003 ) , respiratory rate ( or 4.94 , p = 0.03 ) and oxygen saturation ( or 2.43 , p = 0.006 ) recorded .
nonwhite patients were significantly less likely to be transported to hospital ( or 0.43 , p = 0.03).conclusionthere were significant differences in prehospital ambulance care for nonwhite compared with white patients with suspected cardiac pain .
these differences could be due to differences in clinical condition or casemix , language and cultural barriers , limited understanding of appropriate use of health care services , recording bias or true differences in provider management .
further analysis should involve larger and more complete data sets to explore ethnic differences in greater detail .
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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 approach to diagnosis and management of hyperthyroidism is quite variable in clinical practice with varying dependence on clinical assessment , thyroid autoantibodies , and ultrasound ( us ) examination .
it is quite common that reliance for etiological diagnosis of hyperthyroidism is largely based on clinical assessment and followed by antibody testing .
the initial assessment of these patients is quite variable and is generally guided by individual clinician 's expertise and experience .
the morphology of thyroid gland is generally determined by clinical examination and recommending us of the neck is not a routine clinical practice .
the incidence of cancers in palpable thyroid nodule is approximately 310% ; the risk in incidentally found nonpalpable nodules is quite variable .
however , there has been increasing evidence to the contrary , making it even more pertinent to determine the morphology of the gland accurately .
the aim of our study was to assess the reliability of clinical examination of the thyroid gland by endocrine specialists in real - life clinical practice in comparison to us features and reemphasize the need for us as an objective documentation of the thyroid anatomy in patients with hyperthyroidism .
we conducted an observational analysis of clinical records of 200 consecutive patients referred to our endocrine clinic for assessment of biochemically confirmed hyperthyroidism .
the patients were assessed in the clinic by consultants or specialist registrars in the endocrine clinics .
all patients had a clinical history suggestive of hyperthyroidism and biochemical evidence of hyperthyroid state ( low or suppressed thyroid stimulating hormone and high free t4 and/or t3 ) .
as per the local practice , us examinations were only requested if clinically warranted and at the discretion of the attending endocrinologist .
autoantibodies ( thyroid peroxidase [ tpo ] and/or thyroid receptor antibody ) were tested in patients with suspected graves disease .
the us of the neck was performed by dedicated consultants or specialist registrars in radiology .
the clinical letters were reviewed to document the morphology of the gland on clinical examination .
for the purpose of the analysis , the us findings were classified as :
normal ( in size and shape)solitary noduletwo large nodules ( > 1 cm each)multinodular goiter ( mng ) with enlargement of thyroid glanddominant nodule in an mngothers ( which included diffuse enlargement with no nodularity , asymmetrical enlargement , or present of micronodularity with thyroiditis ) .
normal ( in size and shape ) two large nodules ( > 1 cm each ) multinodular goiter ( mng ) with enlargement of thyroid gland dominant nodule in an mng others ( which included diffuse enlargement with no nodularity , asymmetrical enlargement , or present of micronodularity with thyroiditis ) .
of the 200 patients that were reviewed for the study , 133 were included for the study based on the availability of us report .
clinical findings versus ultrasound findings in patients with hyperthyroidism thirty - nine patients with hyperthyroidism had a normal thyroid gland on us .
twenty - seven of the 39 patients were identified as normal on clinical examination also .
a further 14 patients were correctly identified as having an mng and 19 more to have an enlarged gland .
therefore , of the sixty patients who had significant nodularity on us , twenty were classified as normal and hence may not have been referred for us in routine clinical practice .
we did a sub - analysis on patients who had antibody confirmed diagnosis of graves disease ( n = 73 ) [ table 2 ] .
it was again noted that 12/30 patients could be misdiagnosed as being normal on clinical examination when the us shows evidence of significant nodularity .
our study clearly demonstrates the limitation of clinical examination of the neck in identifying the morphology of the thyroid gland in patients with hyperthyroidism .
about 33% of the patients with hyperthyroidism were classified as normal on clinical examination when the us identified nodularity that may warrant further investigation .
our study also highlights a few important clinical issues in the management of patients with hyperthyroidism and graves disease .
the concordance rate of clinical examination versus us was only 56/133 in hyperthyroidism in general and 32/73 in graves. there is significant variation in normal clinical practice of requesting us for these patients .
a recent survey conducted on practicing endocrinologist in europe showed an increasing trend toward using us for morphological diagnosis of the thyroid gland .
the sensitivity of identifying the nodules reduces with the decreasing size of the nodules ; however , clinical examination is not sensitive in identifying all larger nodules as well .
( ii ) patients with nodular thyroid gland and hyperthyroidism warrant further investigation with radionuclide uptake scans to document if the nodule is hot or cold .
the estimated prevalence of thyroid cancer in hot nodules is variable but can be as high as 3.1% .
the prevalence of follicular thyroid cancer is understandably higher in hot nodules in compared to cold nodules ( 36.4% vs. 10% ) .
the practice recommendations on thyroid nodules recommend using the us imaging to guide the need for biopsy of these nodules .
the prevalence of thyroid cancers may be low in hot nodules ; however , the cold nodules may still need to be investigated in line with practice with euthyroid nodules in the thyroid gland .
furthermore , once remission is achieved with anti - thyroid treatment , the nodules would warrant continued follow - up if appropriate in line with the general management of thyroid nodules .
the usual clinical notion that patients with hyperthyroidism and a nodular gland would need a thyroid uptake scan and if the nodule is hot , risk of malignancy is low , is questionable .
these nodules may also need to be investigated if appropriate based on clinical and ultrasonography appearance .
( iii ) in practices where thyroid receptor antibody or tpo antibodies are not performed as a routine , the role of us is even more vital to prove the etiology of hyperthyroidism .
this is crucial to decide the duration of treatment of anti - thyroid drugs and for assessing the need for earlier definitive treatment . in patients with diagnosed graves disease
there are quite a few important points to take into consideration ( i ) coexistence of nodules in graves disease is quite common , some present at diagnosis and some developing since the onset of the disease .
( ii ) the risk of thyroid cancer developing in a thyroid gland with graves disease , based on epidemiological studies , is considered to be significantly higher compared to background population and the risk is much higher in the first 3 years after diagnosis .
( iii ) thyroid cancers developing in a gland with graves disease could be more aggressive and multifocal malignancy in comparison to toxic adenoma or mng .
although many of these conclusions are derived from thyroidectomy studies ( and hence the carcinoma might have only been incidentally identified and of questionable clinical validity ) , it is important to acknowledge this fact when taking an individual patient into consideration , especially if risk factors are present .
( iv ) the presence of nodules in a thyroid gland with graves increases the risk of thyroid cancer in comparison to patients with diffuse goiter , thereby again negating the common belief that hot nodules are low risk for thyroid cancers .
( v ) the chance of developing thyroid cancer is higher in a patient with graves disease with a cold nodule in comparison to a toxic adenoma or a hot nodule in an mng .
the above findings therefore increasingly validate the need for performing the routine us as standard practice in patients with graves disease .
there are limitations to our study : this study is a retrospective analysis of standard clinical practice hence adjustment for techniques used in the clinical examination , or inter - rater variability of us can not be possible .
the thyroid function test results were not published as part of the study as this would not have made a difference to the results of the conclusion of the study .
the age of the patients and the characteristics of the nodule may influence the need ( or lack of ) to investigate some of the patients , and this could not be accounted for in our study .
there could be variation in epidemiology depending on the iodine levels and iodine intake of a specific population .
our study reemphasizes the need to use a triangulated approach to patients with hyperthyroidism , using clinical examination , antibody testing , and us to derive an etiological diagnosis of hyperthyroidism .
patients with hyperthyroidism and nodules in the thyroid gland would warrant appropriate further investigations as the risk of thyroid cancer in these nodules are not as low as it had been thought of .
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### Summary:
: aim : the aim of our study was to assess the limitation of clinical examination in determining the morphology of thyroid gland in patients with hyperthyroidism and its implications.methods:a retrospective analysis of consecutive patients with hyperthyroidism seen in a tertiary endocrine clinic were analyzed .
sub - analysis was performed on patients with proven graves disease.results:of the 133 patients included in this study with hyperthyroidism , 60 ( 45% ) patients had significant nodularity on ultrasound ( us ) .
however , only 67% of these were identified on clinical examination . in patients with confirmed graves disease ( n = 73 )
, the discordance between us and clinical examination was very similar ( 18 of 30 patients , 60%).conclusion : us should form an essential part of the evaluation of hyperthyroidism as the morphology of thyroid gland could be variable and nodules in these glands would also need to be appropriately investigated .
this would also significantly influence decision - making and appropriate immediate and follow - up management plan .
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:
work in the h. maiato laboratory is funded by the seventh framework program grant precise from the european research council , the flad life science 2020 and the louis - jeantet young investigator career award .
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### Summary:
: chromosome segregation during mitosis is mediated by the mitotic spindle .
formation of this microtubular structure relies on distinct processes such as microtubule nucleation and growth and the consequent focusing of these filaments into spindle poles . here
, we discuss our recent finding that a size - exclusion spindle envelope promotes mitotic fidelity in drosophila cells in light of distinct spindle assembly mechanisms .
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: over the past 25 years , intensive care units ( icus ) have created a body of pathophysiologic knowledge that has enabled advances to be made in the treatment of patients . at the same time , a series of tools have been designed to evaluate , from multiple perspectives , the care outcomes obtained .
research has also been conducted in parallel on improvements in icu management , especially the european research in intensive care units ( euricus ) project . in short ,
a set of central parameters or dimensions has been developed that determine the outcomes obtained .
standing out among these central dimensions are the patient case mix , the technical competence of the medical and nursing teams , the resources available , and the culture and organisational model .
outcomes can in turn be summarised under five different subheadings : mortality , quality of life of survivors , consumption of resources generated and associated costs , level of satisfaction of patients , relatives and health care professionals , and continuous quality improvement .
the simplified acute physiology score ( saps ) iii outcomes research group is developing an ambitious observational study aimed at creating a multidimensional instrument for the global evaluation of icu performance . among its specific objectives are the update of saps in the light of the experience of recent years and the creation or application of novel instruments in the areas of infections and costs .
with respect to mortality , a third version of saps is being prepared that will strengthen some features of the score .
it will thus incorporate the reasons for admission , a larger number of comorbidities and patient location prior to icu admission .
the most novel feature , however , is that the saps will take account of the variability in clinical practice , so that it will gather the withdrawal or not of active therapeutic measures and the transfer to other hospitals .
because mortality is considered at 28 , 60 , and 90 days , the design would be improved if it were taken into account that , after icu discharge , the mortality is affected by other influences that become progressively more important with the passage of time .
this aspect , which receives little attention in existing severity indexes , could improve our ability to predict immediate and late mortality .
on the basis of our experience with the apache iii system , generic tools incorrectly classify and discriminate the mortality of patients with infections .
the creation of a new index of severity and a mortality prediction equation would therefore seem appropriate , especially given the very high cost of new drugs .
we need an instrument that allows us to assess their true effect on the mortality of these patients . regarding resource consumption and costs ,
however , although of great interest , it is highly possible that most icus will not be able to provide this information , which may be difficult for health care professionals to gather .
this is because the decentralised management of economic resources has not been implemented by most icus and because clinicians , even many heads of service , have inadequate knowledge of budget management issues .
the euricus study reported that 51% of icu costs are fixed and 49% are variable .
differences in costs among icus depend especially on the use of certain drugs and the nurse / bed ratio .
it is possible that , with their current level of knowledge , physicians could make a greater contribution to the rationalisation of costs , by managing novel and very costly new therapies using the evidence - based medicine approach . with respect to the nurse / bed ratio , an instrument such as the therapeutic intervention scoring system , in any of its current versions , is needed to evaluate the adequate nursing workload .
saps iii does not gather any of these data , so there may be a loss of information that is important for the interpretation of results obtained in other areas of the study .
one of the advantages of its management as an outcome is that treatments can be selected that offer a substantial improvement in the quality of life of patients for the same mortality .
the best known example in critical medicine is the approval of thrombolytic treatment for ischemic stroke , based on an improvement of the quality of life and not of the mortality , which remains unchangeable .
given the objective relationship that exists between other dimensions that are not analysed in the study ( e.g. satisfaction and culture , among others ) , it would be desirable to include these dimensions in a tool that attempts to offer an overall and multidimensional analysis of icu performance .
the wide variability among countries or even within countries with regard to patient type , resources and professional profile means that tools designed for international application present defects that must be resolved at a local level .
the computer systems now in wide use by hospitals should allow the data for many of these instruments to be collected automatically as part of routine care .
nevertheless , the maintenance and continuous improvement of these systems and the development of the appropriate software support requires novel solutions to be sought , so that this scale of effort is matched by adequate funding during the time required for the definitive incorporation of these instruments in the icus .
euricus = european research in intensive care units ; icu = intensive care unit ; saps = simplified acute physiology score .
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### Summary:
: the simplified acute physiology score iii outcomes research group is developing an international multidimensional instrument for the global evaluation of intensive care unit performance . among its specific objectives
are the update of a severity of illness index ( simplified acute physiology score ) with a mortality prediction equation , with the hindsight of recent years , and the creation or application of novel instruments in the areas of infections and cost - effectiveness .
some important measurements such as the quality of life and the satisfaction of patients and professionals are not included .
a further aim is the achievement of international validation .
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: the local disease is not lethal , but its spread to distant organs is fatal .
the risk of metastasis is evaluated by clinical and pathological criteria , but the performance of these methods is far from optimal .
gene expression profiling of tumors has been used for the supervised classification of cancer outcomes in several studies with promising results for the improvement of risk prediction.14 despite these promising clinical results , limited insights into its biological mechanisms has been obtained from the large amount of gene expression data available .
a very different approach was used in early studies of global gene expression of breast cancer , where unsupervised hierarchical clustering was used to identify 45 molecular subtypes.58 these subtypes arise from at least two cell types : basal cells and luminal epithelial cells .
luminal tumors are mainly estrogen receptor ( er)-positive and cluster in two distinct groups ( termed luminal a and luminal b ) that appear to result in good and poor prognosis , respectively .
a distinct group that mainly consists of er - negative tumors is characterized by the amplification of erbb2 .
these subtypes are biologically very meaningful , but their prediction of metastasis is not optimal . in recent studies , unsupervised and
supervised methods have been used to differentiate the molecular subtypes of breast cancer into further subgroups with different outcomes .
the discriminating genes have subsequently been related to biological function ( for example , immune response among er - negative tumors).9,10 these studies have identified very broad mechanisms , but they have not pointed at specific biochemical pathways . a very different strategy would be to analyze predefined gene sets representing biological mechanisms , such as the pathways for their association to metastasis . we have previously used this strategy for the analysis of the overall pathways involved in the metastasis of breast cancer.11 furthermore , we have applied this approach to gene sets representing genomic regions to identify somatic mutations at the deoxyribonucleic acid ( dna)-level that are involved in metastasis.12 however , the analysis of pathways and genomic aberrations has not been applied to analyze the various metastatic mechanisms found within the different subtypes of breast cancer .
we hypothesize that several somatic genomic aberrations and biological pathways characterize the molecular subtypes in breast cancer . despite the association of the subtypes to metastasis
, we expect that mechanisms within a given subtype may be involved in the higher risk of metastasis for a fraction of the tumors .
furthermore , we anticipate that deregulation of the pathways is reflected in gene expression patterns of primary tumor biopsies .
we also assume that somatic copy number mutations involving chromosomal regions will be reflected in the overall level of gene expression in these regions .
our aim is to elucidate these metastatic mechanisms within the molecular subtypes and , secondly , to determine the mechanisms that differ between the subgroups .
we have used predefined gene sets representing canonical pathways and chromosomal regions to identify metastatic mechanisms within molecular subtypes .
this has been accomplished by a global approach ; gene set enrichment analysis ( gsea ) examining the entire list of genes ranked according to association to metastasis within each molecular subtype . in a single dataset , this analysis will generally not result in significant findings .
however , by performing a meta - analysis of several datasets , we have increased the power to identify somatic mutations among the chromosomal regions and pathways involved in the metastasis of fractions of breast tumors within a specific subtype .
global gene expression data were collected from 1,586 breast tumors with clinical follow up ( table 1 ) .
molecular subtypes were identified by a single sample prediction approach using nearest centroid classification.8 single - sample predictions resulted in 1,394 samples with assigned subtypes .
survival analysis confirmed the prognostic impact of the subtypes , with luminal a and normal - like tumors having significantly better prognosis than luminal b , erbb2 , and basal - like tumors ( fig .
1 ) . to identify the biological characteristics of the molecular subtypes , we divided the 1,394 samples subtyped with a single sample prediction , to a training set of 1,203 tumors corresponding to six entire datasets and a test set of 191 tumors contained in two datasets ( table 1 ) .
we applied gsea analysis to one subtype at a time compared to all other tumors .
this analysis was performed with gene sets representing chromosomal region and with pathway gene sets .
a meta - analysis was performed to identify gene sets that were concordantly differentially regulated in the training datasets . for chromosomal regions , a large number of somatic mutations were indicated by the analysis ( table 2 ) .
the differential expression of several consecutive regions indicated that larger regions are lost or gained .
validation in the test set resulted in 34% of regions being significant ( highlighted in bold in table 2 ) .
pathway analysis using predefined canonical pathways also indicated large differences between the subgroups ( table 3 ) .
of these pathways , 43% were also identified by gsea analysis in the independent mainz dataset ( highlighted in bold in table 3 ) .
the above analyses indicate that molecular subtypes significantly account for the metastasis of breast cancer , and that the subtypes are associated with very different biological pathways and somatic mutations .
to identify the metastatic mechanisms that extend beyond the molecular subtypes , we performed pathway and chromosomal aberration analyses within each subtype , comparing tumors from patients that experienced metastasis to tumors from patients that did not experience metastasis within the follow - up period .
the data were again split into a training set including six datasets , and the two most recently published datasets ( mainz and transbig - s ) were kept for validation purposes .
the training set was composed of datasets with different clinical characteristics and treatment statuses of the patients and performed with different microarray platforms .
in contrast , the test sets ( mainz and transbig - s ) contained data from node - negative patients not receiving adjuvant medical treatment ; all analyses were performed with affymetrix hg133a chips .
the gsea meta - analysis in the training set resulted in the identification of nine significant regions and pathways ( table s1 ) . using gsea for the validation of these regions and pathways in the mainz dataset did not result in any significant gene sets , probably due to the limited sample size when comparing tumors with poor and good outcomes within subtypes ( data not shown ) . in order to validate the identified regions and pathways with a different method , we investigated whether the overall expression level in each gene set could be used as a prognostic marker in survival analysis .
this would also allow us to compare the expression of regions or pathways between single tumors from all datasets .
furthermore , utilizing survival information might help to improve the power of the validation , and combining datasets would also increase the power .
the expression level of all genes in each region or pathway identified previously was implemented in the region scores .
this method is different from the gsea meta - analysis described earlier because only genes represented on all platforms were included in the analysis . in 280 basal - like tumors from the training sets , this different approach supported a high level of expression of 5q14 ( fig .
2a ) and a low level of expression of tumor necrosis factor receptor ( tnfr)2 ( fig .
2e ) as predictors of poor outcomes . for erbb2 tumors , the low expression of 5q33 ( borderline significant ; fig . 3a ) and interleukin ( il)-12 ( fig .
3e ) were associated with poor outcomes , which was in agreement with the gsea meta - analysis .
the remaining five pathways and regions identified by the gsea meta - analysis were not significant in the survival analysis ( table s1 ) .
for the validation of metastatic gene sets in independent datasets , two test sets were used .
the mainz data set , where 41 basal - like tumors were identified by single - sample prediction , was used for the validation of the metastatic mechanisms of basal - like tumors .
however , only 20 erbb2 tumors were identified by single - sample prediction in the mainz dataset . to increase the sample size of erbb2-positive tumors ,
the identification of molecular subtypes failed in this dataset , but erbb2 status was determined from erbb2 expression in both datasets .
the very unbalanced distribution of erbb2 and the coregulation of grb7 located closely to erbb2 supported this method for the classification of erbb2 amplification ( fig .
the disadvantage of high 5q14 expression was validated by the survival analysis in the test set ( fig .
2c ) . to investigate whether this prognostic effect of 5q14 aberration was specific for basal - like tumors , the prognostic performance was also examined in the remaining tumors not belonging to this subgroup
2b ) but , surprisingly , a borderline significant opposite effect was found in the test set ( fig .
2d ) . the prognostic impact of the tnfr2 pathway identified in the gsea meta - analysis and in the survival analysis in the training set ( fig .
2e ) was also supported by a survival analysis in the test set ( fig .
2 g ) . however , this pathway was also significant in nonbasal - like tumors in the training set , but with smaller separation of the groups ( ie , lower hazard ratios [ fig .
2f ] , and the pathway was only borderline significant among the nonbasal - like tumors in the test set [ fig .
2h ] ; in addition , a lower hazard ratio was observed among nonbasal - like tumors when compared to the basal - like tumors ) .
interestingly , these mechanisms were specific for tumors with high levels of expression of erbb2 ( fig .
3b , d , f , and h ) . to identify single metastasis candidate genes in the two 5q regions
, we compared the expression of metastasizing and non - metastasizing tumors at single gene level . for 5q14 ,
no single gene was strongly and differentially expressed at 5q33 ( data not shown ) .
global gene expression data were collected from 1,586 breast tumors with clinical follow up ( table 1 ) .
molecular subtypes were identified by a single sample prediction approach using nearest centroid classification.8 single - sample predictions resulted in 1,394 samples with assigned subtypes .
survival analysis confirmed the prognostic impact of the subtypes , with luminal a and normal - like tumors having significantly better prognosis than luminal b , erbb2 , and basal - like tumors ( fig .
to identify the biological characteristics of the molecular subtypes , we divided the 1,394 samples subtyped with a single sample prediction , to a training set of 1,203 tumors corresponding to six entire datasets and a test set of 191 tumors contained in two datasets ( table 1 ) .
we applied gsea analysis to one subtype at a time compared to all other tumors .
this analysis was performed with gene sets representing chromosomal region and with pathway gene sets .
a meta - analysis was performed to identify gene sets that were concordantly differentially regulated in the training datasets . for chromosomal regions , a large number of somatic mutations were indicated by the analysis ( table 2 ) .
the differential expression of several consecutive regions indicated that larger regions are lost or gained .
validation in the test set resulted in 34% of regions being significant ( highlighted in bold in table 2 ) .
pathway analysis using predefined canonical pathways also indicated large differences between the subgroups ( table 3 ) .
of these pathways , 43% were also identified by gsea analysis in the independent mainz dataset ( highlighted in bold in table 3 ) .
the above analyses indicate that molecular subtypes significantly account for the metastasis of breast cancer , and that the subtypes are associated with very different biological pathways and somatic mutations .
to identify the metastatic mechanisms that extend beyond the molecular subtypes , we performed pathway and chromosomal aberration analyses within each subtype , comparing tumors from patients that experienced metastasis to tumors from patients that did not experience metastasis within the follow - up period .
the data were again split into a training set including six datasets , and the two most recently published datasets ( mainz and transbig - s ) were kept for validation purposes .
the training set was composed of datasets with different clinical characteristics and treatment statuses of the patients and performed with different microarray platforms .
in contrast , the test sets ( mainz and transbig - s ) contained data from node - negative patients not receiving adjuvant medical treatment ; all analyses were performed with affymetrix hg133a chips .
the gsea meta - analysis in the training set resulted in the identification of nine significant regions and pathways ( table s1 ) . using gsea for the validation of these regions and pathways in the mainz dataset did not result in any significant gene sets , probably due to the limited sample size when comparing tumors with poor and good outcomes within subtypes ( data not shown ) . in order to validate the identified regions and pathways with a different method , we investigated whether the overall expression level in each gene set could be used as a prognostic marker in survival analysis .
this would also allow us to compare the expression of regions or pathways between single tumors from all datasets .
furthermore , utilizing survival information might help to improve the power of the validation , and combining datasets would also increase the power .
the expression level of all genes in each region or pathway identified previously was implemented in the region scores .
this method is different from the gsea meta - analysis described earlier because only genes represented on all platforms were included in the analysis . in 280 basal - like tumors from the training sets , this different approach supported a high level of expression of 5q14 ( fig .
2a ) and a low level of expression of tumor necrosis factor receptor ( tnfr)2 ( fig .
2e ) as predictors of poor outcomes . for erbb2 tumors , the low expression of 5q33 ( borderline significant ; fig . 3a ) and interleukin ( il)-12 ( fig .
3e ) were associated with poor outcomes , which was in agreement with the gsea meta - analysis .
the remaining five pathways and regions identified by the gsea meta - analysis were not significant in the survival analysis ( table s1 ) . for the validation of metastatic gene sets in independent datasets ,
the mainz data set , where 41 basal - like tumors were identified by single - sample prediction , was used for the validation of the metastatic mechanisms of basal - like tumors . however , only 20 erbb2 tumors were identified by single - sample prediction in the mainz dataset . to increase the sample size of erbb2-positive tumors ,
the identification of molecular subtypes failed in this dataset , but erbb2 status was determined from erbb2 expression in both datasets .
the very unbalanced distribution of erbb2 and the coregulation of grb7 located closely to erbb2 supported this method for the classification of erbb2 amplification ( fig .
the disadvantage of high 5q14 expression was validated by the survival analysis in the test set ( fig .
2c ) . to investigate whether this prognostic effect of 5q14 aberration was specific for basal - like tumors
, the prognostic performance was also examined in the remaining tumors not belonging to this subgroup .
2b ) but , surprisingly , a borderline significant opposite effect was found in the test set ( fig .
the prognostic impact of the tnfr2 pathway identified in the gsea meta - analysis and in the survival analysis in the training set ( fig .
2e ) was also supported by a survival analysis in the test set ( fig . 2 g ) . however , this pathway was also significant in nonbasal - like tumors in the training set , but with smaller separation of the groups ( ie , lower hazard ratios [ fig .
2f ] , and the pathway was only borderline significant among the nonbasal - like tumors in the test set [ fig .
2h ] ; in addition , a lower hazard ratio was observed among nonbasal - like tumors when compared to the basal - like tumors ) . for erbb2 tumors , the low expression of 5q33 ( fig .
interestingly , these mechanisms were specific for tumors with high levels of expression of erbb2 ( fig .
3b , d , f , and h ) . to identify single metastasis candidate genes in the two 5q regions
, we compared the expression of metastasizing and non - metastasizing tumors at single gene level . for 5q14 ,
no single gene was strongly and differentially expressed at 5q33 ( data not shown ) .
we have conducted a meta - analysis of the tumor gene expression data and identified chromosomal regions and pathways that were strongly associated with the molecular subtypes of breast cancer .
furthermore , some mechanisms were found to be associated with metastasis within the different subgroups .
our results demonstrate that these mechanisms are reflected in the overall gene expression of the chromosomal region and the pathway gene sets , which is in agreement with our hypotheses .
a major finding is the large number of chromosomal regions and pathways associated with the molecular subtypes that were found .
this is in agreement with the supposedly different cellular origins of basal - like and luminal - like tumors .
the universal nature of the subtypes is supported by several studies9,10 that have used different unsupervised methods to identify the subtypes of breast tumors that resemble the subgroups reported by srlie et al.6 er status , erbb2 status , and proliferation level are believed to be major characteristics of the molecular subtypes .
our results support the crucial impact of the following mechanisms : 17q amplification in erbb2-like tumors ( table 2 ) ; estrogen signaling in luminal cancers ( carm_er and estrogen_signaling ; table 3 ) ; and elevated cell cycle in basal - like and luminal b tumors . by comparing metastasizing and nonmetastasizing tumors , without stratifying for subtypes ,
we have previously identified the chromosomal regions and pathways involved in the metastasis of breast cancer.11,12 the identified gene sets strongly overlap with the gene sets that were differentially expressed between molecular subtypes , indicating that the molecular subtypes account for a majority of the metastasis - associated mechanisms .
this is strongly supported by the very few metastasis - linked mechanisms we have identified within the molecular subgroups ( two regions and two pathways ) , even though the cut - off for the false discovery rate ( fdr ) was 0.05 for intra - subgroup analysis and 0.01 for the between - subgroup analysis .
however , the considerably smaller sample size in the within - group analysis may bias this conclusion .
our within - subgroups analysis identified somatic mutations , which were located at different loci on 5q , and which had opposite prognostic effects : high levels of expression of 5q14 were associated with poor outcomes in basal - like cancer , whereas lower levels of expression of 5q33 were associated with poor outcomes among patients with erbb2-amplified breast tumors .
the dual role of 5q aberrations is supported by a few previous publications that used comparative genome hybridization ; friedrich et al13 reported higher frequency of 5q23 losses among cases with distant metastasis and karlsson et al14 showed that poorer outcomes were associated with 5q31~qter gain for cases with er - negative tumors .
callaghan et al15 reported a higher frequency of allelic imbalance at 5q21 in patients with lymph node metastasis , indirectly supporting the prognostic significance of this region .
however , these studies included few patients and did not subdivide tumors according to basal / erbb2 status , hampering the conclusion for these aberrations that , according to our results , are specific for basal - like and erbb2 tumors , respectively .
our method identifies regions by measuring the differential expression of genes , but it does not ( in principle ) determine whether the dna copy number increases in one outcome group or decreases in the opposite group . however , low expression of 5q14 and its surrounding region characterize basal - like tumors according to our analysis , which compared molecular subtypes ( table 2 ) .
this is also supported by adlade et al,16 who used array comparative genomic hybridization ( acgh ) and reported 5q loss to be frequent in basal - like tumors .
this indicates that the loss of 5q14 is common in basal - like tumors , but that patients with basal - like tumors retaining 5q14 have a worse prognosis .
this might be explained by the presence of a tumor suppressor gene involved in basal - like cancer development , and another gene promoting metastasis both of which were located in the region .
a similar effect has previously been observed for 16q loss in breast cancer.12,17 we pinpointed one gene , hyaluronan , and proteoglycan link protein 1 ( hapln1 ) in the 5q14 region , which had a strong association with the metastasis of basal - like cancers , making this a relevant candidate gene that may be a causal factor in the metastasis of basal - like tumors .
an interaction of hyaluronan and its receptor ( cd44 ) induces signaling events that promote cell growth , migration , and metastasis,18 making genes in this pathway relevant .
erbb2-like tumors are not characterized by 5q aberrations , as compared to other subtypes ( table 2 ) , but our results indicate that low expression of the 5q33 region is associated with poor outcomes .
this may be the result of 5q33 loss in the poor prognosis group , or gain of the region in the good prognosis group .
many pathways have previously been linked to metastasis ; however , investigations of the metastatic pathways within different subtypes of breast cancer are sparse , as will be discussed in the following .
we identified the high expression of the tnfr2 pathway as an indicator of good prognosis in basal - like cancers .
tnfr2 is a receptor with equal affinity for tumor necrosis factor ( tnf)a and tnfb .
both of these are produced by activated lymphocytes and can be toxic to many tumor types .
nevertheless , for micropapillary breast carcinomas , overexpression of tnfr2 has been linked with higher incidence of lymph node metastasis , which may conflict with our results.19 however , our finding that the tnfr2 metagene is associated with survival in basal - like and nonbasal - like cancers in both the training set and test set ( borderline significance for the nonbasal - like tumors in the test set ) strongly indicate the prognostic disadvantage of low tnfr2 pathway expression . according to our results ( table 3 ) , the tnfr2 pathway is not differentially expressed between subgroups .
however , the survival analysis within subtypes show smaller separations of high and low tnfr2 score curves ( ie , lower hazard ratios for nonbasal - like tumors compared to basal - like tumors ; fig .
2 ) , indicating stronger metastatic prevention by the pathway in basal - like tumors .
this is also supported by the gsea meta - analysis that exclusively identified tnfr2 only among basal - like carcinomas . to our knowledge
, no previous studies have described a prognostic influence of tnfr2/tnf signaling among basal - like breast tumors .
the other pathway , il-12 , identified within the erbb2 subgroup is also associated with good outcomes .
this is supported by studies showing that il-12 activates natural killer cells and enhances their ability to kill tumor cell lines that are treated with herceptin20 however , no benefit was observed by adding il-12 to the herceptin treatment of breast cancer patients in a small phase 1 study.21 none of the patients in our analysis received herceptin , indicating that il-12 signaling has antimetastatic potential , independent of herceptin treatment .
both il-12 and tnfr2 signaling are involved in immune activation , suggesting that lymphocyte infiltration is beneficial for patients with er - negative tumors .
for instance , mnard et al22 reported selectively higher survival rates in young breast cancer patients when they had lymphocyte infiltrated tumors , and aaltomaa et al23 described the benefit of lymphocyte infiltration among patients with rapid proliferating tumors .
several recent publications using gene expression datasets have also identified immune - related gene signatures that distinguish groups with different outcomes .
schmidt et al9 used hierarchical clustering to identify a b - cell signature with a prognostic impact among high - proliferating tumors .
teschendorff et al10 focused their analysis on er - negative tumors and used an unsupervised clustering technique to identify five subclusters . among tumors with normal erbb2 status
alexe et al24 also used unsupervised clustering of erbb2-positive tumors and reported a subtype with upregulated lymphocyte infiltration signal and improved survival .
rody et al25 clustered immune - related genes and identified seven different gene clusters that were shown to represent different immune cell types . a t - cell cluster was associated with survival rates among er - negative tumors with and without erbb2 amplification .
these studies have used unsupervised clustering techniques and identified subgroups of patients with different rates of survival .
annotation of genes in these patterns showed an overrepresentation of immune system - related genes .
the overall conclusion from these studies is that immune response prevents metastasis among patients with er - negative tumors with or without erbb2 amplification .
however , different mechanisms in tumor cells and immune cells might result in very different outcomes .
elucidation of the most important mechanisms by the global pathway analysis of outcomes within subtypes has not been performed previously .
al26 examined a limited set of seven gene modules based on key processes in breast cancer .
modules were defined as groups of genes that are correlated with the expression of seven key candidate genes .
one of these key mechanisms , the stat1 immune response module , was associated with the survival of patients with er/erbb2 as well as er/erbb2 + tumors . in a method that differed greatly from this approach
, we analyzed a large collection of knowledge - generated canonical pathways and genome regions to screen for biological processes involved in metastasis within subgroups . in agreement with abovementioned studies
however , in addition to the previous studies , our results not only identified a broad immune response , but they also pointed directly at specific signaling pathways , suggesting key roles of metastasis prevention for these cytokine pathways .
furthermore , the identified mechanisms are specifically associated to certain subtypes , suggesting different metastasis - related mechanisms depending on erbb2 status .
our comparison of molecular subtypes has identified comprehensive differences in pathways and genomic aberrations ( tables 2 and 3 ) .
several of the somatic aberrations are supported by previous studies using acgh to compare relevant groups .
bergamaschi et al27 examined 89 tumors by gene expression profiling to identify four molecular subtypes ; adlade et al16 compared 44 basal and 49 luminal tumors via acgh , and a recent large study28 performed a meta - analysis of 773 tumors .
the results from these studies confirmed many of the regions identified in the present investigation . for basal - like tumors , their results supported the extensive loss of 5q , as well as the loss of 10q23 , 12q22 , 14q21 , 14q23 , 15q22 , and the gain of 3q25 - 27 , 6p21 , 7q32 , 10p15 , 12p13 - 12 , and 21q22 . for luminal a tumors , they also observed 1q41 and 8p22 - 21 gains and a 16q loss . for luminal b tumors , gains of 8q22 - 24 , 20p11 , and 20q13 and a loss of 11q were in agreement with our findings .
finally , 8p22 - 21 loss in erb2-amplified tumors was also seen by the cancer genome atlas network.28 some studies have characterized er - positive and er - negative tumors by acgh ( loo et al29 ) or by conventional cgh.30 although this is a more rough differentiation using only two subgroups , many of their results were in agreement with our findings .
loo et al29 identified a gain of 3q25 - 27 and losses of 3p21 , 4p16 , 5q , 10q25 , 14q32 , 16p13 , and 17p11 in er - negative tumors , which is in agreement with our findings for basal - like tumors . among the er - negative tumors
, they also identified a gain of 17q12 and losses of 8p21 and 17p11 , supporting our findings for erbb2-like tumors . for receptor - positive tumors , a gain of 16p11 - 13 and a loss of 16q13 - 24 was in agreement with our results for luminal tumors .
altogether , many of the regions we have identified are supported by other studies measuring the dna copy number by more direct techniques , as compared to our indirect expression - based method .
this strongly supports our conclusions and also justifies using this approach for mechanisms within subgroups .
this may be explained by our different approach ( including using gene expression data instead of directly measuring dna copy numbers , for example , by acgh ) .
this has allowed us to considerably increase the sample size because only few small acgh datasets with relevant information are available .
we have refined the data included in our analysis to obtain rates of distant metastasis or death from breast cancer as the outcome , but for one dataset ( hu ) , only time to relapse was available .
however , this only introduces a minor bias because the majority of the typically observed relapse events included metastasis , and because only one of the six training datasets had this outcome definition .
another potential bias is the inclusion of patients that have received adjuvant treatment , which will bias the conclusion about metastasis biology because some patients will change their outcome status because of the treatment .
however , the fraction of patients that respond to treatment and experience good outcomes as a consequence of treatment will typically be below 10% ( adjuvant online , http://www.adjuvantonline.com ) , meaning that this will also be a minor bias .
a varying fraction of the tumors in the individual datasets have disseminated cells to the lymph nodes .
the classification of lymph node - positive patients without recurrence as nonmetastasis may be controversial .
this may bias the results towards the metastatic mechanisms following primary spread to the lymph node .
we accepted these biases in the study design to obtain a broad representation of tumor subtypes ; the exclusion of lymph node - positive and treated patients would reduce the number of erbb2-positive and basal - like tumors markedly , resulting in a lack of power in these groups . combining the datasets by standardization , as we have done for the survival analysis , assumes that there are comparable characteristics in the included datasets .
however , this results in a more conservative test of gene sets in the survival analysis .
this may explain why only four of the nine gene sets identified in the meta - analysis were significant in the survival analysis of the training set .
furthermore , these four gene sets are all significant in the test set , even though the sample size is considerably smaller .
this is in agreement with the better separation of survival curves and the higher hazard ratios in the test set ( figs .
this may be explained by the very homogeneous test set , which included only node - negative samples from untreated patients performed with the same microarray platform .
by performing a pathway meta - analysis , we have demonstrated that the previously described molecular subtypes account for the majority of metastatic mechanisms in breast cancer . however , by performing the analysis within these subgroups we have identified two different regions on chromosome 5q that impact metastasis among patients with basal - like and erbb2-amplified tumors , respectively .
we suggest one gene , hapln1 at 5q14 , which may potentially be a metastasis gene for basal - like tumors .
the impact of these regions needs to be validated in future large studies using more direct measures of the dna copy number ( for example , acgh ) .
furthermore , the role of hapln1 and other potential driver genes needs to be addressed in further functional studies .
we have also identified two pathways , tnfr2 and il-12 , which are involved in the metastasis of basal - like and erbb2-amplified breast cancer , respectively .
the molecular subgroups already form the basis for different treatments ( such as trastuzumab , which is used against erbb2-amplified tumors ) ; however , future treatment protocols will aim to establish even more individualized strategies .
our study has identified genomic regions , single genes , and pathways that may be potential targets for future drug design for certain subgroups of patients .
eight publicly available datasets examining gene expression at the ribonucleic acid ( rna ) level in primary tumors were included in the analysis .
these studies were performed with different platforms , different populations , and so on , as depicted in table 1 .
the outcome used is distant metastasis or death from breast cancer , which is nearly always caused by distant metastasis .
however , nonmetastatic relapse constitutes a minority of clinical cohorts . for the transbig dataset ,
samples from sweden were removed to avoid sample overlap with the uppsala and stockholm datasets .
the normalizations performed in the studies were retained because the authors found these methods optimal for the datasets , and because the pathway analysis was performed separately in each dataset . to identify the molecular subtypes ,
a single sample predictor was applied as described.8 prior to this , data were preprocessed within each dataset as follows .
first , probe sets with maximal expression values were selected whenever more probe sets recognized the same gene using the collapse to gene symbol function in gsea .
data were then column standardized for each sample by subtracting the mean expression of all genes in that sample from each genes expression value , and dividing by the standard deviation for that sample .
next , row median centering was performed within each dataset by subtracting the median expression for a gene across samples from all expression values for that gene .
pearson s correlation coefficient between each sample and each of the five centroids ( defined by hu et al8 ) were calculated , and the sample was assigned the subtype with highest correlation coefficient . if the correlation coefficient was below 0.1 for any of the centroids , the sample was not assigned a subtype . using this method ,
the samples were forced into the centroids defined by hu et al.8 to analyze genome regions and pathways that were differentially expressed between the subtypes , we compared one subtype at a time with all other tumors . only the seven datasets with successfully identified molecular subtypes
these pathway gene sets are adopted from kegg ( www.genome.ad.jp/kegg ) , genmapp ( http://www.genmapp.org ) , biocarta ( www.biocarta.com ) , and so on , and gathered in the molecular signature database implemented in gsea . furthermore
, we applied the analysis to positional gene sets delimited by cytobands downloaded from the molecular signature database ( http://www.broadinstitute.org/gsea/msigdb/index.jsp ) .
the gsea program ranks genes according to a signal - to - noise value : where x is the mean and s is the standard deviation for the two classes a and b ( one subtype and the remaining tumors , respectively ) .
when several probes recognized the same gene , the probe with the maximum expression value was extracted using the collapse to gene set function .
the output from gsea is an enrichment score , describing the imbalance in the distribution of ranks of gene expression in each gene set between the compared groups .
then , the gene sets were ranked according to the normalized enrichment score , with gene sets upregulated in the subgroup of interest on the top and downregulated gene sets at the bottom .
the ranked lists of gene sets for each analysis generated by gsea from the seven datasets were integrated so that only gene sets represented in the output from all datasets were included .
the initial 639 pathway gene sets were reduced to 347 gene sets passing the threshold ( at least 15 genes in gene sets ) in all datasets .
for the analysis of chromosomal regions , 386 chromosomal gene sets from the molecular signature database were reduced to 188 gene sets . for each dataset , individual gene sets were assigned a ranking value from 1 to the maximum number of gene sets , according to the ranking performed by gsea .
the mean ranking value for each gene set was calculated across the datasets and , finally , the gene sets were ranked according to this value .
our null hypothesis is that the expressions of genes in the pathway gene sets are unrelated to the molecular subtype .
this means that the ranking value for a given gene set in a given dataset is expected to be a random value between 1 and the maximum number of gene sets analyzed . to simulate the distribution of the mean
ranking values across the six test datasets assuming the null hypothesis , a random drawing of the six ranking values was performed 106 times , and the mean value was calculated each time . a null distribution of the mean ranking values was generated from these results .
to test the significance for a given gene set , the observed mean ranking value was compared to the null distribution .
to fulfill the null hypothesis , an observed mean ranking value should be within 95% of the interval of the null distribution .
correction for multiple testing was performed by calculating the fdr , controlling the expected proportion of incorrectly rejected null hypotheses .
validation of the identified gene sets in the test set ( mainz data set ) was performed by gsea analysis using a nominal p - value . to identify the chromosomal regions and pathways involved in metastasis within the molecular subtypes , gsea analysis was performed as described above .
once again , genes were ranked according to the signal - to - noise value : except that the compared groups were now tumors from patients that developed metastasis ( class a ) and tumors from patients that did not develop metastasis ( class b ) .
this analysis was performed within each subtype in each dataset , and the meta - analysis was applied to identify gene sets concordantly deregulated in metastasizing tumors across datasets for each molecular subtype .
again , 347 pathway gene sets and 188 positional gene sets passed the inclusion threshold .
the above gsea analyses were performed independently in each data set . to get a measure of the overall expression level for all genes in an identified region or pathway for each tumor and in order to be able to compare these values across datasets we calculated the region scores as follows .
first , probe sets with maximal expression values were selected whenever additional probe sets recognized the same gene using the collapse to gene symbol function in gsea .
then , probe sets recognizing the same genes from the three different platforms were extracted using the gene symbol as an identifier , resulting in 6,654 annotated genes .
data were then row standardized within each dataset by subtracting the mean expression from each expression value for each gene , and dividing by the standard deviation for that gene .
finally , the standardized datasets were combined to a training set consisting of 1,239 tumors and a test set containing 347 tumors .
the combination of row standardized datasets assumes that the sample characteristics ( such as the clinical parameters ) are comparable between the datasets .
this introduced a bias in the training set because the dataset contained a variable fraction of lymph node - positive samples and patients receiving adjuvant treatment .
however , we retained the node - positive samples to obtain a reasonable number of erbb2 and basal - like tumors .
patients with these tumors are more likely to have lymph node metastasis and are more likely to receive adjuvant medical treatment . for the chromosomal regions and pathways , we calculated a score for each sample as the mean standardized expression values for all genes in the gene set .
the score is thus a continuous variable representing the overall expression level in the region or pathway .
the region score is related to the dna copy number . however , using gene expression data alone , it is not possible to define a cut - off region in the score between different dna copy numbers .
meyer plots and a log - rank test using surv and pchisq packages , respectively , in r. a high score ( region score or pathway score ) subset was defined as the third of samples having the highest score , and a low score subset included the third with the lowest score values .
hazard ratios were calculated by fitting a cox model to the data , assuming a constant hazard ratio over time .
the p - values were calculated using a log - rank test , with the null hypothesis postulating that there were no differences in survival between the groups .
validation of prognostic gene sets was performed in the latest published datasets ( mainz , transbig - s ) .
the patients in these datasets are all node - negative and have not received adjuvant medical treatment ; both studies were performed with affymetrix hg133a chips minimizing bias from the treatment effect , clinical differences , and platform differences . for the validation of metastatic mechanisms in basal - like tumors ,
transbig - s data where the identification of molecular subtypes failed were excluded for that analysis . for erbb2-amplified tumors ,
the number in the mainz dataset was too small , and the transbig - s dataset was included , resulting in 347 samples .
instead of using single - sample prediction , we classified tumor erbb2 status as 20% of tumors with the highest erbb2 expression .
the cut - off was set to 20% of tumors , because this resembles the frequency of erbb2 amplification in breast cancer .
the region and pathway scores were calculated as described for the training set described above , and once again , the extreme groups ( one - third of the highest scores and one - third of the lowest scores ) were compared by survival analysis .
eight publicly available datasets examining gene expression at the ribonucleic acid ( rna ) level in primary tumors were included in the analysis .
these studies were performed with different platforms , different populations , and so on , as depicted in table 1 .
the outcome used is distant metastasis or death from breast cancer , which is nearly always caused by distant metastasis .
however , nonmetastatic relapse constitutes a minority of clinical cohorts . for the transbig dataset ,
samples from sweden were removed to avoid sample overlap with the uppsala and stockholm datasets .
the normalizations performed in the studies were retained because the authors found these methods optimal for the datasets , and because the pathway analysis was performed separately in each dataset .
to identify the molecular subtypes , a single sample predictor was applied as described.8 prior to this , data were preprocessed within each dataset as follows .
first , probe sets with maximal expression values were selected whenever more probe sets recognized the same gene using the collapse to gene symbol function in gsea .
data were then column standardized for each sample by subtracting the mean expression of all genes in that sample from each genes expression value , and dividing by the standard deviation for that sample .
next , row median centering was performed within each dataset by subtracting the median expression for a gene across samples from all expression values for that gene .
pearson s correlation coefficient between each sample and each of the five centroids ( defined by hu et al8 ) were calculated , and the sample was assigned the subtype with highest correlation coefficient . if the correlation coefficient was below 0.1 for any of the centroids , the sample was not assigned a subtype . using this method ,
to analyze genome regions and pathways that were differentially expressed between the subtypes , we compared one subtype at a time with all other tumors
. only the seven datasets with successfully identified molecular subtypes were included in the analysis .
these pathway gene sets are adopted from kegg ( www.genome.ad.jp/kegg ) , genmapp ( http://www.genmapp.org ) , biocarta ( www.biocarta.com ) , and so on , and gathered in the molecular signature database implemented in gsea .
furthermore , we applied the analysis to positional gene sets delimited by cytobands downloaded from the molecular signature database ( http://www.broadinstitute.org/gsea/msigdb/index.jsp ) .
the gsea program ranks genes according to a signal - to - noise value : where x is the mean and s is the standard deviation for the two classes a and b ( one subtype and the remaining tumors , respectively ) .
when several probes recognized the same gene , the probe with the maximum expression value was extracted using the collapse to gene set function .
the output from gsea is an enrichment score , describing the imbalance in the distribution of ranks of gene expression in each gene set between the compared groups .
then , the gene sets were ranked according to the normalized enrichment score , with gene sets upregulated in the subgroup of interest on the top and downregulated gene sets at the bottom .
the ranked lists of gene sets for each analysis generated by gsea from the seven datasets were integrated so that only gene sets represented in the output from all datasets were included .
the initial 639 pathway gene sets were reduced to 347 gene sets passing the threshold ( at least 15 genes in gene sets ) in all datasets . for the analysis of chromosomal regions ,
386 chromosomal gene sets from the molecular signature database were reduced to 188 gene sets . for each dataset , individual gene sets were assigned a ranking value from 1 to the maximum number of gene sets , according to the ranking performed by gsea .
the mean ranking value for each gene set was calculated across the datasets and , finally , the gene sets were ranked according to this value .
our null hypothesis is that the expressions of genes in the pathway gene sets are unrelated to the molecular subtype .
this means that the ranking value for a given gene set in a given dataset is expected to be a random value between 1 and the maximum number of gene sets analyzed . to simulate the distribution of the mean ranking values across the six test datasets assuming the null hypothesis ,
a random drawing of the six ranking values was performed 106 times , and the mean value was calculated each time . a null distribution of the mean ranking values was generated from these results .
to test the significance for a given gene set , the observed mean ranking value was compared to the null distribution . to fulfill the null hypothesis , an observed mean ranking value should be within 95% of the interval of the null distribution .
correction for multiple testing was performed by calculating the fdr , controlling the expected proportion of incorrectly rejected null hypotheses .
validation of the identified gene sets in the test set ( mainz data set ) was performed by gsea analysis using a nominal p - value .
to identify the chromosomal regions and pathways involved in metastasis within the molecular subtypes , gsea analysis was performed as described above . once again
, genes were ranked according to the signal - to - noise value : except that the compared groups were now tumors from patients that developed metastasis ( class a ) and tumors from patients that did not develop metastasis ( class b ) . this analysis was performed within each subtype in each dataset , and the meta - analysis was applied to identify gene sets concordantly deregulated in metastasizing tumors across datasets for each molecular subtype . again , 347 pathway gene sets and 188 positional gene sets passed the inclusion threshold .
the above gsea analyses were performed independently in each data set . to get a measure of the overall expression level for all genes in an identified region or pathway for each tumor and in order to be able to compare these values across datasets we calculated the region scores as follows .
first , probe sets with maximal expression values were selected whenever additional probe sets recognized the same gene using the collapse to gene symbol function in gsea .
then , probe sets recognizing the same genes from the three different platforms were extracted using the gene symbol as an identifier , resulting in 6,654 annotated genes .
data were then row standardized within each dataset by subtracting the mean expression from each expression value for each gene , and dividing by the standard deviation for that gene .
finally , the standardized datasets were combined to a training set consisting of 1,239 tumors and a test set containing 347 tumors .
the combination of row standardized datasets assumes that the sample characteristics ( such as the clinical parameters ) are comparable between the datasets .
this introduced a bias in the training set because the dataset contained a variable fraction of lymph node - positive samples and patients receiving adjuvant treatment .
however , we retained the node - positive samples to obtain a reasonable number of erbb2 and basal - like tumors .
patients with these tumors are more likely to have lymph node metastasis and are more likely to receive adjuvant medical treatment . for the chromosomal regions and pathways , we calculated a score for each sample as the mean standardized expression values for all genes in the gene set .
the score is thus a continuous variable representing the overall expression level in the region or pathway .
the region score is related to the dna copy number . however , using gene expression data alone , it is not possible to define a cut - off region in the score between different dna copy numbers .
meyer plots and a log - rank test using surv and pchisq packages , respectively , in r. a high score ( region score or pathway score ) subset was defined as the third of samples having the highest score , and a low score subset included the third with the lowest score values .
hazard ratios were calculated by fitting a cox model to the data , assuming a constant hazard ratio over time .
the p - values were calculated using a log - rank test , with the null hypothesis postulating that there were no differences in survival between the groups .
validation of prognostic gene sets was performed in the latest published datasets ( mainz , transbig - s ) .
the patients in these datasets are all node - negative and have not received adjuvant medical treatment ; both studies were performed with affymetrix hg133a chips minimizing bias from the treatment effect , clinical differences , and platform differences . for the validation of metastatic mechanisms in basal - like tumors , 41 basal - like tumors from the mainz data were used .
transbig - s data where the identification of molecular subtypes failed were excluded for that analysis . for erbb2-amplified tumors ,
the number in the mainz dataset was too small , and the transbig - s dataset was included , resulting in 347 samples .
instead of using single - sample prediction , we classified tumor erbb2 status as 20% of tumors with the highest erbb2 expression .
the cut - off was set to 20% of tumors , because this resembles the frequency of erbb2 amplification in breast cancer .
the region and pathway scores were calculated as described for the training set described above , and once again , the extreme groups ( one - third of the highest scores and one - third of the lowest scores ) were compared by survival analysis .
notes : for validation of metastatic mechanisms in erbb2 positive tumors , a test set including transbic - s and mainz was used resulting in a total of 347 samples . instead of using single sample prediction
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### Summary:
: backgroundbreast tumors have been described by molecular subtypes characterized by pervasively different gene expression profiles .
the subtypes are associated with different clinical parameters and origin of precursor cells .
however , the biological pathways and chromosomal aberrations that differ between the subgroups are less well characterized .
the molecular subtypes are associated with different risk of metastatic recurrence of the disease .
nevertheless , the performance of these overall patterns to predict outcome is far from optimal , suggesting that biological mechanisms that extend beyond the subgroups impact metastasis.resultswe have scrutinized publicly available gene expression datasets and identified molecular subtypes in 1,394 breast tumors with outcome data . by analysis of chromosomal regions and pathways using gene set enrichment analysis followed by a meta - analysis , we identified comprehensive mechanistic differences between the subgroups . furthermore , the same approach was used to investigate mechanisms related to metastasis within the subgroups .
a striking finding is that the molecular subtypes account for the majority of biological mechanisms associated with metastasis .
however , some mechanisms , aside from the subtypes , were identified in a training set of 1,239 tumors and confirmed by survival analysis in two independent validation datasets from the same type of platform and consisting of very comparable node - negative patients that did not receive adjuvant medical therapy .
the results show that high expression of 5q14 genes and low levels of tnfr2 pathway genes were associated with poor survival in basal - like cancers .
furthermore , low expression of 5q33 genes and interleukin-12 pathway genes were associated with poor outcome exclusively in erbb2-like tumors.conclusionthe identified regions , genes , and pathways may be potential drug targets in future individualized treatment strategies .
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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:
: hemispherectomy is commonly performed for the surgical management of pediatric patients with medically refractory epilepsy .
specific types of hemispherectomy , such as anatomic and functional hemispherectomy , involve removal of diverse areas of the hemisphere .
in particular , anatomic hemispherectomy involves complete removal of the cortex from the hemisphere in which the seizures originate .
many studies indicate that reorganization , particularly in the sensorimotor cortex , occurs in the remaining hemisphere , leading to recovery of function , depending on how early during postnatal development hemispherectomy is performed .
although subcortical structures are left intact in hemispherectomy , degenerative changes can take place and remain long after surgery . in 1966 ,
oppenheimer and griffith published an autopsy report of a patient with hemispherectomy , noting degeneration of the midbrain , pons , and other structures ipsilateral to the resected hemisphere .
a recent magnetic resonance imaging ( mri ) study reported similar findings with respect to degeneration and reorganization of the sensorimotor tracts ( pyramidal tract and medial lemniscus ) after hemispherectomy .
the subcortical auditory pathway , from the acoustic nerve to the lateral geniculate body , ascending through the pons , midbrain , metathalamus , and internal capsule , includes crossed and uncrossed tracts .
similar to the pyramidal tract and medial lemniscus , the auditory pathway might also reorganize in the asymmetric brainstem and remain long after hemispherectomy .
one of the most common tests used to evaluate auditory function in the brainstem is measurement of the auditory brainstem response ( abr ) .
the abr has been used widely in clinical neurology and is of great value in predicting outcome in patients with severe brain injury , in intraoperative monitoring of cranial nerves , and in evaluating neurologic function .
abr includes five major waves ( i v ) that occur within 10 ms after stimulation to one ear . among these , waves i , iii , and v
wave i is generated in the peripheral auditory pathway , and waves iii and v are believed to arise in the cochlear nuclei and lateral lemniscus , respectively .
the latency of abr waves can provide information regarding change and reorganization in the brainstem auditory pathway .
the aim of the present study was to use mri to confirm ipsilateral subcortical structural degeneration in patients after long - term hemispherectomy and to assess the bilateral abr and determine if abr results can be used to identify reorganization of the auditory pathway .
patients were included if they had received hemispherectomy more than 10 years ago and without any relapse of epilepsy regardless of their sex and age , had normal primary neurological and cognitive function ( p300 ) , and preserved sensory and motor function .
eight adult patients with long - term hemispherectomy ( average , 20.5 years ; range , 1824 years ) were tested .
the patients included seven men and one woman ( 27 to 40 years of age at the time of study ) .
etiology included intracranial hemorrhage , neonatal jaundice , tuberculous meningitis , hyperpyrexia , and unknown .
preoperative neurologic examinations ( computed tomography and electroencephalography ) showed various abnormalities as described in a previous study .
three patients underwent right - sided operation , and five underwent left - sided operation .
cortical gray and white matter were removed , and the septum pellucidum was left integrated .
a muscle flap was placed into the foramen of monro and sutured to the cerebral falx to chronically separate the subdural space from the cerebral ventricle [ 1113 ] .
all patients showed contralateral hemiparesis postoperatively but were able to walk unaided and had functional basic social cognitive characteristics to cope with daily life .
seizures disappeared completely after surgery , with no signs of delayed complications , such as hydrocephalus or superficial cerebral hemosiderosis .
the pure - tone threshold in these patients was essentially normal ( 25 db ) or very mildly impaired ( 30 db ) .
a total of 10 age - matched , neurologically intact , control subjects without neurologic disease , including seven women and three men , were also assessed .
the pure - tone threshold of the control subjects was essentially normal ( 25 db ) .
abr measurements were carried out in a low - lit and sound - insulated room with electrical isolation .
the temperature was maintained at ~20c , and relative humidity was maintained within 30% to 75% .
a medelec synergy advanced clinical 10-channel tower iom ( oxford instruments , abingdon , oxfordshire , uk ) system was utilized .
the abr was elicited with an alternating rarefaction and condensation click stimulus delivered via an unshielded headphone ( synergy n&t series ; cardinal health inc . ,
madison , wi , usa ) , with 0.1 ms clicks at a rate of 9.9 click / s .
white - noise masking ( 40 db nhl ) was performed in the contralateral ear .
the abr was recorded with a bilateral recording system consisting of an active needle electrode attached to the vertex ( cz ) and two reference noninverting electrodes attached to the ipsilateral ( mi ) and contralateral ( mc ) mastoid process , with reference to the recognized 1020 standard system of the international federation of eeg societies .
electrode impedance was < 5 k. the filter bandwidth used for recording was 1003000 hz .
each test was carried out 2 or 3 times to ensure that the results were reproducible .
results were recorded both ipsilateral and contralateral to stimulation ; for example , after stimulation of the left ear , cz - mi and cz - mc were recorded concurrently .
the side which received the click stimulation directly is defined as the stimulation side , while the side which the recording electrode is attached to is defined as the recording side . in the control subjects , we used left / right ( l / r ) side to indicate the two sides ; while in the patients , we defined the side of hemispherectomy as the surgical side ( s ) and the contralateral side as the nonsurgical side ( n ) .
analyzed abr waveforms included the absolute latency of waves i ( l - i ) , iii ( l - iii ) , and v ( l - v ) and the interpeak latency ( ipl ) of waves i iii ( ipl i iii ) , i
the amplitudes of wave iii ( a - iii ) and wave v ( a - v ) were also analyzed .
relevant abnormalities were defined as prolonged absolute latency or interpeak latency longer than 0.2 ms .
mri was performed for all eight patients with a sigma 3.0 t mri system ( 3.0 tesla ; ge healthcare , pewaukee , wi , usa ) .
statistical analyses were performed with sas statistical software , version 9.2 ( sas institute , inc . ,
repeated measures analysis of variance ( anova ) with bonferroni 's post hoc tests were used to compare stimulation types and recording side ( comparison of 3 or more groups ) .
a paired t - test was also used to compare stimulation types and recording side ( comparison of two groups ) .
comparisons between patients and control subjects were analyzed by independent two - sample t - test .
mri results for all eight hemispherectomized patients showed that the hemisphere on the surgical side was totally resected .
in addition , atrophy of the thalamus , basal nuclei , and brainstem ( including the midbrain and pons ) ipsilateral to hemispherectomy was obvious .
the medulla oblongata and cervical cord showed no significant differences compared to the contralateral side ( representative results for a single patient are shown in figure 1 ) .
comparisons of absolute latency , interpeak latency , and wave amplitude for the 10 control subjects are summarized in table 2 .
there were no statistically significant differences observed in the absolute latencies of waves i and iii .
however , the absolute latencies of wave v recorded on the contralateral sides ( l / r , r / l ) were longer than that on the ipsilateral side for the r / r group ( 5.67 ms and 5.66 ms versus 5.55 ms , resp . ;
p 0.007 for post hoc test ) . with respect to interpeak latency , ipl iii v waves recorded on the contralateral sides ( l / r , r
/ l ) were longer than that recorded on the ipsilateral side for the r / r group ( 1.96 ms and 1.96 ms versus 1.82 ms , resp . ; p 0.008 for post hoc test ) . with respect to wave iii amplitude ( a - iii ) , waves recorded on the ipsilateral sides ( l / l , r / r ) were larger than those on the contralateral sides ( l / r , r / l ) ( 0.33 v and 0.30 v versus 0.17 v and 0.17 v , resp . ;
p 0.003 for post hoc test ) . for wave v amplitude ( a - v ) , the amplitude recorded on the ipsilateral side for the r / r group was larger than that on the contralateral side for the l / r group ( 0.52 v versus 0.31 v , resp . ; p 0.003 ) . comparisons of absolute latency , interpeak latency , and wave amplitude for the eight hemispherectomized patients are summarized in table 3 and the abr waveforms for all eight patients are shown in figure 2 .
no significant differences in absolute latency were observed for l - i or l - iii .
however , the absolute latencies of wave l - v for the n / n and n / s groups were significantly longer than those for the s / s and s / n groups ( 5.90 ms and 5.97 ms versus 5.56 ms and 5.61 ms , resp . ; p 0.005 for post hoc test ) . with respect
iii for the n / n group were significantly longer than those for the s / s group ( ipl i v : 4.29 ms versus 3.96 ms , resp . ; p = 0.004 ; ipl i iii : 2.30 ms versus 2.16 ms , resp . ;
v wave for the n / s group was significantly longer than that for the s / s group ( 2.15 ms versus 1.80 ms , resp . ; p < 0.001 ) .
no significant differences were observed for a - iii or a - v . given the lack of significant difference between l / l and r / r sides with respect to absolute latency , interpeak latency , and amplitude in the control subjects , values for the ipsilateral sides ( l / l , r / r ) were averaged in the control subjects and used to compare with values for the hemispherectomized patients ( table 4 ) .
no significant differences in absolute latency between patients and control subjects were observed for l - i . for the n / n patient group , l - iii and l - v latencies were significantly longer than those for control subjects ( l - iii : 3.91 ms versus 3.72 ms , resp . ;
p 0.002 ; l - v : 5.90 ms versus 5.56 ms , resp . ;
no significant differences in l - iii or l - v were observed for the s / s patient group compared to control subjects .
iii for the n / n patient group compared to control subjects ( ipl i v : 4.29 ms versus 3.96 ms , resp . ; p 0.013 ; ipl i iii : 2.30 ms versus 2.13 ms , resp .
significantly lower a - iii was observed in the n / n and s / s patient groups compared to control subjects ( 0.13 v and 0.15 v versus 0.32 v , resp .
no significant differences in a - v were observed between patients and control subjects . given the lack of significant difference between l / r and r / l with respect to absolute latency , interpeak latency , and amplitude in the control subjects , values for the contralateral sides ( l / r , r / l ) in the control subjects were averaged and used to compare with values for the hemispherectomized patients ( table 5 ) .
no significant differences in absolute latency between patients and control subjects were observed for l - iii . for the n / s patient group , l - v was significantly longer than that for the control group ( 5.97 ms versus 5.67 ms , resp . ; p 0.004 ) .
no significant differences were observed in l - iii or l - v for the s / n patient group compared to control subjects .
v in the n / s patient group ( 2.15 ms versus 1.96 ms , resp . ;
no significant differences in a - iii or a - v were observed between patients and control subjects .
the aim of the present study was to measure abr in patients with long - term hemispherectomy and to determine if abr can be used to identify reorganization of the auditory pathway in such patients .
results showed that whereas all eight of the hemispherectomized patients showed ipsilateral subcortical structural degeneration , as assessed by mri , they nonetheless showed no significant differences in bilateral recording ( n / n versus
n / s and s / s versus s / n ) abr wave latencies or amplitudes . however , nonsurgical - side stimulation ( n / n , n / s ) elicited significantly longer wave v latencies compared to surgical - side stimulation ( s / s , s / n ) . compared to neurologically intact control subjects , hemispherectomized patients showed significantly longer wave iii and wave v latencies elicited by nonsurgical - side stimulation ( n / n , n / s ) .
no significant differences were seen for wave iii and wave v latencies elicited by surgical - side stimulation ( s / s , s / n ) . after long - term hemispherectomy , degeneration of subcortical structures and a large cranial cavity are common phenomena [ 5 , 6 ] . however , given that bilateral wave latencies ( n / n versus
n / s and s / s versus s / n ) in response to monaural stimulation were not significantly different in the presence of these structural changes in our patients indicates that based on the volume conductor effect , brain volume was not a major factor in the conduction of auditory evoked potentials .
therefore , significant differences in abr in the hemispherectomized patients are thought to be due to reorganization of the brainstem auditory pathways ( crossed and uncrossed pathways ) .
distortion of auditory pathways and/or demyelination of contralateral pathways may be part of the explanation for our findings .
contralateral recording is not thought to contribute significantly to lesion detection ; the main value is to aid in the recognition of certain waves when they are not clearly visible in the ipsilateral recording .
hatanaka and associates suggested that contralateral recordings can be a useful measure of developmental changes in the infant auditory pathway .
our present results showed no significant differences in abr wave latencies elicited by ipsilateral stimulation ( l / l , r / r ) in control subjects .
however , wave v latencies showed slight but statistically significant increases in response to contralateral stimulation ( l / r , r / l ) .
in addition , wave iii showed significantly smaller amplitudes in response to contralateral ( l / r , r / l ) versus ipsilateral ( l / l , r / r ) stimulation in control subjects .
detailed information regarding sites of generation of abr responses would further enhance the clinical applicability and relevance of abr . among the three major waves ( waves i , iii , and v ) , wave i has been demonstrated to originate from the ipsilateral auditory nerve or at its point of entry to the brainstem .
mller and jannetta suggested that wave iii is associated with activity in or near the ipsilateral cochlear nucleus .
wave iii is also associated with activity of the superior olivary complex [ 9 , 26 ] .
wave v has been attributed to activity in the contralateral lateral lemniscus , which terminates in the inferior colliculus [ 9 , 24 , 27 ] .
contrary to the point of view of mller and associates that wave iii originates ipsilaterally and wave v originates contralaterally , studies of patients with brainstem lesions suggest that the ipsilateral auditory pathway might be the main generator of wave v .
casali and dos santos reviewed the literature and stated that both waves iii and v receive contralateral inputs probably in greater number than ipsilateral inputs .
with respect to the hemispherectomized patients in our study , we suggest that the resected hemisphere resulted in retrodegeneration of the ipsilateral subcortical nucleus in the brainstem auditory pathway .
degeneration of an auditory nucleus might result in prolongation of abr latency in response to nonsurgical - side stimulation ( n / n , n / s ) compared to control subjects .
however , it has been reported that the contralateral pathway has a marked advantage over the ipsilateral pathway [ 4 , 31 , 32 ] .
the longer latencies of waves iii and v elicited by stimulation of the nonsurgical side in patients indicate that the contralateral brainstem contributes to waves iii and v .
prolongation of wave v would be related to the marked degeneration of the superior pons and that of wave iii would be related to degeneration of the inferior pons .
although the auditory function of patients in our study was not severely affected by hemispherectomy , there is a report of impaired sound localization in hemispherectomized patients .
those authors suggest that a single hemisphere and/or residual ( subcortical ) structures can not analyze sound localization as efficiently as two fully functional hemispheres .
in addition , de bode and associates tested dichotic listening in hemispherectomized patients and suggested that language function is affected by the absence of a hemisphere , citing specialization of the cortical hemispheres for language . both reports suggested that after hemispherectomy , function of the crossed auditory pathway performs better than that of the uncrossed pathway ; the ear ipsilateral to hemispherectomy shows better function than the ear contralateral to hemispherectomy .
these studies are similar to our results in that the abr latencies elicited from the surgical side ( s / s , s / n ) were shorter than those elicited from the nonsurgical side ( n / n , n / s ) . both of the above reports [ 31 , 32 ] focused on the hemispheric cortex , ignoring subcortical auditory structures such as the inferior colliculus and lateral lemniscus , which also provide a coding mechanism for locating sources in space .
the superior olivary complex of the mammalian brainstem is also involved in computing sound localization .
our present observation of significant differences in bilateral abr wave latencies in hemispherectomized patients indicates that the impaired auditory function occurs , at least in part , at the subcortical level .
it is important to understand the implications of significant differences in bilateral abr wave latency in hemispherectomized patients .
an auditory functional mri study on hemispherectomized subjects demonstrated significantly decreased activity in the intact hemisphere in response to monaural stimulation of surgical side and increased activity in response to stimulation of normal side .
studies have also indicated that after hemispherectomy or diffuse cortical injury , crossed and uncrossed auditory pathways undergo functional reorganization [ 31 , 32 , 35 ] . in the present study , even though significant differences in bilateral abr were observed in hemispherectomized patients , all of the waveforms could be elicited , similar to the control subjects .
thus , we believe that auditory function of the brainstem remains normal rather than being impaired by hemispherectomy .
in addition , differences in bilateral abr latency in hemispherectomized patients indicate that reorganization may take place in the brainstem auditory pathways .
our results also indicate that the prolonged latency of wave v was greater than that of wave iii and thus suggest that reorganization of the subcortical auditory pathways may take place mainly in the lateral lemniscus , between the level of the superior olivary complex and the inferior colliculus .
we suggest that in the event of severe injury to the cortex , auditory function of the subcortical crossed pathway might be impaired and therefore reinforced by the uncrossed pathway .
further studies combining high - resolution neuroimaging and animal histology are needed to elucidate the exact nature of auditory pathway reorganization after hemispherectomy .
potential limitations of the present study include the fact that whereas all but one of the hemispherectomized patients were male , most of the control subjects ( 7/10 ) were female .
there is a report suggesting that abr latency and amplitude can differ according to sex ; however , other research indicates that this difference might be small enough to be nonsignificant . in conclusion ,
the use of bilateral abr measurements in response to monaural stimulation was able to identify prolonged latencies in wave iii , thought to arise in the cochlear nuclei , and wave v , thought to arise in the lateral lemniscus , in response to nonsurgical - side ( i.e. , contralateral to hemispherectomy ) stimulation versus surgical - side ( ipsilateral to hemispherectomy ) stimulation in hemispherectomized patients compared to control subjects .
the use of abr in this clinical situation may be helpful in further elucidating subcortical reorganization of the auditory pathways .
our present results indicate that ( 1 ) differences in bilateral abr latency elicited from monaural stimulation are due mainly to bilateral brainstem auditory pathway activity rather than to changes in brain volume ; ( 2 ) abr waves iii and v originate mainly in the contralateral brainstem ; and ( 3 ) subcortical auditory structures are involved in the functional reorganization of the auditory pathways after hemispherectomy .
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### Summary:
: background .
cortical hemispherectomy leads to degeneration of ipsilateral subcortical structures , which can be observed long term after the operation .
therefore , reorganization of the brainstem auditory pathway might occur .
the aim of this study was to assess reorganization of brainstem auditory pathways by measuring the auditory brainstem response ( abr ) in long - term hemispherectomized patients .
methods .
we performed bilateral monaural stimulation and measured bilateral abr in 8 patients ~20 years after hemispherectomy and 10 control subjects .
magnetic resonance imaging ( mri ) was performed in patients to assess structural degeneration .
results .
all patients showed degenerated ipsilateral brainstem structures by mri but no significant differences in bilateral recording abr wave latencies . however , nonsurgical - side stimulation elicited significantly longer wave v latencies compared to surgical - side stimulation .
differences in bilateral abr were observed between hemispherectomized patients and control subjects .
waves iii and v latencies elicited by nonsurgical - side stimulation were significantly longer than those in control subjects ; surgical - side stimulation showed no significant differences .
conclusions .
( 1 ) differences in abr latency elicited by unilateral stimulation are predominantly due to bilateral brainstem auditory pathway activity rather than to changes in brainstem volume ; ( 2 ) abr waves iii and v originate predominantly in the contralateral brainstem ; and ( 3 ) subcortical auditory pathways appear to reorganize after long term hemispherectomy .
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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 scientific treatment of sustainability transitions or , for that matter , any transition as distinct from just change
requires a certain conceptual clarity and self - discipline : clarity in defining the unit of analysis , in how to distinguish different phases or stages , and in how to conceptualize the directionality of time . what is an adequate unit of analysis ?
the system should be self organizing and sufficiently complex to maintain itself under changing conditions .
for such a system , there would be environmental boundary conditions : if they are transgressed , major features of the systems functioning will change . in the extreme case ,
the system may collapse ( if it is an organism , die ) , or else it may resume its self organization in a new state . both would then be called a transition .
can such a system be or become sustainable ? which criteria could be used to evaluate sustainability ? in our opinion , the key answer is the following : the system is unsustainable if it behaves in ways that actively bring about those very boundary conditions in the system 's environment . so the unit of analysis can not just be the system itself , but the system in interaction with relevant other systems in its environment .
a system as such can not be judged as sustainable or unsustainable . in the case of social systems , as well as with organisms ,
the system is unsustainable if it triggers changes in the environment that threaten its basic metabolic requirements .
the second consideration , again very abstract , is the distinction of stages or phases . the typical model of alternating phases is the s - curve ( rotmans et al . , 2001 ) , although other models have also been considered , such as the so - called lazy eight ( berkes and folke , 1998 ) , lock - in situations or system collapse ( tainter , 1988 ) , or tipping points in earth systems ( lenton et al . , 2008 ) .
from the notion of transition , there follows an understanding that no linear , incremental path leads from one state or phase to the other , but rather a possibly chaotic and dynamic intermediate process , or a discrete jump from one state of the system into another .
one has to be aware , though , that these distinctions are extremely sensitive to the observer 's choice of scale
. from a wider perspective something may appear as a continuous process , progressing steadily .
but from a closer perspective the same process may appear as whimsical , sharply fluctuating .
for example , the process of walking from a certain distance looks like a linear movement ; from close distance , one sees muscles contracting and relaxing again , weight shifting from one leg to the other , so the process appears as cyclical . from a still closer and
thus descriptions of processes as transitions or as gradual change do not necessarily exclude each other .
nevertheless , the idea of a system gradually behaving ever more sustainably ( as suggested in theories of ecological modernization sometimes , see mol and spaargaren , 1998 ) does not comply with the term sustainability transition .
a third consideration relates to the order of phases or stages , in other words , the understanding of directionality of time .
this directionality can either imply consecutive stages of a developmental type ( like herbert spencer 's notion of evolution , or marxist historical materialism , or rostow 's stages of economic growth ) , or it may follow a darwinian type of evolutionary theory by assuming the future to be contingent upon the past but an open process into the future : you know the mechanisms driving it but not where it will lead to . in the first case ,
when a developmental model is employed , each consecutive stage follows with a certain necessity from the previous stage , and it is , as a rule , considered superior , more mature .
the progress to this more mature stage can be accelerated or delayed . in the second ,
darwinian case , the direction of change is principally unknown ( gould , 2002 ) .
many people believe earlier transitions ( such as the industrial revolution ) to have been of a developmental type , simply human progress .
can we think of sustainability transitions as a kind of inevitable , logical step beyond the past , leading to a more mature state of the system ?
it says the appropriate unit of analysis is society , interpreted as a socio - metabolic system ( fischer - kowalski and weisz , 1999 ) that interacts with systems in the natural environment .
it claims that a transition to a ( more ) sustainable state implies a major transformation , on a par with the great transformations in history such as the neolithic or the industrial revolution ( haberl et al . , 2011 ) .
sieferle ( 2001 ) goes even as far as stating that industrial society as such is but a transitory stage from agrarian society to a very different as yet unknown type of social organization . and
finally , there is the presumption that a sustainability transition is both inevitable and improbable .
it is inevitable , because the present sociometabolic dynamics can not continue for very long any more , and it is improbable because the changes need to depart from known historical dynamics rather than being a logical step from the past into a more mature future state .
a regime , according to the socio - metabolic approach , is rooted in the energy system a society depends upon , that is the sources and dominant conversion technologies of energy.1 the theory of socio - metabolic regimes has been developed by sieferle , 1982 , sieferle , 2001 and elaborated by fischer - kowalski and haberl ( 2007 ) .
depending on the reasons for and the speed of an energy transition , parts of the system may at a certain point in time be under different energy regimes : urban industrialized centers , for instance , may coexist with traditional agricultural communities , or industrialized countries with agrarian colonies .
( fllsack , 2011 ) influences the overall course of transitions . how these processes evolve is contingent upon specific conditions .
the socio - metabolic approach shares with complex systems theory the notion of emergence : neither can one state be deliberately transformed into the other , nor can the process be fully controlled .
one is confronted with self - organizing dynamics ( maturana and varela , 1975 ) to which orderly governance or steering can not be applied .
the sustainability transition with regard to energy needs to be a change away from fossil fuels , and probably back to solar energy again , thus somehow reversing the historical transition from the agrarian to the industrial society and ongoing contemporary development that was and is a shift from solar energy to large scale fossil fuel use.2 what drives socio - metabolic regime transitions ?
on such a broad and long term scale one can not easily talk about actors and their deliberate efforts .
what one can mainly analyze is structural change of interlinked social and natural systems , across a broad range of variables . among these
, the socio - metabolic approach focuses on a relatively narrow set describing the society - nature interface for which quantitative measurements can be reliably obtained in very different contexts .
the advantage of this self - restraint is that it is possible to demonstrate the interconnectedness of socio - economic changes and changes in natural systems ( between population growth , diets , land use and species extinction , for example ) and to generate models for important biophysical requirements and boundary conditions for system perpetuation .
when an energy regime changes , society and its metabolism alter , and also the natural systems it interacts with .
a regime can be characterized by the socio - metabolic profile of the society involved , and the associated modifications in natural systems that occur either as an unintended consequence ( such as resource exhaustion or pollution ) or as intentional change induced by society ( such as land cover change).3 based upon the socio - metabolic approach , research has been undertaken into historical cases of transitions .
winiwarter ( 2003 ) and mcneill and winiwarter ( 2004 ) have approached the issue of soils as the main resource base of agriculture , and made a modeling effort to determine when for example a historical agricultural village would have to be given up ( winiwarter and sonnlechner , 2000 ) .
( 2008 ) have shown the role of resource and land scarcity for european history on various scale levels .
there was a modeling effort to determine the limits to city growth under agrarian conditions , given certain yields and the constraints to land transport , while considering metabolic needs for food , construction material and firewood , as well as varying rates of appropriation of agricultural surplus by cities ( fischer - kowalski et al . , 2004 ) .
these are no more than examples of first efforts to understand what happens when social systems challenge the boundary conditions of their environment and transgress their own coping capacity , and attempts at explaining under which conditions transitions ( collapses sometimes ) occur . under the agrarian regime , this is easier to determine , as its resource base is much narrower and local constraints play a key role.4 table 1 makes an attempt at using the insights gained from such historical studies .
it spells out a set of hypotheses on a more general level , so that they might also be applicable to a sustainability transition .
it is claimed that what drives a transition is the structural exhaustion of opportunities , and at the same time the opening of new opportunities ( see fig .
if only previous opportunities are exhausted , and no substantial new opportunities open up , one may rather expect system collapse ( diamond , 2005 ) .
if previous opportunities are not exhausted when new resources / opportunities offer themselves , vested interests in the status quo will often be strong enough to prevent change .
this case seems an inherently unstable situation , though : as long as the interest groups benefiting from the use of the old resources are very strong ( such as the landed aristocracy at the beginning of coal utilization , or the oil industry at present5 ) , they may delay the use of the new opportunities for a long time , maintaining the status quo.6 they also may give in gradually and allow for the additional utilization of the new resources that are connected to different interest groups .
this may result in expansion ( building one resource use upon the other ) , but in the longer run would give rise to a transition .
1 involve objective criteria ( such as changes at the interface of society and nature ) , and subjective elements of human perception and learning .
new energy sources , superior in energy density and cost , have of course been the prototype of new opportunities , and such a grand new opportunity at present is not in sight .
but probably also other new opportunities , such as sophisticated solar technologies in combination with low - energy it , could play the same role .
the environmental historian mcneill ( 2000 ) summarized the 20th century using the ironical title something new under the sun . according to the statistics he assembled
, there is rarely any dimension of human social life and interference with the environment that has not undergone a rapid expansion worldwide . during this one century , many indicators of human activity and human use of the environment exceeded the fivefold growth of the human population , substantial in itself , sometimes by an order of magnitude . taking mcneill 's reconstruction of the 20th century seriously , humans are driving a biophysical explosion in limited space .
this explosion , as is to be briefly demonstrated further down , derives from multiple transitions .
the countries that had already undergone a transition from the agrarian to the industrial socio - metabolic regime during the 19th century made a transition from the coal - based to the oil - based mode . during the same period ,
many other countries started their transition from an agrarian regime to the coal based and oil based mode on a faster track .
some countries have not as yet really started this transition ( lankao et al . , 2008 ) .
( 2011 ) have interpreted , after analyzing a large number of country metabolic profiles , the s - curve in fig . 1 as a global result of such transitions .
energy is measured as domestic energy consumption ( dec)7 in gigajoules per capita , and material use as domestic material consumption ( dmc ) in tonnes per capita .
the interpretation , in short , is as follows : the dynamics of global energy and materials use was , for most of the 20th century , marked by the highly developed industrial countries .
the apparent global patterns may be distinguished into a coal - dominated phase of industrial development that raised overall energy and materials use but at the same time population thus while there was huge growth in capital , per capita consumption stagnated .
this phase started before 1900 and ended globally around 1930 , a date also marked by a world economic crisis .
the next phase , dominated by the use of petroleum , realized what many dreamed of : a sharp increase in consumption opportunities for each person , in other words the american way of life.8 this pattern dominated the global metabolic profile from around 1930 to the early 1970s , as can be gathered from the steep increase in per capita metabolic rates in fig .
a new pattern emerged : there was again a relative stagnation of metabolic rates , but this time in combination with low population growth .
after the year 2000 , in the industrial countries , per capita energy and material consumption continued to stagnate , but global metabolic rates again turned sharply upwards ( fig .
1 ) . interpreting changing growth patterns of material and energy use as socio - metabolic transitions seems only justified if confirmed by a broader analysis .
such an analysis is ongoing and requires giving attention to demographic variables , technological variables , political variables and last but not least economic variables , on various scale levels .
it extends the scope of this paper to go into any detail . nevertheless , we found it surprising that such a simple quantification as global metabolic rates seems to reflect major other well - known changes.9 demographically , the coal phase was linked to massive population growth in the industrializing countries ; and one can register a substantial drop in population growth around 1930 ( and again after 1970 ) . technologically , the breakthrough of coal use was associated with the steam engine and railroads , while the breakthrough of petroleum was linked to automobiles , electricity and the industrialization of agriculture , the green revolution . the phase after 1970 was marked by the rise of information and communication technologies .
politically and culturally , the transition to coal was connected to the rise of the british empire , and the transition to petroleum to american hegemony that possibly started to decline around the time of the us oil peak in 1973 ( hubbert , 1971 ) . from then on
, there is a continuous rise of emerging economies mainly emulating the patterns of the previous industrial transformation .
this rise is also responsible for the sharp turn upwards in metabolic rates after the year 2000 .
we found it very surprising how many events ( such as global crises ) and changes in structural variables fitted neatly to apparent turning points in a timeline of per capita energy and materials use .
this encourages us to talk of transitions in this context . at the time of writing ,
will the curves later resume their course upwards ? according to our guess , they will not : a period of strong fluctuations will ensue , driven by a rising and volatile oil price ( global oil peak ? ) , supply shortages and a new trend of price increases for important raw materials . from the perspective of a potential sustainability transition , the phase of stagnation of metabolic rates ( but not of global income ) between the early 1970s and the late 1990s is very interesting .
quite obviously , there had occurred structural change terminating the rapid increase in per capita material and energy consumption , in industrial countries and globally.10 this may have signaled a historical window of opportunity for physical degrowth in industrial countries , in alliance with the rise of new information and communication technologies . but
politically , this window of opportunity was ignored , or even forcefully shut . instead of utilizing the structural opportunity of heading for a less material and energy intensive lifestyle in the oecd world and more calmly accepting the emerging economies to catch up , the limits to growth message ( meadows et al . , 1972
) was discarded.11 most political efforts were invested in returning to the higher growth rates of the previous period .
this strategy was not fully successful in re - establishing the previous high rates of economic growth .
it also missed out on the chances to stabilize employment and mitigate rebound effects by reductions in working time , to stabilize climate change by taxing fossil fuels , or to tackle social inequality .
policy measures were directed at maintaining business as usual , and despite major accidents ( three mile islands , chernobyl , now topped by the meta - gau in fukushima ) , huge public investment continued to be spent for nuclear energy in denial of a possible lower energy future based on renewable sources .
what distinguishes a socio - metabolic analysis conceptually and methodologically from other approaches to study historical transitions ?
conceptually , it differs from storylines on technological change or from storylines on economic cycles by systematically bringing in empirical information about biophysical variables and attributing an important role to nature . in the socio - metabolic approach , nature matters in terms of providing easily accessible , high density energy from limited geological sources as a key ingredient of the economic growth engine ( ayres and warr , 2009 ) .
forces of nature matter as stochastic events in demonstrating the limitations of human technology , such as winds over chernobyl distributing radioactive particles all across europe , hurricanes over the mexican gulf destroying offshore drilling platforms , or sea level rise threatening the survival of island states and influencing climate negotiations .
but more systematically , natural systems matter as they coevolve with human interventions and exert pressure upon societies to keep on changing .
much effort has been devoted to creating consistent long term databases with variables across many domains and across several scale levels , from local communities ( or small pixels ) to countries , regions and the global level .
but adequate modeling techniques allowing the reconstruction and simulation of structural change are still pending ( see www.matisse-project.net ) .
it may be expected that the declining belief in 19th century type of progress continuing forever will , in combination with unexpected and possibly catastrophic events , trigger new approaches for analyzing and modeling major transformations of society - nature relations .
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### Summary:
: this essay seeks to specify the theoretical choices and assumptions involved in studying sociometabolic transitions , such as sustainability transitions , in a way that distinguishes them from mere changes .
these generalizations draw on experiences with the empirical analysis of historical transitions on various scale levels .
this perspective is illustrated by using material and energy flow data to demonstrate global sociometabolic regime transitions during the 20th century .
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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:
: idiopathic osteosclerosis ( io ) is an area of increased bone production in the jaw and generally appears to be round , elliptical , or irregular and radiopaque in shape.13 according to the literature , although this disorder is sometimes described as a dense bone island , bone scar , focal periapical osteopetrosis , or enostosis,3 io is often preferred because of its unknown origin.46 these lesions may be accepted as developmental intraosseous anatomic variations7 and should be classified separately from the cases resulting from inflammatory origin or systemic disease.46 these asymptomatic lesions are generally discovered as incidental findings on radiographs taken for other reasons.7 on radiographic evaluation , io may be detected in various sizes , ranging from 2 or 3 mm to 1 or 2 cm in diameter,2,3,810 or the lesions may be very large , almost the entire height of the body of the mandible .
11,12 they may occur at root apexes , between the roots , or in a separate location away from the teeth , primarily in the premolar / molar region and with a predilection for the mandibular arc.2,3,5,13,14 the purpose of this study was to determine the prevalence and distribution of the io in the jaws of the patients attending our facility by examining the panoramic radiographs the patient records , and to investigate the relationship of the findings to the age and gender in the population of the cappadocia region .
a total of 2,211 dental patients admitted to the faculty of dentistry , erciyes university , in the cappadocia region of turkey participated in the study , which was based on the panoramic radiographs ( prs ) of the patients taken during routine dental examination , and all the radiographs were examined by ys in terms of the presence of io on a standard light - box under normal room lighting .
all the prs were obtained with an orthopantomograph op 100 ( orthopantomography op100 , tuusula , finland ) .
the prs were processed according to the manufacturer s recommendations in an automatic film processor .
the radiographs that displayed the jaws , without asymmetry , distortion , or error in patient positioning or exposure processing were included in the study .
for the diagnosis , io was defined as the symptomless , radiopaque areas that are often elliptical or round in shape and vary in size from a minimum of 3 mm to more than 2 cm .
the patients who had a questionable io and who met the following criteria were excluded from this study.2,8,15 radiopacities directly associated with deep caries or large restorations ; the characteristics of the lesion were mixed with radiopaque - radiolucent areas in the form of periapical cemental dysplasia and other benign fibro - osseous lesions or an odontome ; the remnants of deciduous or permanent teeth were clearly identifiable ; the radiopacities were interpreted as a tori or exostoses , salivary calculus , tonsolith , or calcified lymph node ; there is an increased thickening of the lamina dura around teeth with marked malposition or which were serving as abutments for fixed bridges or partial dentures ; solitary radiopacities in edentulous regions .
radiopaque areas that were depicted as io were classified as follows2 ( figures 1a e ) :
interradicular : if the sclerotic area was confined between the roots and interrelated with the adjacent teeths lamina dura;interradicular and separate : if the sclerotic area was confined between the roots and not interrelated with the adjacent teeths lamina dura;apical and interradicular : if the radiopacities were at the apices and showed significant extension between the roots;apical : if the lesions were located around the apices of the roots;separate : if the masses were located apically and clearly separated from the teeth and lamina dura .
interradicular : if the sclerotic area was confined between the roots and interrelated with the adjacent teeths lamina dura ; interradicular and separate : if the sclerotic area was confined between the roots and not interrelated with the adjacent teeths lamina dura ; apical and interradicular : if the radiopacities were at the apices and showed significant extension between the roots ; apical : if the lesions were located around the apices of the roots ; separate : if the masses were located apically and clearly separated from the teeth and lamina dura . for each patient ,
demographic data was recorded in order to investigate the relationship between the findings and age , gender , and localization .
the observed results were analyzed with spss 16.0 ( statistical package for social science inc . ,
data was obtained using the chi - square test , and the results were considered to have a significant difference if the significance level was less than .05 .
for each patient , demographic data was recorded in order to investigate the relationship between the findings and age , gender , and localization .
the observed results were analyzed with spss 16.0 ( statistical package for social science inc . ,
data was obtained using the chi - square test , and the results were considered to have a significant difference if the significance level was less than .05 .
osteosclerosis was identified in 135 of the 2,211 patients , for an overall prevalence of 6.1% of patients . in these 135 patients ,
one hundred twenty - three patients had 1 io , nine patients had 2 ios , two patients had 3 ios , and one patient had four foci of ios .
there is a statistically significant difference between the rates of occurrence in the jaws ( p<.001 ) ; the vast majority occurred in the mandible , and only 19 foci were detected in maxilla and 134 in the mandible . the patient population as a whole consisted of approximately 59% females and 41% males
the prevalence of io among females was 5.9% ( 77 females ) and 6.3% ( 58 males ) among males .
there was no statistically significant difference in the prevalence of io between the males and females ( p=.768 ) .
the ages of the study group ranged from 10 to 77 years with a median of 26 years .
no significant difference in prevalence of io was found among age groups ( table 1 ) ( p=.3654 ) . in the maxilla ,
the most common location of io was the anterior area whereas in the mandible , most lesions were detected in the molar region .
most of the lesions of io , approximately 51.6% , were associated with the root apices .
separate localization in which the lesions were apical to and clearly separated from the teeth and lamina dura was the second most common localization with 22.9% prevalence .
seventeen percent of the lesions were detected at the apices and showed extension to the interradicular areas ; 6.5% were in interradicular areas ; and 2% were detected in interradicular and separate localizations ( table 2 ) .
the frequency of io observed in this study was 6.1% , the same as the prevalence found by yonetsu et al.4 in the literature , the prevalence varies from 4% to 31% , and our findings fall within this range.2,8,16,17 one of the reasons for the variation in the studies is the different definitions of osteosclerosis .
4 some researchers included radiopacities that are related to traumatic occlusion or pulpal inflammation , while others excluded these kinds of lesions from their study.2,4 in our study , solitary radiopacities in edentulous regions were not included , and asymptomatic radiopaque masses within the jaws which had no certain relationship to any known sources of hard tissue production were accepted as idiopathic osteosclerosis.2 another reason may be the choice of radiography . in some studies ,
periapical radiographs were examined1,2 whereas in some others , panoramic radiographs were used as the tool of investigation.3,4 in our study , we also preferred using panoramic radiographs in order to detect larger areas in jaws .
some researchers reported a female predilection for the incidence of io5 while others showed no significant difference in prevalence between males and females as in our study.4,8,15,17 the ages of our study group were ranged from 10 to 77 and there was no significant difference in prevalence of io among age groups similar to results of yonetsu et al4 and kawai et al.18 although in their studies geist and katz2 and sun et al18 reported the highest occurrence in the premolar region , the results of this study support the previous findings , which indicated the most common location of io is in the first molar region of the mandible.4,5,13,18 in our study , most of the lesions of io were found to be associated with the root apices .
traumatic occlusion and traumatic movement of teeth is known to be a possible explanation for io.2 although the radiopacities around teeth that showed malposition or seemed to be subject to abnormal occlusal forces were excluded from our study group , slight imbalances in occlusion that provide enough vibratory stimulus to provoke bone formation might escape radiographic detection , and this might explain why the highest predilection of the lesions was associated with the root apices . in some studies ,
io was reported to be an anatomic variation.2,19,20 in our study , separate localizations , where the lesions were apical to and clearly separated from the teeth and lamina dura , was the second most common localization with 22.9% prevalence .
because the lesions were clearly separated from the teeth , and there were no residual tooth fragments or the stimulatory effects of excessive occlusion would not be a factor in this localization , may support the possibility that io may be a developmental anatomic variation .
in light of these findings , we can define io as developmental variations of normal bony architecture unrelated to local stimuli .
the lesions can arise at any age , at any location , and with no sex predilection , and io usually requires no treatment other than diagnosis by recognition.7 generally , the lesions are likely to remain for years , and surgical intervention is not recommended . to be sure that the clinical diagnosis is correct ,
although it is rare , if resorption occurs in the associated root over time , endodontic treatment or extraction of the affected tooth may be necessary.7
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### Summary:
: objectives : to determine the prevalence of idiopathic osteosclerosis ( io ) in the jaw by radiographic evaluation and to investigate the relationship between the findings in relation to age , gender , and localization.methods:the study included 2,211 panoramic radiographs obtained from the patients ( 915 men and 1,296 women ) whose ages ranged from 1077 and who visited the department of oral diagnosis and radiology in the faculty of dentistry , erciyes university between 2008 and 2009.results:of 2,211 patients , 135 patients ( 6.1% ) had io .
the prevalence obtained in our study was in the range reported in the literature .
io was detected more often in mandible rather than the maxilla .
in addition , mandibular molar localization was the most common localization , and most of the lesions were associated with root apices.conclusions:in view of the findings , io can be defined as developmental variations of normal bony architecture , which are unrelated to local stimuli .
the lesions can arise at any age , any location with no sex predilection , and io usually requires no treatment other than diagnosis .
because all these lesions were located in the jaw and could only is detected in panoramic evaluations , this indicates the importance of careful diagnostic evaluation of radiographies in dental examinations .
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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:
: expressed sequence tags ( ests ) are small pieces of dna sequences ( usually 200 to 500 nucleotides long ) derived by either unidirectional or bidirectional sequencing of cdna libraries .
the information generated from ests has been utilized not only to identify novel gene transcripts , gene locations , and intron - exon boundaries in human and mouse genome drafts [ 2 , 3 ] but also to assess gene expression levels of given tissues .
the large volume of information generated by the rapidly increasing number of ests59 million est entries in the dbest in january 2009 alone provides an excellent resource for comparative studies , so we have constructed an est service website , bio301 , to facilitate comparative studies based on these est data .
bio301 is equipped with not only an est annotation pipeline but also functional comparative functionality .
bio301 has five characteristics considered to be essential for est analysis tools that aid in functional comparative studies : accurate preprocessing , advanced functional annotation methods , flexibility in comparing multiple est libraries , retrieval of est data with respect to the annotation ontology , and integrated online est service open to the entire research community .
these tasks are very important because accurate preprocessing leads to accurate functional annotation , which is crucial for functional comparison studies .
bio301 uses one of the best programs for sequence cleaning , seqclean ( http://compbio.dfci.harvard.edu/tgi/software/ ) .
concordantly , bio301 also uses state - of - the - art programs for clustering and assembly , tgicl and cap3 [ 5 , 6 ] . since reference genomes with extensive genome annotation
have been shown to be helpful for annotation and clustering [ 7 , 8 ] , bio301 also is equipped with an option for clustering ests wherein ests are mapped into a user - specified genome using blat , and bio301 then assembles these ests using cap3 .
bio301 also has an option for processing input data in ace format , a format commonly used by many third - party assembly programs or next - generation sequencing technologies like the roche 454 pipeline .
second , bio301 has advanced functional annotation methods . these methods , in conjunction with public sequence database searching , enable biologists to deal with uncommon organisms .
bio301 utilizes e2d to retrieve go annotations via recognized potential interpro domains . in testing , e2d performed as well as the interproscan ( precision 96.1% versus 96.6 and recall 53.8% versus 30.3% ) but ran approximately 69 times faster . in our case study ( see section 3 ) , the combination of e2d and public sequence database searching allowed us to annotate 4% ~ 6% more tentative unique genes than we were able to do previously with public sequence database searching alone .
third , bio301 gives users flexibility in comparing multiple est libraries by performing statistical comparisons based on expression profiles and go annotations .
this flexibility in comparing multiple est libraries is essential because est libraries are often sampled from organisms that are of special interest to biologists .
biologists often have to sequence more than one library in order to determine the difference in genomic function .
however , they often encounter problems when trying to functionally compare two or more est libraries , especially when the annotations of those est libraries were not derived using the same vocabulary . bio301
first performs statistical comparisons based on expression profiles and go annotations , and it then ranks go terms according to significant levels computed by the chi - squared test for goodness of fit .
for example , a top - ranked go term implies a stronger expressional difference between libraries with respect to this function .
this kind of data aids biologists in conducting further investigation of specific est data . as shown in the table 1
, users can select est data that are related to a given go term belonging to a given library .
last , bio301 integrates est services and makes them easily accessible online to the entire research community .
bio301 should not only eliminate some dependence on in - house it support , but , through bio301 's library management interface , it should make it easier for researchers to share est libraries with authorized users and to compare these est libraries in a kind of next - generation collaboration over the internet . in the creation of our next - generation bio301
, we analyzed various advanced est analysis tools that have been developed in recent years and looked for their best features .
orest has a user - friendly web interface for annotating ests and compares them with model organisms .
since each of these tools has its own strength and shortcomings , in the creation of bio301 , we sought to combine the best aforementioned features of all of the aforementioned advanced est tools such that bio301 would facilitate ongoing and future functional comparison studies based on est data .
est libraries are often sampled from organisms that are of special interest to biologists . for instance , biologists may sequence more than one library from different tissues of the same organism or from similar tissues belonging to different organisms in order to study the difference in genomic functions .
however , biologists often encounter problems when trying to compare two or more est libraries .
second , the annotations of est data in different libraries may not be derived using the same vocabulary .
developing a unified approach for library comparison is thus very important if the research community wishes to achieve the aforementioned goal of comparing multiple est libraries . in bio301
, we overcame these constraints by designing two library comparison approaches based on go terms .
initially , an expression matrix is constructed in which the rows are indexed by go terms and the columns are indexed by libraries
. for convenience , let n denote the number of libraries and m denote the number of involved go terms .
each cell of the matrix is filled with fij , the number of ests that belong to the corresponding library ( column i ) and go term ( row j ) .
our first approach considers the hierarchical clustering of libraries based on the expression patterns of libraries , that is , the hierarchical clustering of n vectors ( fi1 , fi2 , , fim ) for i = 1,2 ,
, n , where(1)fij=fijy=1mfiy1000,fij here expresses the average number of ests that belong to go term j for every 1000 ests from library i. through this hierarchical clustering , the libraries are clustered in such a way that those with similar expression patterns ( with respect to go terms ) are closer to each other than to libraries with dissimilar patterns .
the results are presented as a hierarchical cluster tree , as shown in figure 1 . while the first approach clusters normalized columns in the expression matrix , the second comparison ranks rows according to their relative deviation from an expected frequency . by treating each row j as a vector of frequencies
( f1j , f2j , , fnj ) , the expression frequencies of libraries with respect to go term j , each row j is assigned a chi - squared value j according to the following formula:(2)j2=x=1n(fxjexj)2exj ,
where ( 1 ) e1j , e2j , , enj are proportional to the numbers of ests in libraries 1,2 , ,
this formula is the same as the one that is used to calculate the chi - squared value for goodness of fit .
a higher j value means that at least one library has a stronger difference between its empirical expression level and the expected expression level . on the comparison result page ,
go terms are ranked according to the chi - squared values , from high to low .
that is , go terms with stronger deviation in expression from the expectation have higher ranks .
as in the conventional chi - squared test , we compute the p values for all related go terms . however , it should be noted that first , the chi - squared test might not be appropriate if some of the expected frequencies are too small .
second , the p values might be too significant if the total number of ests is large .
that is , users should treat the ranks and p values as references , not as sufficient evidence per se . go ids and
go terms are shown in the attached ranked expression matrix ( see table 1 ) .
users may click on the go ids to obtain term descriptions from the amigo website ( http://www.genedb.org/cgi-bin/amigo/go.cgi/ ) or click on the number of ests to obtain the corresponding tugs .
although this comparison is similar to the one provided by go - diff , our method allows for the comparison of more than two libraries simultaneously and , furthermore , it is integrated well into the bio301 website .
one of our major motivations in developing bio301 was to enable users like ourselves to compare the genomic functions of different cdna libraries derived from a single or multiple species . in the development of bio301
, we used a particular case study to assess its capacity to carry out this task .
our case study focused on the difference between the genomic functions of the gills of fishes and those of amphibian species at the molecular level , of which currently much still remains unknown . in aquatic lower vertebrates , for example , fish ,
gills are believed to play an essential role in both osmoregulation and respiration . however , in most amphibian species , gills are merely transient structures and are thought to play a more important role in respiration than in osmoregulation . with the aid of bio301
, we sought an answer to the question : how much of a difference is there between the genomic functions of gills in aquatic lower vertebrates and amphibians at the molecular level ? to address this question , we first constructed gill cdna libraries of zebrafish and tilapia .
we also collected gill ests from salmon , stickleback ( from ncbi dbest ( http://www.ncbi.nlm.nih.gov/dbest/ ) ) , and axolotl for cross - species comparison . in supplementary material
available online at doi : 10.1155/2012/139842 , we summarize the information about est sequencing , clustering , and annotation . with the aid of bio301
first , the functional hierarchical clustering showed that the axolotl gill is not a member of the fish gill family ( figure 1 ) .
second , respiration - related go terms , for example , hemoglobin complex , oxygen binding , and heme binding , were ranked at the top because of their higher expression levels in axolotl gills rather than in fish species table 1 .
last , the discovery rates of osmoregulation - related go terms like sodium : potassium - exchanging atpase activity did not show significant deviation in expression ( data not shown ) .
the first and second results both follow the prevailing understanding of biology , but the second result confirms what many biologists have speculated , namely , that the axolotl gill does play a more important role in respiration at the molecular level . the est libraries , being comprised of samples in steady states , that is , samples with less osmoregulation , might account for the lack of significant deviation in expression in the third observation .
first , it combines advanced functional annotation methods and thus enables users to annotate more genes than they could with one method alone ( see supplementary material ) , which is particularly useful for studying uncommon organisms .
second , its library comparison module gives users the flexibility of comparing any number of libraries at the same time using statistical methods .
third , the well - designed web interface does not require switching among different bioinformatics tools and can be accessed using any operating system platform without any in - house it support .
our case study shows that this combination of features yields meaningful biological information and ideas for further investigation .
although , in this paper , we emphasized bio301 's effectiveness in functional comparative studies , bio301 could also be effective in at least other applications : ( 1 ) preprocessing and/or annotation of nucleotide sequences , ( 2 ) comparative studies on in - house est libraries and/or publicly available est libraries , for example , libraries in the dbest database , and ( 3 ) design of cdna / oligo array probes for an est dataset
. additionally , the ace input option also enables all aforementioned functionalities for preassembled data from third - party software or next - generation sequencing technologies , like the roche 454 pipeline .
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### Summary:
: in this postgenomic era , a huge volume of information derived from expressed sequence tags ( ests ) has been constructed for functional description of gene expression profiles .
comparative studies have become more and more important to researchers of biology . in order to facilitate these comparative studies ,
we have constructed a user - friendly est annotation pipeline with comparison tools on an integrated est service website , bio301 .
bio301 includes regular est preprocessing , blast similarity search , gene ontology ( go ) annotation , statistics reporting , a graphical go browsing interface , and microarray probe selection tools .
in addition , bio301 is equipped with statistical library comparison functions using multiple est libraries based on go annotations for mining meaningful biological information .
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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:
: coronary artery bypass graft ( cabg ) surgery is a common form of treatment for patients with coronary stenosis and more than 73 million surgeries are performed annually only in the united states . despite achieving technical success for most patients , clinically significant morbidities such as cardiologic shock , dysrhythmia , gastrointestinal bleeding , pain , anxiety , and vital sign changes are common .
cabg is reported to be associated with pre- and postoperative anxiety and may impair the coronary circulation and , hence , increase the risk of angina pectoris and myocardial infarction . in one of the studies , the prevalence of anxiety after open heart surgery in patients has been reported to be 24.7% .
there are a number of factors that may increase anxiety in patients admitted in the intensive care unit ( icu ) , including pain , sleep disorder , absence from home and work , long - term treatment and disease , economic problems , and lack of social support such as insurance , family and social problems anxiety can cause tachypnea , increased blood pressure , hypothermia , arterial vasoconstriction , and decreased tissue perfusion through stimulation of the sympathetic response .
anxiety is a considerable challenge that can indirectly increase postoperative pain and analgesic usage , decrease resistance against infection , prolong postoperative wound healing , and increase the duration of hospitalization .
sedative medications are frequently used to decrease anxiety among patients who had undergone cabg , which is usually associated with adverse effects such as sedation and respiratory depression .
complementary and alternative medicine ( cam ) therapies are safer than pharmacologic approaches and have less adverse effects .
aromatherapy is a natural treatment method that utilizes the chemical structure and effects of essential oils .
it can be applied in various forms such as massage , inhalation , compress , and baths with herbal and mineral substances .
inhalation aromatherapy is a technique in which essential oils are used in inhalation , which can decrease pain , anxiety , depression , and improve the vital signs .
lavender is one such plant that is widely used in aromatherapy , with aromatic leaves and attractive bracts at the top of flowers .
some of its effects are sedative , antidepressant , antispasmodic , antibacterial , and local anesthetic .
studies about the benefits of lavender 's aroma showed that linalool and linalyl acetate present in this plant can stimulate parasympathetic system .
this herb improves the heart function and as a circulatory stimulant , it has beneficial effects on coronary blood flow .
studies have shown that inhalation of lavender aromatherapy is effective in reducing depression , pain , and anxiety in women undergoing cesarean section and in patients undergoing dental procedures or abdominal surgery .
it is usually a stressful event for patients , indicating the importance of anxiety reduction strategies and stable vital signs in them .
the intensive care nurses have an important role in assessment of anxiety and changes in vital signs , implementation of appropriate measures , and evaluation of therapeutic effects . accordingly ,
this study was carried out with an aim to investigate the effects of inhalation aromatherapy using lavender oil to reduce anxiety in patients after cabg .
a double - blinded randomized controlled trial was conducted on 60 patients who had undergone cabg in ekbatan therapeutic and educational center , hamadan city , iran .
the entire study process was approved by the research ethics committee of hamadan university of medical sciences , and the protocol was registered by iranian registry of clinical trials ( no . :
the details of the study were explained to the participants and their informed consent was obtained in writing . in order to avoid inductive effect of the medication ,
for this purpose , the medications were given to the patients by one researcher and the effect of treatments was evaluated by another researcher independently .
the inclusion criteria included the absence of ( a ) chronic respiratory disease , ( b ) addiction to alcohol or narcotic substances , ( c ) history of head trauma or convulsion , ( d ) impaired sense of smell , ( e ) using anti - anxiety drugs , and ( f ) acute mental illness according to physician diagnosis and obtaining a score of less than 20 with spielberger 's questionnaire .
patients were excluded if they had ( a ) eczema or allergy to plants , ( b ) impaired consciousness , ( c ) been intubated for more than 24 h , ( d ) hemodynamic instability , and ( e ) severe acute pain at the time of completing the questionnaire .
the eligible patients were randomly assigned to the aromatherapy and control groups using balanced block randomization with a block size of four .
for this purpose , the aromatherapy and control groups were randomly assigned to letters a and b. thus , for each block of four patients , two sequence different assignments were made for each treatment .
were written all the possible states , i.e. paper no . 1 for aabb , paper no . 2 for abab , paper no .
then the number were selected randomly via table of random numbers . according to number of selected papers ,
participants ( n = 70 ) were randomly assigned to two groups : aromatherapy ( n = 35 ) and control group ( n = 35 ) .
follow - up of patients was lost in the aromatherapy ( n = 3 ) and control groups ( n = 4 ) due to them getting discharged on the 3 day after surgery .
intervention was discontinued in the aromatherapy group ( n = 2 ) due to intolerance of aromatherapy and in the control group ( n = 1 ) due to lack of cooperation .
thus , in each of the aromatherapy and control groups , n = 30 were analyzed .
data collection was based on completing the questionnaire , interviewing , and recording the vital signs .
the data collection tool included a questionnaire with two parts and a checklist of items .
the first part of the questionnaire contained demographic information such as age , gender , body mass index ( bmi ) , educational level , and marital status .
additional information obtained included history of hospitalization or open heart surgery in the family , as well as the duration of operation and admission in the icu . for assessing the scientific validity of this part of the questionnaire ,
content validity was used . the second part of the questionnaire consisted of the standard questionnaire of spielberger .
the least score of 20 that could be obtained indicated no anxiety and the maximum score of 80 illustrated the highest level of anxiety .
a score of 40 - 59 indicated moderate anxiety , and a score of 60 - 80 indicated severe anxiety .
its reliability had already been confirmed on 600 people in mashhad and the cronbach 's alpha coefficient obtained was 0.94 in the norm population .
the checklist of items was used to recode vital signs such as systolic and diastolic blood pressure , heart and respiratory rates , and temperature measured by a monitoring machine manufactured by sairan co. iran .
based on a single - blind clinical trial conducted in 2011 by hadi et al .
, the sample size needed in our study was estimated to be 30 subjects in each arm ( totally 60 ) with p at 0.05 and 90% power
. there were 30 subjects in the aromatherapy group and 30 subjects in the control group , who contributed data to the study according to the trial profile [ figure 1 ] .
the eligible patients were randomly assigned to the aromatherapy and control groups using balanced block randomization with a block size of four .
the patients in the aromatherapy group inhaled two drops of 2% lavender essential oil , produced by barij esans co. iran ( kashan ) , via an absorbable patch connected inside an oxygen mask for 20 min on the 2 and 3 days after surgery .
the patients in the control group received two drops of distilled water as placebo via an oxygen mask at the same time as the aromatherapy group . on the 2 and the 3 days after surgery , in the aromatherapy and control groups ,
vital signs including heart rate , respiratory rate , and systolic and diastolic blood pressure were measured before the intervention and then at 5 , 30 , and 60 minute after the intervention by a monitoring machine .
all statistical analyses were performed at a confidence level of 0.05 using the statistical software stata 11 ( stata corp .
the relationship between the dependent and independent variables was investigated using independent statistical t - test for continuous variables and chi - square test for categorical variables .
the eligible patients were randomly assigned to the aromatherapy and control groups using balanced block randomization with a block size of four .
for this purpose , the aromatherapy and control groups were randomly assigned to letters a and b. thus , for each block of four patients , two sequence different assignments were made for each treatment .
were written all the possible states , i.e. paper no . 1 for aabb , paper no . 2 for abab , paper no .
then the number were selected randomly via table of random numbers . according to number of selected papers ,
participants ( n = 70 ) were randomly assigned to two groups : aromatherapy ( n = 35 ) and control group ( n = 35 ) .
follow - up of patients was lost in the aromatherapy ( n = 3 ) and control groups ( n = 4 ) due to them getting discharged on the 3 day after surgery .
intervention was discontinued in the aromatherapy group ( n = 2 ) due to intolerance of aromatherapy and in the control group ( n = 1 ) due to lack of cooperation .
thus , in each of the aromatherapy and control groups , n = 30 were analyzed .
data collection was based on completing the questionnaire , interviewing , and recording the vital signs .
the data collection tool included a questionnaire with two parts and a checklist of items .
the first part of the questionnaire contained demographic information such as age , gender , body mass index ( bmi ) , educational level , and marital status .
additional information obtained included history of hospitalization or open heart surgery in the family , as well as the duration of operation and admission in the icu . for assessing the scientific validity of this part of the questionnaire ,
content validity was used . the second part of the questionnaire consisted of the standard questionnaire of spielberger .
the least score of 20 that could be obtained indicated no anxiety and the maximum score of 80 illustrated the highest level of anxiety .
a score of 40 - 59 indicated moderate anxiety , and a score of 60 - 80 indicated severe anxiety .
its reliability had already been confirmed on 600 people in mashhad and the cronbach 's alpha coefficient obtained was 0.94 in the norm population .
the checklist of items was used to recode vital signs such as systolic and diastolic blood pressure , heart and respiratory rates , and temperature measured by a monitoring machine manufactured by sairan co. iran .
based on a single - blind clinical trial conducted in 2011 by hadi et al . ,
the sample size needed in our study was estimated to be 30 subjects in each arm ( totally 60 ) with p at 0.05 and 90% power .
there were 30 subjects in the aromatherapy group and 30 subjects in the control group , who contributed data to the study according to the trial profile [ figure 1 ] .
the eligible patients were randomly assigned to the aromatherapy and control groups using balanced block randomization with a block size of four .
the patients in the aromatherapy group inhaled two drops of 2% lavender essential oil , produced by barij esans co. iran ( kashan ) , via an absorbable patch connected inside an oxygen mask for 20 min on the 2 and 3 days after surgery .
the patients in the control group received two drops of distilled water as placebo via an oxygen mask at the same time as the aromatherapy group . on the 2 and the 3 days after surgery , in the aromatherapy and control groups ,
vital signs including heart rate , respiratory rate , and systolic and diastolic blood pressure were measured before the intervention and then at 5 , 30 , and 60 minute after the intervention by a monitoring machine .
all statistical analyses were performed at a confidence level of 0.05 using the statistical software stata 11 ( stata corp . , college station , tx , usa ) .
the relationship between the dependent and independent variables was investigated using independent statistical t - test for continuous variables and chi - square test for categorical variables .
table 1 shows the distribution of individual characteristics of the patients in aromatherapy and control groups .
majority of patients in the aromatherapy group ( n = 19 ) and the control group ( n = 23 ) were males and the rest females .
the mean age in the aromatherapy group was 65.13 9.76 years and in the control group was 65.63 10.80 years . according to the results presented in the table
, there was no statistically significant difference between the aromatherapy and control groups regarding the individual characteristics that might have an effect on the treatment .
distribution of individual characteristics of the patients in aromatherapy ( lavender ) and control ( placebo ) groups table 2 shows the mean score of anxiety based on the spielberger 's questionnaire on the 2 day after surgery , the mean score of anxiety before intervention in the aromatherapy group was 48.73 5.08 and in the control group was 48 6.98 , which reduced after the intervention to 42.6 5.44 and 42.73 7.30 , respectively ( p = 0.541 ) . on the 3 day after surgery ,
the mean score of anxiety before intervention in the aromatherapy group was 46.76 4.07 and in the control group was 46.53 7.05 , which reduced after the intervention to 41.33 3.65 and 41.56 6.18 , respectively ( p = 0.672 ) .
however , the mean score of anxiety decreased significantly after surgery in both groups ( p = 0.032 , p = 0.036 ) , but the difference between aromatherapy and control groups before and after intervention was significant neither on the 2 day ( p = 0.36 ) nor on the 3 day ( p = 0.41 ) after surgery comparison of the mean difference of anxiety among the intervention ( lavender ) and control ( placebo ) groups according to spielberger 's questionnaire using independent t - test table 3 shows the changes in vital signs of the patients in aromatherapy and control groups before the intervention and at 5 , 30 , and 60 minute after the intervention on the 2 and 3 days after surgery .
there was no statistically significant difference in the vital signs ( p = 0.06 ) , except in the systolic blood pressure ( p = 0.004 ) , between the aromatherapy and control groups either on the 2 day or on the 3 day after surgery .
comparison of the mean difference in homodynam ic measurements in intervention ( lavender ) and control ( placebo ) groups using independent t - test
some studies have reported that the level of anxiety is different between males and females .
nonetheless , we did not find any significant difference in the mean score of anxiety between the two sexes .
several studies have reported that patients who had undergone cabg suffer from anxiety after surgery .
we found that patients had moderate anxiety before the intervention in both aromatherapy and control groups .
however , their anxiety deceased significantly after the intervention , although no statistically significant difference was observed between the two groups .
one possible reason for this is that pain and other reasons of stress like fear of surgery and anesthesia had been resolved .
fear and anxiety of the future health status may remain after surgery which may affect the mental health status .
rymazewska et al . reported that patients who are candidates for cabg have severe anxiety before surgery , but their anxiety decreases considerably a few days after surgery and increases gradually 3 months thereafter .
many studies have been conducted with an aim to decrease anxiety in the patients using aromatherapy . in accordance with our results ,
muzzarelli et al . indicated that inhalation aromatherapy using lavender essential oil had no significant effect on anxiety ( p = 0.630 ) . the result reported by garham et al .
indicated that inhalation aromatherapy did not have any effect on reducing anxiety in patients who underwent radiotherapy ; even the level of anxiety in the control group was less than that in the aromatherapy group .
the reason for increase in anxiety level could be due to the association between specific odor and anxiety caused by radiotherapy .
on the other hand , the study of lehrner et al . showed that inhalation aromatherapy with lavender essential oil could reduce the anxiety level before the dental procedure ( p = 0.039 ) , which was not in accordance with the present study .
lavender essential oil combined with orange had been used , whereas in this study , pure herbal essential oil was used .
the study of conrad et al . indicated that inhalation aromatherapy with lavender essential oil could reduce anxiety and depression postpartum , which was not in accordance with the results of this study .
the reason for the dissimilarity could be the duration of intervention . in conrad et al .
's study , 15-min sessions as 2 times per week for 4 consecutive weeks were used , whereas 20-min sessions for two consecutive days were used in the present study .
the mean level of anxiety might become statistically different between the two groups if the duration of intervention is changed .
the results of the study by lee et al . showed that inhalation aromatherapy with lavender essential oil could reduce anxiety in women undergoing cesarean section , which was not in accordance with the results of this study .
the reason for the dissimilar results could be the duration of inhalation . in the study of lee et al .
, women received aromatherapy with lavender essential oil for 5 min , whereas it was 20 min in the present study . in this study
, we found that lavender essential oil had no significant effect on the vital signs except systolic blood pressure . in accordance with the results of our study , hwang et al .
, in their investigation on the effect of inhalation aromatherapy with lavender essential oil on blood pressure , reported that lavender could significantly reduce the blood pressure ( p < 0.05 ) . on the other hand ,
shiina et al . reported that lavender essential oil had no effect on blood pressure .
the discrepancy between the study results may be due to the difference in the dose of lavender used in the studies .
rho et al . reported that aromatherapy had no significant effect on the respiratory rate as we showed in this study .
if the smell of essential oils closely associated with the negative memories is applied to the patient , it may lead to negative results .
in summary , inhalation aromatherapy with lavender essential oil had no significant effect on anxiety and vital signs , except for systolic blood pressure , in patients who had undergone coronary artery bypass surgery ; so our hypothesis was rejected .
these results could be influenced by the relationship between specific smell and stressful experience in coronary artery bypass surgery . applying inhalation aromatherapy with lavender essential oil
can be considered by nurses , physicians , and other members of the treatment team based on the results of this study and also since using complementary methods reduces the side effects of medications .
further studies about the long - term effects of usage of this method for reducing anxiety are recommended .
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### Summary:
: background : open heart surgery can cause high levels of anxiety in patients . nowadays , lavender essential oil is widely used in medical research .
this study was conducted with an aim to investigate the effects of lavender essential oil to reduce the anxiety of patients after coronary artery bypass surgery.materials and methods : this research is double - blinded randomized controlled trial on 60 patients who had undergone coronary artery bypass surgery in a 2-day intervention targeting reduction of anxiety .
this study was conducted in ekbatan therapeutic and educational center , hamadan city , iran , in 2013 .
the patients in the inhalation aromatherapy group inhaled two drops of 2% lavender essential oil and those in the control group inhaled two drops of distilled water as placebo for 20 min on the 2nd and 3rd days after surgery .
the level of anxiety was evaluated by spielberger 's state anxiety questionnaire before and after intervention and the vital signs were documented as well .
data were analyzed using stata 11 ( stata corp . , college station , tx , usa ) by independent t - test for continuous variables and chi - square test for categorical variables.results:the mean score of anxiety in the aromatherapy group was 48.73 5.08 and in the control group was 48 6.98 before the intervention ( p = 0.64 ) , which reduced after the intervention to 42.6 5.44 and 42.73 7.30 , respectively .
on the 3rd day after surgery , the mean score of anxiety in the aromatherapy group was 46.76 4.07 and in the control group was 46.53 7.05 before the intervention , which reduced to 41.33 3.65 and 41.56 6.18 , respectively , after the intervention . however , there was no statistically significant difference in the mean scores of anxiety between the aromatherapy and control groups.conclusions:lavender essential oil has no significant effect on anxiety in patients after coronary artery bypass surgery , although it decreased the level of anxiety in the 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:
: both alopecia areata ( aa ) and vitiligo are autoimmune diseases , and their coexistence in the same patient is not uncommon , as vitiligo has been reported to occur in 4.1% of patients of aa and is about 4 times more common in patients with aa than in the general population . however , their colocalization over the same site is exceedingly rare , with less than five cases being reported in the literature .
we present a case of a 15-year - old male child who had vitiligo and later developed aa over the existing lesions of vitiligo over face and scalp and have attempted to elucidate the current understanding of mechanisms of coexistence of these two diseases .
a 12-year - old boy presented to the skin outpatient department with history of depigmented areas on the scalp , face , neck , arms and legs for 5 years .
he also gave a history of development of patchy loss of hair over some of these lesions for 3 years .
, there were depigmented macules over the scalp , forehead , eyebrows , periorbital , perioral , preauricular regions , neck , elbows , hands , feet , shins , nose , chin , hands , knees and feet [ figures 1 and 2 ] . patches of hair loss were seen , limited to some of these depigmented areas over the vertex and occipital region of the scalp and eyebrows [ figure 3 ] .
on histopathological examination [ figure 4 ] of the skin biopsy specimen obtained from the scalp , dense peribulbar infiltrate was seen in the dermis .
other features were in keeping with the diagnosis of aa . additionally , the basal layer of the epidermis was almost devoid of pigment , [ figure 5 ] confirming the diagnosis of vitiligo over the same site
. depigmented macules over the scalps forehead , eyebrows , periorbital , perioral , preauricular regions , nose and chin depigmented macules over the hands and feet patches of alopecia over some of the depigmented areas over the scalp histopathological examination of scalp biopsy : dense peribulbar infiltrate in dermis and other features in keeping with the diagnosis of alopecia areata basal layer of the epidermis over the same site is almost devoid of pigment , confirming the diagnosis of vitiligo
aa is a non - scarring , autoimmune , inflammatory hair loss on the scalp , and/or body .
this is evidenced by the presence of antibodies in both these diseases and their frequent association with other autoimmune disorders , such as thyroid diseases , diabetes mellitus , bullous pemphigoid , pemphigus vulgaris , lichen planus or pernicious anemia etc . in case of aa ,
the autoreactive t - lymphocytes are predominantly present in the peribulbous inflammatory infiltrate and are directed against an unknown antigen of the hair follicle .
some common factors that appear to be implicated in the etiopathogenesis of both these diseases are autoimmunity , genetic pre - disposition , environmental factors , and emotional or physical stress .
our case lends support to the hypothesis that aa and vitiligo share a common pathogenic pathway including autoimmune response against some common antigens like those derived from the bulb melanocytes .
melanocytes - derived peptide antigens released during vitiligo pathogenesis could act as auto - antigens not only for vitiligo , but also for aa , and autoimmune th - cells against them could also trigger a response against the hair follicle melanocytes , thus , pre - disposing to aa .
this is evidenced immunohistologically by the findings of helper t - lymphocytes and antibodies against abnormal hair bulb melanocytes in both these diseases .
this hypothesis is also supported by the chronological order of vitiligo followed by aa in this patient .
thus , stimulation of proinflammatory th-1 cell mediated immunological response or inactivation of a suppressor t - cell mediated response could be the common underlying phenomenon .
moreover , the frequent clinical observation that after aa , the regrown hair is initially white in color may also be due to the coexistent damage to the hair follicle melanocytes in aa . during recovery from vitiligo ,
this has led to the recent debate over the current understanding of their pathogenesis , and whether this association is merely a coincidence . according to the mosaic of autoimmunity theory ,
autoimmune diseases are a result of the complex interplay of various factors like immunological , genetic , hormonal and environmental .
this multifactorial etiology brings about diversity in the clinical presentation of autoimmune diseases and may be the cause of rarity of colocalization of these two diseases inspite of some common processes involved in their etiopathogenesis .
another difference in these two diseases lies in the site of the target melanocytes . while the populations of melanocytes targeted by the autoimmune t - lymphocytes in aa are present in the hair bulb , in case of vitiligo the epidermal melanocytes are involved .
these factors may be the cause of the very low incidence of the colocalization of these two diseases even though the common pathogenic mechanisms would suggest otherwise .
as both aa and vitiligo are frequent and chronic dermatological disorders , it is of utmost importance to gain more understanding into their pathogenic mechanisms so that more definitive treatment modalities may be devised and the quality of life of these patients can be improved .
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### Summary:
: both alopecia areata ( aa ) and vitiligo are autoimmune diseases , and their coexistence in the same patient is not uncommon , as vitiligo has been reported to occur in 4.1% of patients of aa .
we present a case of a 15-year - old male child who had vitiligo and later developed aa over the existing lesions of vitiligo over face and scalp and have attempted to elucidate the current understanding of mechanisms of coexistence of these two diseases .
our case lends support to the hypothesis that aa and vitiligo share a common pathogenic pathway including autoimmune response against some common antigens like those derived from the bulb melanocytes .
stimulation of proinflammatory t - helper(th)-1 cell mediated immunological response or inactivation of a suppressor t - cell mediated response could be the common underlying phenomenon .
however , the striking rarity of colocalization of these two diseases has led to the recent debate over current understanding of their pathogenesis , and whether this association is merely a coincidence .
as both aa and vitiligo are frequent and chronic dermatological disorders , it is of utmost importance to gain more understanding into their pathogenic mechanisms so that more definitive treatment modalities may be devised and the quality of life of these patients can be improved .
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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:
: patient ii-1 was the first daughter of first - cousin palestinian parents ( figure , a ) .
these were initially mild and intermittent and confined to the face , predominantly around the mouth , as twitching of the lips .
within several months , the movements became more persistent and spread to the fingers and thighs ( video at neurology.org/ng ) .
neurologic examination at 15 years revealed purposeless insuppressible choreiform movements involving the face and hands .
the facial movements were mainly perioral and consisted of involuntary movements of the upper lip upward , grimacing , and movement of the lower jaw from side to side .
purposeless movements of the thighs and the head were also observed but at a lesser frequency .
( a ) the family pedigree showing symptomatic patients ( filled symbols ) and genotype of the c.c873a , p.c291x mutation in the gpr88 gene .
( b ) the chromatogram of the mutation ( asterisk ) , a patient ( upper panel ) , a carrier ( middle panel ) , and a healthy control ( lower panel ) .
psychomotor delay was evident in infancy ; she walked independently at 2 years and had markedly retarded speech acquisition , with short sentences uttered only at 8 years of age .
her school performance was poor because of severe learning difficulties , and at 10 years , she could read only simple words and had marked dyscalculia .
involuntary movements were first noted at 8 years and consisted of intermittent rising of the eyebrows and forward head movements . at 10 years , she developed choreiform movements with constant flexion / extension of the fingers and hands , grimacing , side - to - side movement of the pelvis and trunk , upward shrugging of the shoulders , and flexion of the thighs ( see video ) .
patient ii-5 had a similar course ; she started walking at 18 months and her speech acquisition was delayed , with first words uttered at 3 years of age .
repetitive rising of the eyebrows and occasional forward head movements were noted at 8 years .
her school performance was always poor , and at 8 years , she was unable to read or calculate .
the pregnancy and delivery were uneventful , and her gross motor development was normal ; she could sit at 8 months and walked independently at 18 months .
routine laboratory investigations including a battery of tests for inborn errors of metabolism were normal in patient ii-1 .
this patient also underwent brain mri at 14 years of age , which was normal .
the other children in the family ( individuals ii-2 , ii-3 , ii-6 , and ii-7 ) aged 3.513.5 years had normal motor development and no involuntary movements . all had age - appropriate fluent speech and average learning performance .
exome analysis was performed as previously described in the dna samples of patients ii-1 and ii-4 .
the study was performed with the approval of the ethics committees of hadassah medical center and the ministry of health .
patient ii-1 was the first daughter of first - cousin palestinian parents ( figure , a ) .
these were initially mild and intermittent and confined to the face , predominantly around the mouth , as twitching of the lips .
within several months , the movements became more persistent and spread to the fingers and thighs ( video at neurology.org/ng ) .
neurologic examination at 15 years revealed purposeless insuppressible choreiform movements involving the face and hands .
the facial movements were mainly perioral and consisted of involuntary movements of the upper lip upward , grimacing , and movement of the lower jaw from side to side .
purposeless movements of the thighs and the head were also observed but at a lesser frequency .
( a ) the family pedigree showing symptomatic patients ( filled symbols ) and genotype of the c.c873a , p.c291x mutation in the gpr88 gene .
( b ) the chromatogram of the mutation ( asterisk ) , a patient ( upper panel ) , a carrier ( middle panel ) , and a healthy control ( lower panel ) .
psychomotor delay was evident in infancy ; she walked independently at 2 years and had markedly retarded speech acquisition , with short sentences uttered only at 8 years of age .
her school performance was poor because of severe learning difficulties , and at 10 years , she could read only simple words and had marked dyscalculia .
involuntary movements were first noted at 8 years and consisted of intermittent rising of the eyebrows and forward head movements . at 10 years , she developed choreiform movements with constant flexion / extension of the fingers and hands , grimacing , side - to - side movement of the pelvis and trunk , upward shrugging of the shoulders , and flexion of the thighs ( see video ) .
patient ii-5 had a similar course ; she started walking at 18 months and her speech acquisition was delayed , with first words uttered at 3 years of age .
repetitive rising of the eyebrows and occasional forward head movements were noted at 8 years .
her school performance was always poor , and at 8 years , she was unable to read or calculate .
the pregnancy and delivery were uneventful , and her gross motor development was normal ; she could sit at 8 months and walked independently at 18 months .
routine laboratory investigations including a battery of tests for inborn errors of metabolism were normal in patient ii-1 .
this patient also underwent brain mri at 14 years of age , which was normal .
the other children in the family ( individuals ii-2 , ii-3 , ii-6 , and ii-7 ) aged 3.513.5 years had normal motor development and no involuntary movements . all had age - appropriate fluent speech and average learning performance .
exome analysis was performed as previously described in the dna samples of patients ii-1 and ii-4 .
the study was performed with the approval of the ethics committees of hadassah medical center and the ministry of health .
the exome analyses of the dna of patients ii-1 and ii-4 yielded 47.9 and 61.0 million reads , respectively ( mean coverage x72.1 and x91.9 ) .
after alignment to the reference genome ( hg19 ) and variant calling , we removed variants that were called less than x8 ; were off - target , synonymous , or heterozygous ; those with minor allele frequency ( maf ) > 1% in the exome aggregation consortium ( exac ) , cambridge , ma ( http://exac.broadinstitute.org ) ; and those with maf > 2% in the hadassah in - house database .
four homozygous variants were shared by the 2 sisters , but using sanger sequencing we found that only 1 of the variants , chr1:101005395c > a , nm_022049:c.c873a , p.c291x in the gpr88 gene , was carried by the parents and was found to be homozygous in patients ii-5 and ii-8 .
none of the other siblings , whose development was age appropriate at 3.513.5 years , was homozygous for the variant ( figure , a and b ) .
the variant was not carried by any of the 60,000 individuals whose exome analyses were deposited in exac ( accessed june 2015 ) .
the 4 female patients , ages 1.515 years , presented in infancy with developmental delay , marked speech retardation , and learning disability .
the older 3 , when reaching 89 years of age , developed movement disorder , which consisted of choreiform movements involving mainly the face and hands with involuntary movements of the shoulders , pelvis , and thighs .
gpr88 encodes a 384amino acid protein , an orphan g protein coupled receptor that is abundantly expressed in the striatal medium spiny neurons ( msns ) .
the motor cortex receives input from other cortical areas , the cerebellum , and the basal ganglia , always through the thalamus .
the thalamus is under inhibitory activity of the globus pallidus pars interna ( gpint ) ; this inhibition can be released when the striatal gabaergic msn transmits an inhibitory signal to the gpint .
the inhibition is further relieved by stimulation of the msn dopamine ( d1 ) receptors .
the opposing indirect pathway aims at preventing movement by using another striatal subpopulation of msns , which transmit an inhibitory signal to the globus pallidus pars externa ( gpext ) .
the gpext transmits inhibitory signal to the subthalamic nucleus , which in turn makes excitatory connections to cells in the gpint , maintaining the gpint inhibitory effect on the thalamus .
the abundant expression of gpr88 in both d1 and d2 receptor expressing msns suggests that gpr88 has an instrumental role in movement control . in agreement ,
our patients who were homozygous for a deleterious gpr88 mutation had a hyperkinetic movement disorder and the gpr88 knockout mice had increased locomotion , nonhabitual hyperactivity in novel environment ( which is a primary landmark of striatal dysfunction ) , increased circling , and prolonged duration of burying episodes , suggesting stereotypic behavior . in the mutant animals , the msns had higher average firing , which was attributed to decreased tonic gabaergic inhibition resulting from low level of 3 protein , a gabaa receptor subunit , and to an increased glutamatergic excitatory synaptic transmission proposed to result from enhanced phosphorylation of the ampa - type glutamate receptor subunit glur1 .
speech delay and poor school performance in our patients recapitulated the marked impairment in motor skill learning of the mutant mice despite normal coordination and strength .
this deficit was confined to striatal learning and memory and did not affect hippocampal learning behavior .
gpr88 has been the center of scientific attention because administration of antidepressants , lithium , and valproate alters its expression , which likely mediates some of the adverse effects of these drugs .
in addition , association studies proposed gpr88 as a candidate gene in major psychoses . with the clear reservation that our oldest patient is currently 15 years of age , we can not lend support to these findings .
furthermore , the extended family has no known cases of psychiatric illness and the parents who carry the mutation have normal mental health .
we propose that gpr88 deficiency in humans manifests as developmental delay with pronounced speech acquisition impairment , learning disabilities , and hyperkinetic movement disorder at 89 years of age .
although further functional studies are needed , our clinical data corroborate those observed in the gpr88 knockout mice and underscore the role of gpr88 in movement control and learning .
bassam abu - libdeh designed and conceptualized the study and drafted and revised the manuscript .
dr . avraham shaag designed the study , analyzed and interpreted the data , and drafted the manuscript .
orly elpeleg designed the study , analyzed and interpreted the data , and drafted and revised the manuscript .
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### Summary:
: objective : to identify the underlying molecular basis of a familial developmental disorder characterized by chorea , marked speech delay , and learning difficulties in 4 sisters from a consanguineous family.methods:whole-exome analysis of dna of the 2 older patients followed by sanger sequencing of the mutated exon in all family members.results:a homozygous deleterious mutation , p.c291x , was identified in the gpr88 gene in both exome analyses . the mutation segregated with the disease in the family and was absent from a large cohort of controls.conclusions:homozygous deleterious mutation in gpr88 in humans is associated with marked speech delay , learning disabilities , and chorea , which manifest at 89 years of age .
the finding is consistent with the reported abundant expression of gpr88 in the striatum and the hyperkinetic activity and learning impairment observed in gpr88 knockout mice .
although further functional characterization is needed , the finding underscores the importance of gpr88 in movement control and learning .
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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 primary pathogenic mechanism is defective transepithelial chloride reabsorption in thick ascending limb of loop of henle ( talh ) .
the disease is characterized by hypokalemia , metabolic alkalosis , and secondary hyperaldosteronism with normal to low blood pressure due to renal loss of sodium and hyperplasia of juxtaglomerular apparatus [ 1 , 2 ] .
there are two distinct presentations of bartter syndrome , namely ; antenatal bartter syndrome ( abs ) and classical bartter syndrome .
the typical features include fetal polyuria , early onset maternal polyhydramnios , intrauterine growth restriction , preterm birth , postnatal polyuria , episodes of dehydration , recurrent vomiting , and failure to thrive [ 3 , 4 ] .
this is a rare autosomal recessive disorder characterized by late onset hypokalemic metabolic alkalosis , hypocalciuria , and hypomagnesemia .
plasma renin and aldosterone are increased but not to the degree seen in bartter syndrome .
antenatal bartter syndrome has four variants [ 5 , 6 ] with mild differences in phenotype and genotype ( table 1 ) .
principal clinical features in most of them include early onset polyhydramnios , failure to thrive , prematurity , and nephrocalcinosis .
types i , ii , and iii have severe antenatal symptoms , prematurity , and failure to thrive , while type iv is a mild salt losing nephropathy with mild antenatal symptoms .
type iv involves chloride channels which are present in distal nephron as well as in inner ear resulting in sensorineural hearing loss in addition .
table 1 shows the new pharmacology based classification with details of the types and molecules affected in each of them .
this classification is designed on bartter syndrome for easy understanding as students and young physicians are more familiar with pharmacologic actions of diuretics at each level of nephron .
thick ascending loop of henle ( tal ) has channels , namely , na - k-2cl cotransporter , k ( romk : rat outer medulla potassium ) , and chloride ( cic - kb ) channels which are responsible for electrolyte absorption .
each of these channels is coded by a specific gene ( table 1 ) . any mutation in gene results in impaired channel function and hence defective electrolyte reabsorption .
k transport occurs through romk channel , whereas na and cl get absorbed from the luminal space .
passage of cl from the cell into the interstitium can take place through kidney - specific chloride channels ( cic - kb ) and via k / cl cotransport system . in the apical membrane
thus , the handling of chloride ions by the thick ascending loop of henle ( talh ) is an intimate part of the normal function of na k 2ci electroneutral cotransport , as well as k channels ( romk ) and cl channels ( cic - kb ) .
any loss or altered function of na - k-2ci cotransporter and/or k channels as well as chloride channels results in defective cl transport .
this defect will result in malreabsorption of na , k , cl , and ca in the talh and delivery of large volumes of urine with a high content of na , k , cl , and ca to the distal tubule . in the distal tubule , part of the delivered na will be reabsorbed in exchange for intracellular k. hence , potassium wasting occurs . impaired na absorption in talh
increased pge2 will exacerbate primary defect of chloride transport in talh which will stimulate renin angiotensin - aldosterone axis causing hypokalemia ( due to hyperaldosteronism ) , and impede water reabsorption in collecting ducts leading to hyposthenuria ( figures 1 and 2 ) .
hyperaldosteronism increases k wasting and stimulates exchange of intracellular h ions for k ions for intraluminal k ( distal tubule and collecting duct ) resulting in exaggeration of metabolic alkalosis . the normal blood pressure despite high levels of renin and angiotensin is thought to be due to nonresponsive of their blood vessels to angiotensins [ 17 ] .
mothers of fetus with bartter syndrome often present with unexplained polyhydramnios between 24 and 30 weeks of gestation [ 3 , 4 , 7 ] . intrauterine growth restriction may also be associated .
important biochemical abnormality in amniotic fluid is normal sodium and potassium but consistently elevated chloride levels [ 4 , 812 ] .
urine examination shows low specific gravity , normal potassium but high sodium and chloride levels .
however , after 13 weeks , level of potassium considerably rises above normal with relatively less sodium than in the first week of life .
prostaglandin levels are high in blood and urine as a secondary phenomenon [ 5 , 6 , 9 , 13 ] .
impaired sodium absorption in talh will result in increased levels of prostaglandin e2 [ 13 , 14 ] .
if the diagnosis gets delayed , infants may present with poor feeding , dehydration , and severe electrolyte imbalance .
blood pressure is usually normal . growth faltering , dwarfism , polydipsia , and weakness may be present in older children .
facial features such as triangular face , prominent forehead , large eyes , protruding ears , and drooping mouth may be present [ 15 , 16 ] .
strabismus , convulsions , and increased susceptibility to infections are also reported [ 15 , 16 ] .
urinary electrolytes except potassium in second trimester are low in mother 's urine in cases of bartter syndrome .
when there is early onset unexplained maternal polyhydramnios , ultrasonography should be performed to confirm structurally normal fetus and placenta .
if abs is strongly suspected , one should do amniocentesis and subject amniotic fluid for biochemical analysis .
high chloride in amniotic fluid is a consistent finding and diagnostic of abs [ 4 , 9 , 17 ] .
ultrasonography of the kidneys detects bilateral medullary nephrocalcinosis which is observed after several weeks of severe hypercalciuria [ 2 , 4 , 11 ] .
the important complications of abs include hypercalciuria leading to nephrocalcinosis [ 2 , 4 , 11 , 12 ] and growth restriction .
defects in the barttin subunit of the clc - ka and cic - kb channels are responsible for sensorineural deafness . very rarely progressive
prenatal diagnosis can be made by the high chloride content of the amniotic fluid [ 1820 ] and mutational analysis of genomic dna extracted from cultured amniocytes obtained by amniocentesis .
once abs is confirmed , mother should be treated antenatally at the earliest with indomethacin ( 1 mg / kg / day ) in two divided doses .
indomethacin inhibits prostaglandin synthetase , decreases renal salt wasting , reduces fetal urine output , and thereby controls polyhydramnios .
following birth , neonate should be monitored for urine output , hydration , weight loss , and electrolyte balance .
indomethacin at a dose of 15 mg / kg is usually recommended and well tolerated [ 18 , 22 , 23 ] . early initiation of indomethacin may be required in neonatal bartter syndrome caused by mutations at gene coding for the nkcc2 transporter .
benefit from initiation of indomethacin therapy at 46 weeks and doses below 1 mg / kg / day is likely in patients with mutations at the romk channel gene .
other drugs used are acetylsalicylic acid ( 100 mg / kg / day ) , ibuprofen ( 30 mg / kg / day ) , or ketoprofen ( 20 mg / kg / day ) .
addition of potassium sparing diuretics may be initially effective in the control of hypokalemia , but their effect is transient .
caution in such treatment is required as treatment with potassium sparing diuretics may be dangerous in situations of gross salt and water wasting and circulatory volume contraction . long - term prognosis is guarded .
lack of satisfactory control may lead to morbidity , growth failure , and renal insufficiency [ 2 , 18 , 23 ] .
timely and appropriate therapy results in clinical improvement and catch up growth in majority of children .
long - term outcome including mental development and puberty is usually normal [ 2 , 18 , 23 ] .
hypokalemia , hypercalciuria , and nephrocalcinosis may lead to chronic tubulointerstitial nephropathy and progressive reduction in gfr .
brochard et al . reported chronic renal failure in 3 out of 42 children with a median followup of 8.3 years .
satisfactory prognosis after a median followup of more than 10 years and gallstones representing a new complication of abs has also been reported .
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### Summary:
: antenatal bartter syndrome ( abs ) is a rare autosomal recessive renal tubular disorder .
the defective chloride transport in the loop of henle leads to fetal polyuria resulting in severe hydramnios and premature delivery .
early onset , unexplained maternal polyhydramnios often challenges the treating obstetrician .
increasing polyhydramnios without apparent fetal or placental abnormalities should lead to the suspicion of this entity .
biochemical analysis of amniotic fluid is suggested as elevated chloride level is usually diagnostic .
awareness , early recognition , maternal treatment with indomethacin , and amniocentesis allow the pregnancy to continue .
affected neonates are usually born premature , have postnatal polyuria , vomiting , failure to thrive , hypercalciuria , and subsequently nephrocalcinosis .
hypokalemia , metabolic alkalosis , secondary hyperaldosteronism and hyperreninaemia are other characteristic features .
volume depletion due to excessive salt and water loss on long term stimulates renin - angiotensin - aldosterone system resulting in juxtaglomerular hyperplasia .
clinical features and electrolyte abnormalities may also depend on the subtype of the syndrome .
prenatal diagnosis and timely indomethacin administration prevent electrolyte imbalance , restitute normal growth , and improve activity . in this paper , authors present classification , pathophysiology , clinical manifestations , laboratory findings , complications , and prognosis of abs .
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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:
: hyperventilation is an easy and safe procedure for inducing physiological eeg morphologic changes , interictal discharges , and certain seizures.1 physiologically , the eeg morphologic change consists of a buildup of medium to high amplitude , bisynchronous delta and theta waves and an increase in the amplitude of the theta and alpha waveforms.1 children show these changes more intensely than adults , especially between the ages of 8 to 12 years.2 in addition to these physiological changes , hyperventilation can also elicit certain clinical seizures , especially in patients with idiopathic generalized epilepsy or symptomatic generalized epilepsy.2 the mechanism of the hyperventilation - induced eeg changes ( hv - eeg changes ) is still debated.1,3 the hypoxia theory holds that cerebral hypoxia associated with vasoconstriction induced by hyperventilation is an explanation of the cause of these changes.3 but several studies on the change in pco2 during hyperventilation have raised an objection to this theory.4 they reported that a wide range of pco2 could induce eeg changes and that the absolute value of the pco2 was meaningless . as a result
the direct effects of pco2 , cerebral alkalosis , and individual sensitivity to hypoxia , as well as hypoxia itself , all may be part of the mechanism of these eeg changes.3 although the effects of hyperventilation on the eeg are well - known , there is no standard protocol for hyperventilation ; few studies have examined standardization of the hyperventilation procedure.5,6 in one study of the topographical quantitative eeg changes after hyperventilation , the maintenance of the end - tidal pco2 at 15 mmhg had a greater mean spectral power density than non - standardized hyperventilation.5 a study of hyperventilation in children suggested that maintaining a respiration rate of 30/min and a threefold elevation of the resting expiratory volume for 4 min were the optimal conditions for evoking eeg changes.6 however , there is no widely accepted standardized protocol for hyperventilation .
the duration and methods of hyperventilation differ according to the each laboratory , and the prevalence and amount of the hv - eeg changes also vary .
the effect of pco2 in the hv - eeg changes has been investigated using various modalities , including ictal spect,2
trans - cranial doppler,7 and capnography3,4,5,811 ; however , it is not known whether a certain pco2 level induces the eeg changes and the relationship between the hv - eeg changes and pco2 level is also unclear .
although hyperventilation is a useful method for eliciting certain clinical seizures and epileptiform discharges , recent studies of hyperventilation and eeg seems to have focused on seizure induction , and not the basic physiology.8,12,13 we can not neglect the basic aspects of hyperventilation . in this study , we conducted trans - nasal pco2 monitoring during hyperventilation while recording the eeg in consecutive patients .
we analyzed level and change of pco2 and eeg of patients , to define the relationship between pco2 and hv - eeg changes ; the frequency of hv - eeg changes , presence of certain level of pco2 which could induce hv - eeg changes and other factors of pco2 which could affect hv - eeg changes .
the study group consisted of patients with proven epilepsy , as well as non - epileptic patients who underwent an eeg for other reasons , including loss of consciousness , involuntary movements , and headache . in total , 139 patients were diagnosed with various types of epilepsy and were prescribed medication , and the remaining 51 patients had no definitive evidence of clinical seizures .
the patients ranged in age from 5 to 65 ( 32.015.7 ; meansd ) years .
we divided the patients into children - adolescents ( n=45 , age range : 517 years , mean : 13.163.46 ) and adults ( n=145 , age range : 1865 years , mean : 37.8 13.26 ) groups using the age boundary of 17 years . by sex , 134 patients were male and 56 were female .
there was no statistically significant difference in the numbers of epileptic patients in the two groups divided by age .
there was also no statistically significant difference in the number of children - adolescents patients in the two groups divided by the presence of epilepsy ( p=0.321 ; chi - square test ) .
all the eegs in this study were recorded using a telefactor aurora eeg machine ( grass - telefactor , melbourne , australia ) and reviewed using telefactor twin 2.6 software .
the eegs were recorded using 21 channels with scalp electrodes according to the international 1020 system ( fp1 , fp2 , f3 , f4 , c3 , c4 , p3 , p4 , o1 , o2 , t1 , t2 , f7 , f8 , t3 , t4 , t5 , t6 , fz , cz , pz ) .
the recording time was at least 30 min , including a 5 min hyperventilation period .
the hyperventilation procedure involved the maximal respiratory effort of the patient while encouraged by the eeg technician about 4045/min .
a trans - nasal pco2 monitoring device ( co2smo etco2/spo2 monitor ; novametrix , wallingford , ct , usa ) was used to measure the pco2 during the hyperventilation period .
we defined the hv - eeg changes as summation of all eeg changes that presented more than at least 10 sec , and consisted of theta and delta induction with amplitude increment .
we divided the patients in two groups according to the presence of hv - eeg changes : the response and no - response groups .
we also examined the trace for electrical or clinical seizures during the hyperventilation period ; no electrical or clinical seizure activity was provoked in the 190 patients .
we used the novacard data archive system ( novametrix ) to collect the pco2 data recorded during the hyperventilation period .
we gathered data on the baseline pco2 level ( b - pco2 ) , the pco2 level after 5 min of hyperventilation ( 5 min - pco2 ) , and the mean pco2 level ( m - pco2 ) for each group .
we also determined the change in the pco2 level ( pco2 ) , which was the difference between the b - pco2 and 5 min - pco2 .
chicago , il , usa ) to compare the four variables between the response and no - response groups .
we also made the same comparisons within the epileptic patients , non - epileptic patients , children - adolescents , and adults groups .
the mann - whitney u test was used for the comparisons . with normality and equal variance
, student s t - test was performed . to compare the frequency of the hv - eeg changes between epileptic and non - epileptic patients and between children - adolescents and adult patients , we used chi - square analysis . in all analyses ,
the study group consisted of patients with proven epilepsy , as well as non - epileptic patients who underwent an eeg for other reasons , including loss of consciousness , involuntary movements , and headache . in total , 139 patients were diagnosed with various types of epilepsy and were prescribed medication , and the remaining 51 patients had no definitive evidence of clinical seizures .
the patients ranged in age from 5 to 65 ( 32.015.7 ; meansd ) years .
we divided the patients into children - adolescents ( n=45 , age range : 517 years , mean : 13.163.46 ) and adults ( n=145 , age range : 1865 years , mean : 37.8 13.26 ) groups using the age boundary of 17 years . by sex , 134 patients were male and 56 were female .
there was no statistically significant difference in the numbers of epileptic patients in the two groups divided by age .
there was also no statistically significant difference in the number of children - adolescents patients in the two groups divided by the presence of epilepsy ( p=0.321 ; chi - square test ) .
all the eegs in this study were recorded using a telefactor aurora eeg machine ( grass - telefactor , melbourne , australia ) and reviewed using telefactor twin 2.6 software .
the eegs were recorded using 21 channels with scalp electrodes according to the international 1020 system ( fp1 , fp2 , f3 , f4 , c3 , c4 , p3 , p4 , o1 , o2 , t1 , t2 , f7 , f8 , t3 , t4 , t5 , t6 , fz , cz , pz ) .
the recording time was at least 30 min , including a 5 min hyperventilation period .
the hyperventilation procedure involved the maximal respiratory effort of the patient while encouraged by the eeg technician about 4045/min .
a trans - nasal pco2 monitoring device ( co2smo etco2/spo2 monitor ; novametrix , wallingford , ct , usa ) was used to measure the pco2 during the hyperventilation period .
we defined the hv - eeg changes as summation of all eeg changes that presented more than at least 10 sec , and consisted of theta and delta induction with amplitude increment .
we divided the patients in two groups according to the presence of hv - eeg changes : the response and no - response groups .
we also examined the trace for electrical or clinical seizures during the hyperventilation period ; no electrical or clinical seizure activity was provoked in the 190 patients .
we used the novacard data archive system ( novametrix ) to collect the pco2 data recorded during the hyperventilation period .
we gathered data on the baseline pco2 level ( b - pco2 ) , the pco2 level after 5 min of hyperventilation ( 5 min - pco2 ) , and the mean pco2 level ( m - pco2 ) for each group .
we also determined the change in the pco2 level ( pco2 ) , which was the difference between the b - pco2 and 5 min - pco2 .
chicago , il , usa ) to compare the four variables between the response and no - response groups .
we also made the same comparisons within the epileptic patients , non - epileptic patients , children - adolescents , and adults groups .
the mann - whitney u test was used for the comparisons . with normality and equal variance ,
student s t - test was performed . to compare the frequency of the hv - eeg changes between epileptic and non - epileptic patients and between children - adolescents and adult patients , we used chi - square analysis . in all analyses
eeg changes were seen in 48 of the 190 patients ( 25.3% ) . in the children - adolescents group , 18 of 45 patients ( 40.0% ) had eeg changes . in the adults ,
30 of 145 patients ( 20.7% ) exhibited eeg changes ( p=0.016 ; chi - square test ) .
seven of the 51 non - epileptic patients ( 13.7% ) showed eeg changes versus 41 of the 139 epileptic patients ( 29.5% ) ( p=0.042 ; chi - square test ) .
the b - pco2 was 39.83.7 mmhg in the response group and 39.33.6 mmhg in the no - response group ( p=0.353 ) .
the 5 min - pco2 was 25.64.5 and 26.95.1 mmhg ( p=0.124 ) ; the m - pco2 was 30.33.9 and 31.24.0 mmhg ( p=0.200 ) ; and the pco2 was 14.25.0 and 12.45.0 mmhg ( p=0.033 ) , respectively .
only the pco2 differed significantly between the response and no - response groups ( table 1 ) . in children - adolescents group ,
the b - pco2 was 39.33.4 and 40.03.7 mmhg ( p=0.490 ) ; the 5 min - pco2 was 27.75.3 and 29.66.3 mmhg ( p = 0.298 ) ; the m - pco2 was 32.14.3 and 33.04.9 mmhg ( p=0.494 ) ; and the pco2 was 11.65.5 and 10.44.8 mmhg ( p=0.465 ) , respectively . in the adults group ,
the values of the 5 min - pco2 and pco2 differed significantly between the response and no - response groups .
the b - pco2 was 40.03.9 and 39.13.6 mmhg ( p=0.117 ) ; the 5 min - pco2 was 24.33.4 and 26.24.6 mmhg ( p=0.048 ) ; the m - pco2 was 29.23.3 and 30.73.7 mmhg ( p=0.075 ) ; and the pco2 was 15.84.0 and 12.95.0 mmhg ( p=0.004 ) , respectively ( table 2 ) . in the epileptic group , there was no statistically significant difference in any variable between the response and no - response groups .
the b - pco2 was 39.83.8 and 39.43.9 mmhg ( p=0.468 ) ; the 5 min - pco2 was 25.94.7 and 27.15.6 mmhg ( p=0.343 ) ; the m - pco2 was 30.54.1 and 31.54.3 mmhg ( p=0.280 ) ; and the pco2 was 13.95.1 and 12.35.5 mmhg ( p=0.101 ) , respectively . in the non - epileptic group ,
the value of the 5 min - pco2 differed significantly between the response and no - response groups .
the b - pco2 was 39.33.6 and 39.03.0 mmhg ( p=0.833 ) ; the 5 min - pco2 was 23.42.2 and 26.33.8 mmhg ( p=0.026 ) ; the m - pco2 was 28.92.5 and 30.5 3.3 mmhg ( p=0.205 ) ; and the pco2 was 15.94.3 and 12.73.9 ( p=0.053 ) , respectively ( table 3 ) .
eeg changes were seen in 48 of the 190 patients ( 25.3% ) . in the children - adolescents group , 18 of 45 patients ( 40.0% ) had eeg changes . in the adults ,
30 of 145 patients ( 20.7% ) exhibited eeg changes ( p=0.016 ; chi - square test ) .
seven of the 51 non - epileptic patients ( 13.7% ) showed eeg changes versus 41 of the 139 epileptic patients ( 29.5% ) ( p=0.042 ; chi - square test ) .
the b - pco2 was 39.83.7 mmhg in the response group and 39.33.6 mmhg in the no - response group ( p=0.353 ) .
the 5 min - pco2 was 25.64.5 and 26.95.1 mmhg ( p=0.124 ) ; the m - pco2 was 30.33.9 and 31.24.0 mmhg ( p=0.200 ) ; and the pco2 was 14.25.0 and 12.45.0 mmhg ( p=0.033 ) , respectively .
only the pco2 differed significantly between the response and no - response groups ( table 1 ) . in children - adolescents group ,
the b - pco2 was 39.33.4 and 40.03.7 mmhg ( p=0.490 ) ; the 5 min - pco2 was 27.75.3 and 29.66.3 mmhg ( p = 0.298 ) ; the m - pco2 was 32.14.3 and 33.04.9 mmhg ( p=0.494 ) ; and the pco2 was 11.65.5 and 10.44.8 mmhg ( p=0.465 ) , respectively .
in the adults group , the values of the 5 min - pco2 and pco2 differed significantly between the response and no - response groups .
the b - pco2 was 40.03.9 and 39.13.6 mmhg ( p=0.117 ) ; the 5 min - pco2 was 24.33.4 and 26.24.6 mmhg ( p=0.048 ) ; the m - pco2 was 29.23.3 and 30.73.7 mmhg ( p=0.075 ) ; and the pco2 was 15.84.0 and 12.95.0 mmhg ( p=0.004 ) , respectively ( table 2 ) . in the epileptic group , there was no statistically significant difference in any variable between the response and no - response groups .
the b - pco2 was 39.83.8 and 39.43.9 mmhg ( p=0.468 ) ; the 5 min - pco2 was 25.94.7 and 27.15.6 mmhg ( p=0.343 ) ; the m - pco2 was 30.54.1 and 31.54.3 mmhg ( p=0.280 ) ; and the pco2 was 13.95.1 and 12.35.5 mmhg ( p=0.101 ) , respectively . in the non - epileptic group ,
the value of the 5 min - pco2 differed significantly between the response and no - response groups .
the b - pco2 was 39.33.6 and 39.03.0 mmhg ( p=0.833 ) ; the 5 min - pco2 was 23.42.2 and 26.33.8 mmhg ( p=0.026 ) ; the m - pco2 was 28.92.5 and 30.5 3.3 mmhg ( p=0.205 ) ; and the pco2 was 15.94.3 and 12.73.9 ( p=0.053 ) , respectively ( table 3 ) .
the b - pco2 was 39.83.7 mmhg in the response group and 39.33.6 mmhg in the no - response group ( p=0.353 ) .
the 5 min - pco2 was 25.64.5 and 26.95.1 mmhg ( p=0.124 ) ; the m - pco2 was 30.33.9 and 31.24.0 mmhg ( p=0.200 ) ; and the pco2 was 14.25.0 and 12.45.0 mmhg ( p=0.033 ) , respectively .
only the pco2 differed significantly between the response and no - response groups ( table 1 ) .
in children - adolescents group , none of the variables differed significantly between the response and no - response groups .
the b - pco2 was 39.33.4 and 40.03.7 mmhg ( p=0.490 ) ; the 5 min - pco2 was 27.75.3 and 29.66.3 mmhg ( p = 0.298 ) ; the m - pco2 was 32.14.3 and 33.04.9 mmhg ( p=0.494 ) ; and the pco2 was 11.65.5 and 10.44.8 mmhg ( p=0.465 ) , respectively . in the adults group ,
the values of the 5 min - pco2 and pco2 differed significantly between the response and no - response groups .
the b - pco2 was 40.03.9 and 39.13.6 mmhg ( p=0.117 ) ; the 5 min - pco2 was 24.33.4 and 26.24.6 mmhg ( p=0.048 ) ; the m - pco2 was 29.23.3 and 30.73.7 mmhg ( p=0.075 ) ; and the pco2 was 15.84.0 and 12.95.0 mmhg ( p=0.004 ) , respectively ( table 2 ) .
in the epileptic group , there was no statistically significant difference in any variable between the response and no - response groups .
the b - pco2 was 39.83.8 and 39.43.9 mmhg ( p=0.468 ) ; the 5 min - pco2 was 25.94.7 and 27.15.6 mmhg ( p=0.343 ) ; the m - pco2 was 30.54.1 and 31.54.3 mmhg ( p=0.280 ) ; and the pco2 was 13.95.1 and 12.35.5 mmhg ( p=0.101 ) , respectively . in the non - epileptic group ,
the value of the 5 min - pco2 differed significantly between the response and no - response groups .
the b - pco2 was 39.33.6 and 39.03.0 mmhg ( p=0.833 ) ; the 5 min - pco2 was 23.42.2 and 26.33.8 mmhg ( p=0.026 ) ; the m - pco2 was 28.92.5 and 30.5 3.3 mmhg ( p=0.205 ) ; and the pco2 was 15.94.3 and 12.73.9 ( p=0.053 ) , respectively ( table 3 ) .
in this study , we determined three major findings concerning the hv - eeg changes and pco2 .
first , hyperventilation - induced eeg changes were more frequently observed in the children - adolescents group than in the adults group and in the epileptic group than in the non - epileptic group .
second , the 5 min - pco2 differed significantly in responders in the adults and non - epileptic patients groups . finally , the pco2 had a significant effect on inducing hv - eeg changes in all the enrolled patients and the adults group .
it is widely known that children show these responses more frequently , but the prevalence of the responses has varied from study to study .
the most widely accepted data on the prevalence of hv - eeg changes were reported by gibbs et al.9 in 1943 .
they studied hyperventilation and eeg responses in 2,281 normal controls and 1,107 epileptic patients and reported that a response to varying degrees was seen more in children than in adults and in epileptic patients more than in the normal population .
they reported that 697 of the 1,027 normal controls and epileptic patients under the age of 20 years showed an eeg response ( 67.9% ) , while 807 of 2,391 participants over 20 years of age showed eeg changes ( 33.8% ) .
in addition , they reported that 763 of 1,107 epileptic patients ( 68.9% ) and 751 of 2,281 normal controls showed these responses ( 32.5% ) . in our study , the prevalence was 40% in the children - adolescents group , 20.7% in the adults group , 29.5% in the epileptic group , and 13.7% in the non - epileptic group .
although these prevalences were lower than those of gibbs et al . , they showed the same tendency , i.e. , young individuals and epileptic patients showed hv - eeg changes more frequently .
we believe that the lower prevalence in our study was mainly due to differences in the hyperventilation protocol .
the protocol gibbs et al . used for hyperventilation was stricter , and required approximately 50 deep breaths / min for 2 min .
because we monitored the pco2 level , we thought that a strict hyperventilation protocol may not be needed in our study .
the end - tidal pco2 level after voluntary hyperventilation is reported to be critical in inducing eeg changes.5,6 this provided strong support for the hypoxia theory concerning the hv - eeg changes.3 because other studies reported that a wide range of pco2 could induce these responses,4 investigators no longer focused on attempts to determine the threshold pco2 level inducing hv - eeg changes .
we found a statistically significant effect of the 5 min - pco2 on hv - eeg changes in the adults and non - epileptic patients groups .
however , a range of pco2 induced eeg changes in our study , as previously reported .
we believe finding that a wide range of pco2 levels induced hv - eeg changes is more meaningful than finding that the 5 min - pco2 was significantly effective in inducing hv - eeg changes .
the pco2 had a significant relationship with whether there was a response for the patients as a whole and the adults group and a tendency in the non - epileptic patients group ( p=0.053 ) .
this implies that it is the change in the pco2 level between before and after hyperventilation that is important for inducing eeg changes , and not the absolute pco2 level . to our knowledge
, this is the first study to report that the change in the pco2 level is more associated with eeg changes .
we also believe that it is meaningful that the 5 min - pco2 and pco2 were statistically significant in the adults and non - epileptic patients groups .
the pco2 did not appear to make an important contribution to the eeg changes in the children - adolescents and epileptic patients groups .
we suggest that factors other than the pco2 are more important for inducing the hv - eeg changes in these groups .
there are reports that the cerebrovascular responsiveness to co2 varies with age , and that the difference in the eeg response to hyperventilation in children and adults may result from differences in decreased cerebral blood flow and sensitivity of the cns to the change in cerebral blood flow.10,11 this may explain why eeg changes were more common in the children - adolescents group , but not in the epileptic patients group . in addition , we think that the well - known neuronal hyperplasticity , immaturity , or excitability of those patients is a plausible explanation for the increase in eeg changes versus the adults and non - epileptic patients groups
regardless of whether they had epilepsy , the pco2 was the only statistically significant contributing factor for hv - eeg changes . in the adults - epileptic group
, pco2 was 15.454.1 mmhg in the response group and 13.15.5 mmhg in the no - response group ( p=0.045 ) .
in the adults - non - epileptic group , pco2 was 17.82.2 and 12.43.7 mmhg in the respective groups ( p=0.007 ) .
pco2 may have a critical role in inducing eeg changes in adults and non - epileptic patients .
pco2 monitoring according to the change from the baseline pco2 level may be important for properly provoking the hv - eeg changes for a limited group of patients .
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### Summary:
: background and purpose : we conducted this study to define the relationship between the hyperventilation - induced eeg changes ( hv - eeg changes ) and pco2methods : in consecutive eeg recordings of 190 patients , we gathered data on pco2 during the hyperventilation procedure .
the data included baseline pco2 ( b - pco2 ) , pco2 after 5 min of hyperventilation ( 5 min - pco2 ) , the mean value of the pco2 ( m - pco2 ) , and the difference between b - pco2 and 5 min - pco2 ( pco2 ) .
we divided the enrolled patients into two groups by hyperventilation response ( response group and no - response group ) , presence of epilepsy ( epileptic group and non - epileptic group ) and age ( child - adolescent group and adult group ) repeatedly .
we compared the four variables between the two groups in each pair.results:pco2 was 14.25.0 mmhg ( meansd ) in response group ( n=48 ) and 12.45.0 in no - response group ( n=142 ; p=0.033 ) for all the patients . for adult patients only , 5 min - pco2 was 24.33.4 in response group ( n=30 ) and 26.24.6 in no - response group ( n=115 ; p=0.048 ) , and pco2 was 15.84.0 and 12.95.0 , respectively ( p=0.004 ) . in non - epileptic patients ,
5min - pco2 was 23.42.2 in response group ( n=7 ) and 26.33.8 in no - response group ( n=44 ; p=0.026 ) , and pco2 was 15.94.3 and 12.73.9 , respectively ( p=0.053).conclusions : in adults and non - epileptic patients , pco2 and 5 min - pco2 may be crucial to the induction of eeg changes by hyperventilation .
pco2 could be a crucial factor for provoking hv - eeg changes in a limited group of 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:
: toxoplasmosis is a common disease in humans , domestic and wild animals ( 1 , 2 ) .
the mechanism of abortion due to toxoplasmosis is not fully defined , and the effects of this parasite on corpus luteum function have not been explored ( 4 ) .
in addition , chronic infection influences noradrenergic mechanisms in hypothalamus ; which may be responsible for reduced reproductive activity ( 6 ) .
since toxoplasma could also be deployed in brain tissue , it could affect the function of different parts of the brain like hypothalamus ( 6 ) .
transient hypogonadism and testosterone changes may be observed in men with toxoplasmosis ( 7 , 8) . the change of serum and salivary testosterone levels in toxoplasma - infected men and women is confirmed ( 9 ) .
although the mechanism of relationship between testosterone and toxoplasmosis is important but the process is not clear ( 10 ) .
histological examination of toxoplasma - infected female mice showed distinct hypertrophy of the endometrium and myometrium .
the result of fux study on toxoplasma - infected mice compared to the uninfected animals showed that a tendency for a reduction in folliculogenesis and the formation of corpora lutea in the ovaries ( 11 ) .
since pathological changes in the placenta are more common and severe than in the fetus , it seems that placental damage is probably the primary cause of fetal death ( 12 ) .
epidemiological studies have shown high prevalence of toxoplasmosis in iran ( 13 , 14 ) .
molecular methods have confirmed the presence of toxoplasma gondii in tissues of ovary and uterus of mice , infected vaginally ( 15 ) .
the purpose of this study was to investigate the pathological changes in the ovaries due to toxoplasmosis .
eight to 12 wk old female nmri mice were obtained from pasteur institute of iran .
the mice were maintained in polyethylene cages with free access to food and water in a room with controlled humidity and temperature ( 2224 c ) on a 12-h light / dark cycle .
this study was approved by the medical ethical committee of arak university of medical sciences , arak , iran ( code no . 607 ) .
the rh strain of toxoplasma gondii was provided by department of parasitology , faculty of health , tehran university of medical sciences .
tachyzoites of parasite were harvested from peritoneal fluid of white mice which 4 days earlier had been experimentally infected .
these parasites were used for infection of experimental animals via intra - vaginal ( iv ) in first day of pregnancy .
the pregnant mice were divided into 2 groups : 1 ) experimental group that infected by 15 l of normal saline containing parasite ( contain 510 parasite ) via intra - vaginal ( iv ) .
after euthanasia by cervical dislocation , ovaries and uterine horns were removed from each animal .
a : right ovary organ of experimental and control groups were fixed in 10% formalin for 48 hour . before fixation
, the tissues were briefly washed with saline and then excised tissues were fixed in formalin ( ph 6.8 ) and embedded in paraffin .
the sections of each paraffin block were stained with hematoxylin and eosin ( 16 ) .
finally , sections were studied and photographed with light microscopy in this relation a 10100 objective lens were used to capture photos ( nikon eclipse e2000-videocamera dsfi1 , japan ) .
healthy and atretic follicles were evaluated with image tool ( uthscsa , version 2.03-alpha 6 ) . according to jolly
( 17 , 18 ) all healthy follicles , with intact oocytes , were classified in : a ) number of primary follicles , without follicular antrum , b ) number of secondary follicle , showing follicular antrum , c ) number of atretic primary follicles , ( d ) number of atretic secondary follicles , e ) number of courpus luteum .
the atretic follicles ( c and d ) were characterized by degenerating oocytes , disorganized granulosa cell layers , folded zona pellucida , partially or completely separated from corona radiata and from granulosa cells of the oocyte as well .
apoptotic bodies were common inside , outside the oocytes , and in granulosa cells ( 19 ) .
the degenerating primordial or primary follicles were termed atretic follicles and those with degeneration in the secondary of graaf follicles , atretic secondary follicles .
the number of all type of follicles and corpus luteum bodies per ovary were counted with imaging software image tools ( uthscsa , version 3 ) .
the mean sd of each variable was studied in experimental and control groups and the statistically significant difference was determined with kruskal wallis and u mann whitney tests .the analysis was performed between the groups by oneway anova test ( p<0.05 ) .
eight to 12 wk old female nmri mice were obtained from pasteur institute of iran .
the mice were maintained in polyethylene cages with free access to food and water in a room with controlled humidity and temperature ( 2224 c ) on a 12-h light / dark cycle .
this study was approved by the medical ethical committee of arak university of medical sciences , arak , iran ( code no . 607 ) .
the rh strain of toxoplasma gondii was provided by department of parasitology , faculty of health , tehran university of medical sciences .
tachyzoites of parasite were harvested from peritoneal fluid of white mice which 4 days earlier had been experimentally infected .
these parasites were used for infection of experimental animals via intra - vaginal ( iv ) in first day of pregnancy .
the pregnant mice were divided into 2 groups : 1 ) experimental group that infected by 15 l of normal saline containing parasite ( contain 510 parasite ) via intra - vaginal ( iv ) .
after euthanasia by cervical dislocation , ovaries and uterine horns were removed from each animal .
a : right ovary organ of experimental and control groups were fixed in 10% formalin for 48 hour . before fixation
, the tissues were briefly washed with saline and then excised tissues were fixed in formalin ( ph 6.8 ) and embedded in paraffin . sectioning was conducted in 5 m thickness by microtome from ovary organ totally .
the sections of each paraffin block were stained with hematoxylin and eosin ( 16 ) .
finally , sections were studied and photographed with light microscopy in this relation a 10100 objective lens were used to capture photos ( nikon eclipse e2000-videocamera dsfi1 , japan ) .
healthy and atretic follicles were evaluated with image tool ( uthscsa , version 2.03-alpha 6 ) . according to jolly
( 17 , 18 ) all healthy follicles , with intact oocytes , were classified in : a ) number of primary follicles , without follicular antrum , b ) number of secondary follicle , showing follicular antrum , c ) number of atretic primary follicles , ( d ) number of atretic secondary follicles , e ) number of courpus luteum .
the atretic follicles ( c and d ) were characterized by degenerating oocytes , disorganized granulosa cell layers , folded zona pellucida , partially or completely separated from corona radiata and from granulosa cells of the oocyte as well .
apoptotic bodies were common inside , outside the oocytes , and in granulosa cells ( 19 ) .
the degenerating primordial or primary follicles were termed atretic follicles and those with degeneration in the secondary of graaf follicles , atretic secondary follicles .
the number of all type of follicles and corpus luteum bodies per ovary were counted with imaging software image tools ( uthscsa , version 3 ) .
a : right ovary organ of experimental and control groups were fixed in 10% formalin for 48 hour . before fixation
, the tissues were briefly washed with saline and then excised tissues were fixed in formalin ( ph 6.8 ) and embedded in paraffin . sectioning was conducted in 5 m thickness by microtome from ovary organ totally .
the sections of each paraffin block were stained with hematoxylin and eosin ( 16 ) .
finally , sections were studied and photographed with light microscopy in this relation a 10100 objective lens were used to capture photos ( nikon eclipse e2000-videocamera dsfi1 , japan ) .
healthy and atretic follicles were evaluated with image tool ( uthscsa , version 2.03-alpha 6 ) . according to jolly et al . and fortune et al .
( 17 , 18 ) all healthy follicles , with intact oocytes , were classified in : a ) number of primary follicles , without follicular antrum , b ) number of secondary follicle , showing follicular antrum , c ) number of atretic primary follicles , ( d ) number of atretic secondary follicles , e ) number of courpus luteum .
the atretic follicles ( c and d ) were characterized by degenerating oocytes , disorganized granulosa cell layers , folded zona pellucida , partially or completely separated from corona radiata and from granulosa cells of the oocyte as well .
apoptotic bodies were common inside , outside the oocytes , and in granulosa cells ( 19 ) .
the degenerating primordial or primary follicles were termed atretic follicles and those with degeneration in the secondary of graaf follicles , atretic secondary follicles .
the number of all type of follicles and corpus luteum bodies per ovary were counted with imaging software image tools ( uthscsa , version 3 ) .
the mean sd of each variable was studied in experimental and control groups and the statistically significant difference was determined with kruskal wallis and u mann whitney tests .the analysis was performed between the groups by oneway anova test ( p<0.05 ) .
ovaries of pregnant mice that were vaginally infected by toxplasma presented gross morphologic differences compared to those of the control groups .
the primary and secondary healthy follicles and corpus luteum of the control groups showed normal appearance ( fig .
all ovarian sections in experimental groups showed great defects in follicles , atretic follicles and corpus luteum in developmental stages ( fig .
furthermore , in these groups some of the primary follicles showed normal appearance , although with high congestion compared to the control group ( fig .
1 ) corpus luteum , 2 ) primary follicle 3 ) secondary follicle 4 ) atretic primary follicles 5 ) atretic secondary follicles atretic primary follicles presented retracted primary oocytes with vacuolated cytoplasm , eccentric nucleoli , and an irregular membrane .
granulosa cells were observed around the oocytes with piknotic nuclei the corona radiata cells were detached from the zona pellucida , which was folded . in general , the tissue sections in subjects compared to the controls , increased follicle atresia ( fig .
were observed the effects of toxoplasmosis on corpus luteum as polyhedral luteal cells , higher staining of paraluteal cells , increased heterochromatin , a prominent nucleolus , cytoplasmic inclusions with vacuolar appearance , and poor staining ( fig .
generally the number of corpus luteum in experimental group is reduced compared to the control by increasing gestational age , but this decrease is not regular ( fig .
2 , comparing experimental and control groups , the number of atretic primary follicles is higher than the experimental group . as shown in fig .
the comparison of number of atretic primary follicles in experimental and control groups at 4 , 9 and 16 days of pregnancy as shown in fig .
3 , comparing experimental and control groups , the number of atretic secondary follicles is higher than the experimental group .
the comparison of number of atretic secondary follicles in experimental and control groups at 4 , 9 and 16 days of pregnancy according to fig .
4 , comparing experimental groups , the maximum number of atretic primary follicles and atretic secondary follicles were shown on the fourth day of pregnancy .
the comparison of number of follicles ( primary and secondary follicle , atretic primary and secondary follicles ) in 4 , 9 and 16 days of pregnancy in the experimental groups comparing the experimental and control groups revealed that the number of all type of follicles ( primary and secondary follicle , atretic primary and secondary follicles ) had significant differences ( p0.001 ) . according to fig .
5 , in control group by increasing gestational age the number of corpus luteum decreases but approximately in experimental groups of 9 and 16 days of gestation number of corpus luteums is equal . the comparison of corpus luteum number in experimental and control groups
ovaries of pregnant mice that were vaginally infected by toxplasma presented gross morphologic differences compared to those of the control groups .
the primary and secondary healthy follicles and corpus luteum of the control groups showed normal appearance ( fig .
all ovarian sections in experimental groups showed great defects in follicles , atretic follicles and corpus luteum in developmental stages ( fig .
furthermore , in these groups some of the primary follicles showed normal appearance , although with high congestion compared to the control group ( fig .
1 ) corpus luteum , 2 ) primary follicle 3 ) secondary follicle 4 ) atretic primary follicles 5 ) atretic secondary follicles atretic primary follicles presented retracted primary oocytes with vacuolated cytoplasm , eccentric nucleoli , and an irregular membrane .
granulosa cells were observed around the oocytes with piknotic nuclei the corona radiata cells were detached from the zona pellucida , which was folded . in general , the tissue sections in subjects compared to the controls , increased follicle atresia ( fig .
were observed the effects of toxoplasmosis on corpus luteum as polyhedral luteal cells , higher staining of paraluteal cells , increased heterochromatin , a prominent nucleolus , cytoplasmic inclusions with vacuolar appearance , and poor staining ( fig .
generally the number of corpus luteum in experimental group is reduced compared to the control by increasing gestational age , but this decrease is not regular ( fig .
2 , comparing experimental and control groups , the number of atretic primary follicles is higher than the experimental group . as shown in fig .
the comparison of number of atretic primary follicles in experimental and control groups at 4 , 9 and 16 days of pregnancy as shown in fig .
3 , comparing experimental and control groups , the number of atretic secondary follicles is higher than the experimental group .
the comparison of number of atretic secondary follicles in experimental and control groups at 4 , 9 and 16 days of pregnancy according to fig .
4 , comparing experimental groups , the maximum number of atretic primary follicles and atretic secondary follicles were shown on the fourth day of pregnancy .
the comparison of number of follicles ( primary and secondary follicle , atretic primary and secondary follicles ) in 4 , 9 and 16 days of pregnancy in the experimental groups
comparing the experimental and control groups revealed that the number of all type of follicles ( primary and secondary follicle , atretic primary and secondary follicles ) had significant differences ( p0.001 ) . according to fig .
5 , in control group by increasing gestational age the number of corpus luteum decreases but approximately in experimental groups of 9 and 16 days of gestation number of corpus luteums is equal .
histological changes in the ovaries of pregnant mice that had contact with t. gondii , already has not been reported . in the present study ,
our results showed that t. gondii could alter ovarian follicular growth and development in mice . in accordance with our results , during pregnancy significant increase in the number of atretic follicles could be due to infection with toxoplasma .
in the first stage of embryonic development , increase in follicular atresia is caused by cytotoxicity process .
if steroid concentrations increase in infected mice , it may lead to physiological imbalances in hypophysial - hypothalamic axis of ovary , which eventually inhibit the secretion of gnrh , lh and fsh .
probably , increase in steroid synthesis leads to hypertrophy of granulosa and the cal cells , physiological and morphological changes in the follicle and eventually it leads to apoptosis ( 2022 ) .
accordance to our results , significant differences were observed between corpus luteum number in experimental and control groups .
its main function is secreting of progesterone , which is necessary to continue the pregnancy .
the follicular cells just like rays are drawn from the center to the perimeter and begin to proliferation , differentiation and angiogenesis that is like no other tissue is the body ( 23 ) .
it seems that the macrophages play a role in follicular growth and ovulation and contribution in vascular homeostasis ( 2426 ) .
macrophages suddenly after ovulation start migrating toward the growing corpus luteum in humans , mice and rats ( 2728 ) .
these cells affect steroidogenesis of corpus luteums cells and play an important role in tissue repair after luteal regression ( 2930 ) . during each step of follicular phase
moreover , cell death may be stimulated in some certain neighboring cell after initiating appotosis in granulosal cells ( 24 ) .
the amount of apoptosis in human granulosal cells will increase after ovulation stimulation ( 25 ) .
the present data findings approved increased intercellular space in various areas of the corpus luteum in ovarian induction group .
it seems that ovarian stimulation acts through reduction of intercellular adhesions and results in intercellular space formation .
finally , it will lead to increase in apoptosis induction rate in corpus luteum cells .
cell adhesions and interactions in the granulosa cells are effective in cell signaling , interacellular substrates transfer and hemostasis maintenance that finally increased intercellular space in the granulosa cells and leads to deficiency in proliferation and maturation ( 26 , 28 ) .
we observe in this study that increase in ovarian macrophages may accelerate the luteal regression process and reduces the size of the corpus luteum .
in addition , it alters number of all follicles ( primary and secondary follicle , atretic primary and secondary follicles ) and corpus luteum in ovaries of mice .
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### Summary:
: background : congenital toxoplasmosis is one cause of abortion .
infection can disrupt ovarian cycles and because toxoplasmosis is an infectious disease may have a similar effect on the ovaries .
the purpose of this study was to investigate the pathological changes in the ovaries due to toxoplasmosis.methods:tachyzoites of toxoplasma gondii were harvested from peritoneal fluid of mice , experimentally infected .
two females and one male mouse were housed per cage for mating in the overnight .
the pregnant mice were divided into experimental and control groups .
experimental group were infected by parasite but the control group received the normal saline .
the experimental and control mice were euthanized .
ovaries and uterine horns of animals were removed and prepared for light microscopy.results:ovaries of infected pregnant mice presented gross morphological differences compared to the control groups . in ovaries of experimental groups ,
changes of corpus luteum were observed .
the comparison of experimental and control groups revealed that the number of primary follicles , secondary follicle , atretic primary follicles and atretic secondary follicles had significant differences ( p0.001).conclusion : toxoplasma gondii alters ovarian follicular growth and development in mice .
in addition , it alters number of different phases of follicles and corpus luteum in ovaries of mice .
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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:
: nasal carriage of staphylococcus aureus plays a key role in the epidemiology and pathogenesis of infection and is a major risk factor for the development of both community - acquired and nosocomial infections .
currently , the health problems associated with this microorganism have become more serious due to the increasing incidence of methicillin - resistant s. aureus ( mrsa ) .
several studies worldwide have reported the rate of nasal carriage of s. aureus strains , varying from 16.8% to 90% . a causal relationship between s. aureus nasal carriage and infection
is supported by the fact that the nasal strain and the infecting strain share the same genotype . in recent years
colonized employees are generally asymptomatic , although they are a potential reservoir of infections acquired by patients . colonized or infected hospital personnel ( hcws )
it acts by binding specifically to the bacterial isoleucyl - trna synthetase ( irs ) enzyme and inhibits its protein synthesis . with the increased use of mupirocin ,
mupirocin was first introduced in the uk in 1985 and was used to treat staphylococcal and streptococcal wound infections and to eradicate nasal carriage of s. aureus including mrsa . within 2 years after its introduction , mupirocin resistance among mrsa isolates emerged in the uk and since then in ireland 2% , new zealand 12.4% , the usa 24% , and in trinidad and tobago 44.1% . although no performance standards or interpretive criteria have been published for mupirocin susceptibility testing , two mupirocin resistance phenotypes namely low level ( mul ) and high level ( muh ) mupirocin resistance are defined in staphylococci . low - level resistance ( minimal inhibitory concentration [ mics ] , 8 - 256 g / ml )
is usually associated with point mutations in the chromosomally encoded iles gene whereas high - level resistance ( mics , 512 g / ml ) is generally due to a plasmid - mediated gene , mupa ( also referred to as iles2 ) , which encodes an additional modified irs and is typically located on mobile genetic elements , which likely facilitates the dissemination of this resistance mechanism .
the mupa gene is typically plasmid mediated , and some of these plasmids are conjugative .
various studies suggest that during mupirocin prophylaxis transfer of mupa gene from normal commensal flora of the skin such as staphylococcus epidermidis to mrsa is responsible for the emergence of mupirocin resistance .
the risk of the emergence of such resistance appears to be greater among methicillin - resistant strains of s. aureus than among methicillin - susceptible strains .
the presence of high - level mupirocin resistance ( muh ) excludes its clinical use , however low - level mupirocin resistance ( mul ) can be overcome by recommending higher than usual dosage .
therefore , it is essential not only to discriminate between susceptible and resistant strains but also to determine the level of resistance .
thus , this study was carried out to with the following aims and objectives .
to find
the prevalence of s. aureus from the nasal swabs of hcwsto find the prevalence of mupirocin resistance in s. aureus and coagulase - negative staphylococcus ( cons ) spp . by disc diffusionto
determine the rates of muh and mul in s. aureus and cons spp . by disc diffusionto
know the antimicrobial susceptibility patterns of s. aureus .
to find the prevalence of s. aureus from the nasal swabs of hcws to find the prevalence of mupirocin resistance in s. aureus and coagulase - negative staphylococcus ( cons ) spp . by disc diffusion to determine the rates of muh and mul in s. aureus and cons spp .
to find the prevalence of s. aureus from the nasal swabs of hcwsto find the prevalence of mupirocin resistance in s. aureus and coagulase - negative staphylococcus ( cons ) spp . by disc diffusionto
determine the rates of muh and mul in s. aureus and cons spp . by disc diffusionto know the antimicrobial susceptibility patterns of s. aureus .
to find the prevalence of s. aureus from the nasal swabs of hcws to find the prevalence of mupirocin resistance in s. aureus and coagulase - negative staphylococcus ( cons ) spp . by disc diffusion to determine the rates of muh and mul in s. aureus and cons spp .
to find the prevalence of s. aureus from the nasal swabs of hcwsto find the prevalence of mupirocin resistance in s. aureus and coagulase - negative staphylococcus ( cons ) spp . by disc diffusionto
determine the rates of muh and mul in s. aureus and cons spp . by disc diffusionto know the antimicrobial susceptibility patterns of s. aureus .
to find the prevalence of s. aureus from the nasal swabs of hcws to find the prevalence of mupirocin resistance in s. aureus and coagulase - negative staphylococcus ( cons ) spp . by disc diffusion to determine the rates of muh and mul in s. aureus and cons spp .
a prospective cross - sectional study was carried out from the period of december 2013 to april 2014 .
a total of 140 hcws ( doctor , nursing staff , housekeeping staff ) were randomly selected .
the age , sex , designation , duration of working in the critical care unit and other relevant information were obtained in a proforma which was made for this purpose .
participants were hcws in the intensive care unit and operation theatre for more than 1 year .
nasal swabs from both nostrils were collected by rotating a sterile cotton swab pre - wetted with sterile saline 5 times on the vestibule of both anterior nares .
nasal swabs from both nostrils were streaked on blood agar for 24 h at 37c .
all the confirmed s. aureus strains were subsequently tested for methicillin resistance using cefoxitin disc ( 30 g ) .
the isolates were considered methicillin - resistant if the zone of inhibition was 21 mm or less .
this was done by the disk diffusion method using 5 g and 200 g mupirocin discs to determine low and high level resistance respectively .
criteria of zone diameter breakpoints for susceptible and resistant isolates were set at > 14 mm and < 13 mm respectively .
three different phenotypes are :
mupirocin susceptible : a zone diameter of 14 mm for both 5 g and 200 g discslow - level resistance : isolates that showed zone diameters < 14 mm in the 5 g disc but more than or equal to 14 mm in the 200 g dischigh - level resistance : isolates with zone diameters < 14 mm for both 5 g and 200 g .
mupirocin susceptible : a zone diameter of 14 mm for both 5 g and 200 g discs low - level resistance : isolates that showed zone diameters < 14 mm in the 5 g disc but more than or equal to 14 mm in the 200 g disc high - level resistance : isolates with zone diameters < 14 mm for both 5 g and 200 g .
staphylococcus aureus isolates was then subjected to antimicrobial susceptibility testing by modified kirby - bauer 's disc diffusion method on mueller - hinton agar plates using as per clinical and laboratory standards institute guidelines except for fusidic acid where the french society of microbiology recommendations were used .
the following antibiotics were tested amikacin ( 30 g ) , erythromycin ( 15 g ) , clindamycin ( 2 g ) , linezolid ( 30 g ) , gentamycin ( 30 g ) , fusidic acid ( 10 g ) , trimethoprim - sulfamethoxazole ( 25 g ) , teicoplanin ( 30 g ) , rifampicin ( 10 g ) and vancomycin ( 30 g ) , mupirocin ( 5 g ) and mupirocin ( 200 g ) ( discs were procured from hi - media laboratories , mumbai , india and mast group , uk ) .
out of 140 hcws , s. aureus was isolated in 38 ( 27.14% ) out of which mrsa and methicillin - sensitive s. aureus ( mssa ) were 20 ( 14.28% ) and 18 ( 12.86% ) respectively .
cons was isolated in 73 ( 52.14% ) workers , among them methicillin - resistant coagulase - negative staphylococci ( mrcons ) was found in 34 ( 24.29% ) and methicillin - sensitive coagulase negative staphylococci ( mscons ) 39 ( 27 .
the prevalence of the s. aureus nasal carriage was higher among female hcws 21 ( 55.26% ) than males 17 ( 44.74% ) .
there is statistically no significance between colonization of female hcw and male hcw [ table 2 ] .
culture results of 140 nasal swabs of hcw gender - wise prevalence of s. aureus and mrsa isolates in relation to the professional category , doctors have presented the lowest prevalence of colonization ( 21.05% ) , followed by the housekeeping staff ( 31.58% ) and the high prevalence was found in nursing staff ( 47.37% ) [ table 3 ] .
category - wise prevalence of s. aureus and mrsa isolates in our study among the 140 health care workers , mssa and mscons isolates were 100% sensitive to mupirocin but two isolates from mrsa ( 1.43% ) and five from mrcons ( 3.57% ) showed mupirocin resistance .
mupirocin resistance in staphylococcus spp ( a ) mupirocin susceptible ( b ) low - level resistance ( c ) high - level resistance
methicillin - resistant s. aureus has been recognized as an important nosocomial pathogen worldwide because of the increased rate of multidrug resistant strains among the hospital acquired mrsa .
the prevalence of s. aureus in a nasal carriage of hcws in our study was 38 ( 27.14% ) .
the prevalence of mrsa and mssa in our study was 20 ( 14.28% ) and 18 ( 12 .
recent studies have shown that the prevalence of mrsa colonization among health staff changes according to the location and with the characteristics of each institution . in this study ,
female hcws were more colonized 21 ( 55.26 ) when compared to male hcws 17 ( 44.74 ) .
similar were the findings of shakya et al . who observed males hcws ( 42% ) and females hcws ( 57% ) .
in relation to the professional category , doctors have presented the lowest prevalence of colonization ( 21.05% ) , followed by the housekeeping staff ( 31.58% ) and the high prevalence was found in nursing staff ( 47.37% ) [ table 3 ] .
other workers reported the prevalence of colonization among doctors to the tune of 25% and 22.7% .
observe that to develop activities like respiratory therapists or laboratory technicians represent a risk factor for the colonization by s. aureus . these individual possesses 4.57 times greater probability of being colonized when compared to doctors .
and the author believe that the high prevalence among nursing staff probably occurs because these professionals are less provided with information related to risks , for the team and for the patients , caused by health staff , colonized by pathogenic microorganisms .
mupirocin is the cornerstone of decolonization regimens , a successful strategy to prevent healthcare - associated staphylococcal infections .
observed 0% resistance to mupirocin in the hcw 's whereas in our study among the 140 hcw 's , mssa and mscons isolates were 100% sensitive to mupirocin but two isolates from mrsa ( 1.43% ) and five from mrcons ( 3.57% ) were mupirocin resistance [ table 4 and figure 1 ] .
prolonged , widespread or uncontrolled use and multiple courses of mupirocin are all associated with the development of mupirocin resistance exposure of cons on skin surfaces during prolonged or repeated topical application of mupirocin may lead to the development of a reservoir of high - level resistance determinants in cons which may then be transferred to s. aureus in patients on mupirocin therapy .
observed the rate of mupirocin resistance in s. aureus as 1.02% but the rate of mupirocin resistance in cons ( 16% ) . in a study by gadepalli et al .
which first documented the extent of mupirocin resistance in an indian hospital , it was found that 1% of 200 s. aureus isolates ( including 0.9% of mrsa and 1.1% of mssa ) showed low - level resistance and 5% showed high - level resistance ( 8.2% of mrsa and 1.1% of mssa isolates ) . in a study that included staphylococci from 19 european hospitals , the prevalence of muh
was found to be 1.6% in s. aureus and 5.6% in cons . in our study
higher percentage of antibiotic resistance was noted to erythromycin ( 66.67% ) , gentamicin ( 50% ) , clindamycin ( 47.61% ) , trimethoprim - sulfamethoxazole ( 42.85% ) and lower resistance was observed for rifampicin ( 2.38% ) and fusidic acid ( 11.90% ) .
none of our isolates showed resistance to teicoplanin , vancomycin and linezolid [ table 5 ] .
reported that mrsa strains with mupirocin resistance were often more susceptible to other antimicrobial agents , such as tetracycline and trimethoprim - sulfamethoxazole .
in contrast , mupirocin - resistant isolates were more likely to be resistant to fusidic acid .
it is speculated by the author that the fusb determinant , which is responsible for fusidic acid resistance is on the same plasmid as the mupa gene in isolates with muh . however , there are studies that demonstrate that some isolate bacterial of s. aureus already present genes resistant to mupirocin , compromising the therapeutic value of the latter .
if stable chromosomal muh were to become prevalent , reducing the antibiotic selection pressure may not lead to a reduction in rates of resistance and control measures will have to rely on prevention of transmission .
mupirocin is a topical antibiotic used for treating mrsa associated skin and soft tissue infections and eliminating nasal colonization of mrsa among patients and medical staff .
hospitals need to develop more stringent hospital infection control policies , but also to create awareness among housekeeping and nursing staff by educating them to eradicate mrsa carriage .
mupirocin nasal ointment should be reserved for the eradication ( in both patients and staff ) of nasal carriage of mrsa .
alternative preparations such as chlorhexidine and neomycin cream ( naseptin - manufactured by alliance pharmaceuticals ) should be considered if colonization persists after two courses of mupirocin or if swabs confirm mupirocin resistance .
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### Summary:
: introduction : mupirocin ( pseudomonic acid a ) is a topical antimicrobial agent with excellent antistaphylococcal and antistreptococcal activity . a nasal formulation is approved by the united states food and drug administration for eradicating nasal carriage in adult patients as well as in health care personnel .
resistance to mupirocin has already been reported worldwide .
the increasing prevalence of mupirocin resistance among staphylococcus aureus and coagulase - negative staphylococcus ( cons ) species could be an important threat to the future use of mupirocin against methicillin - resistant s. aureus ( mrsa ) .
thus , this study was carried out to find the prevalence of mupirocin resistance in s. aureus and cons by disc diffusion and to determine the rates of high - level and low - level mupirocin resistance in s. aureus and cons by disc diffusion.materials and methods : a total of 140 healthcare workers ( hcws ) ( doctor , nursing staff , housekeeping staff ) were randomly selected .
s. aureus and cons isolates were tested for mupirocin resistance by the disk diffusion method using 5 g and 200 g mupirocin discs .
mrsa isolates were tested for antibiotics by kirby - bauer disc - diffusion method as per clinical and laboratory standards institute guidelines.results:out of 140 nasal swabs collected from hcws , s. aureus was isolated in 38 ( 27.14% ) , and cons was isolated in 73 ( 52.14% ) .
mrsa was isolated in 20 ( 14.28% ) and methicillin - resistant coagulase - negative staphylococci ( mrcons ) in 34 ( 24.29% .
methicillin - sensitive s. aureus ( mssa ) and mscons isolates were 100% sensitive to mupirocin , but two isolates from mrsa ( 1.43% ) and five from mrcons ( 3.57% ) were mupirocin resistant.conclusion:the presence of mupirocin resistance in mrsa and mrcons is a cause for concern
. it could be limited by regular surveillance and effective infection control initiatives so to inform health care facilities to guide therapeutic and prophylactic use of mupirocin .
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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 efforts to develop renewable alternatives to petroleum - based chemicals and fuels , there is rejuvenated interest in clostridial acetone - butanol - ethanol ( abe ) fermentation .
abe fermentation was first commercialized in the 1910s in the united kingdom for the production of acetone , which was used as a solvent in the production of cordite , a smokeless ammunition propellant ( 1 ) .
the abe process spread across the globe during the first and second world wars and was further capitalized upon for the production of butanol ( i.e. , 1-butanol ) , which remains an important feedstock for the production of paints and coatings today . in the 1950s , however , the oxo process , which hydroformylates and hydrogenates propylene to butanol , displaced the abe process as the most economically viable method of butanol production . fast - forward to today , when the abe process is competitive with the oxo process for manufacturing butanol to be sold as a chemical ( 1 ) .
butanol is also used as an alternative liquid transportation fuel and blending agent and has demonstrably better physical properties than ethanol ( 2 ) .
moreover , it can be catalytically converted into jet fuels ( 3 ) . however , before butanol can stake a significant claim in the advanced biofuel markets , the economics of abe manufacturing must improve .
three areas of greatest opportunity are ( i ) reaching theoretical maximum yields of butanol , ( ii ) expanding substrate utilization such that a diversity of feedstocks can be used , and ( iii ) minimizing energy consumption during separation and purification .
thus , employing the cheapest feedstock and reaching the theoretical maximum conversion to butanol will result in the optimal abe process
. papoutsakis previously calculated the theoretical maximum to be 0.939 mol butanol/1 mol glucose , which is based upon abe fermentation equations ( 4 ) .
more recently , fast and papoutsakis calculated that this could be further improved to ~1.33 mol butanol/1 mol glucose by mixotrophic fermentation whereby glucose and co2 ( evolved during fermentation ) are fully utilized in the presence of sufficient h2 ( 5 ) . as reviewed previously ( 6 ) ,
a major limitation is the production of acetone and co2 during acid reassimilation , which jang et al . investigated and minimized for butanol production in their study in mbio ( 7 ) .
investigate the two butanol production pathways in clostridium acetobutylicum atcc 824 ( i.e. , cold and hot channel[s ] ) and propose a metabolic strategy to improve yields of butanol .
the cold channel refers to the metabolic process of reassimilating organic acids , acetate and butyrate , into acetyl and butyryl coenzyme a ( coa ) , respectively , through the coa transferase ( coat ) pathway .
acetyl - coa is then reduced to ethanol or converted to butyryl - coa through condensation and a series of hydrogenation reactions .
butyryl - coa is then reduced to butanol . for every mole of reassimilated acid , 1 mol of acetoacetate
is generated , which is then decarboxylated into acetone and co2 , and detracts from butanol yields .
the hot channel avoids acid reassimilation and refers only to the direct route of acetyl - coa condensation to butyryl - coa and subsequent reduction to butanol .
previous studies attempted to reduce the cold channel and force carbon flux through the hot channel .
( 8) decreased cold - channel flux by separately downregulating the activity of the two coa transferase subunits ( coat a and b , coded , respectively , by the genes ctfa and ctfb ) via antisense rna ( asrna ) expression from a multicopy plasmid .
acetone production was reduced , suggesting that the cold channel was impaired . however , acetate production increased and butanol production decreased , suggesting that the hot channel was unchanged or even impaired .
subsequently , they realized that the primary , bifunctional alcohol / aldehyde dehydrogenase ( i.e. , adhe1 , coded by adhe1 ) is translated from the same transcript as ctfa / b .
consequently , downregulating the activity of coat a and b also likely downregulated the activity of adhe1 .
performed another study ( 9 ) in which they concurrently overexpressed adhe1 along with the ctfb asrna from a multicopy plasmid .
the resulting strain exhibited reduced acetone levels , wild - type ( wt ) atcc 824 levels of butanol , and 23-fold - higher levels of ethanol .
since adhe1 catalyzes the production of both ethanol and butanol , a follow - up study ( 10 ) attempted to reduce and increase the pool of acetyl- and butyryl - coa by increasing the activity of the thiolase enzyme .
additionally , they varied the promoters used for overexpressing adhe1 and the asrna against ctfb .
. fortunately and as reviewed elsewhere ( 11 ) , genetic tools have improved , and a recent article by al - hinai et al . ( 12 ) demonstrates the latest of these improvements .
accordingly , a more recent study ( 13 ) attempted to reduce the cold - channel flux by disrupting the acetoacetate decarboxylase gene , adc , in a mutant c. acetobutylicum strain designated 2018 .
with ph control , the adc mutant exhibited reduced acetone levels and 2018 levels of butanol , but it also exhibited high titers of acids , particularly acetate . since butanol production requires sufficient reducing equivalents ( e.g. , nadh ) , they decided to supplement cultures with methyl viologen ( mv ) to increase the nadh throughput . as a result , acetone remained low , butanol levels remained constant , and acid production was reduced .
however , acid levels were still not as low as they were in the 2018 cultures , and butanol yields maxed out at 70.8% .
present a more comprehensive and systematic analysis of deleting cold - channel pathways individually and in combination and overexpressing genes in hot - channel pathways ( 7 ) . in accordance with previous investigations
interestingly , the best approach for improving the ratio of hot - to cold - channel fluxes did not include modifying the acid reassimilation path .
rather , they determined that a particular combination of acid formation gene disruptions was optimal , which they combined with overexpression of a mutant adhe1 that they proposed had increased affinity for nadph .
finally they optimized continuous cell culture conditions to demonstrate the highest reported butanol yields to date at 0.76 mol butanol/1 mol glucose .
interestingly , they did not witness an increase in ethanol production with the overexpression of the mutant adhe1 , as seen by two previous studies ( 9 , 10 ) .
there is no report of the mutated adhe1 having increased affinity for butyryl - coa over acetyl - coa , but these results suggest that this could be the case .
additionally , acid production was not fully eliminated , which is consistent with even the earliest acid formation gene disruption study in atcc 824 ( 14 ) .
returning to the issue of feedstock cost , another way to minimize that expense is commercializing strains that utilize a diversity of substrates . as colleagues and i recently reviewed ( 11 ) ,
clostridia can directly utilize numerous monomeric sugars , complex carbohydrates ( e.g. , starch , hemicellulose , and cellulose ) , industrial wastes ( e.g. , cheese whey and glycerol ) , short - chain fatty acids ( e.g. , acetic , butyric and lactic acids ) , and gaseous feedstocks ( e.g. , co and co2/h2 ) .
although atcc 824 can not ferment cellulose , it does contain a cellulosome ( 15 ) that appears to be nonfunctional due to a single inactive component , cel48a ( 16 ) . assuming cellulosome function is reinstated , atcc 824
would be an ideal platform for a consolidated bioprocess ( cbp ) for butanol production .
cbp refers to combining enzyme production , hydrolysis , and fermentation into a single - unit operation , which has bioprocessing and economic advantages over separate unit operations ( 17 ) .
lastly , there are acetogenic clostridia , such as clostridium carboxidivorans ( 18 ) , that perform chemoautotrophic growth on co2 and h2 to form butanol .
other acetogens , such as clostridium ljungdahlii , can be genetically engineered to produce butanol ( 19 ) .
thus , there are opportunities to use syngas and industrial waste gases as cheap feedstocks .
additionally and as previously mentioned , co2 evolved during glucose fermentation can be fed to an acetogenic culture or used concurrently in the same culture to generate theoretical yields of 1.33 mol butanol/1 mol glucose ( 5 ) .
lastly , it was shown ( 20 ) that the energy required just for butanol separation from fermentation broth by distillation ( the industry standard ) can be multiples of the energy embodied in the actual butanol , which attenuates the argument for butanol as a fuel .
the major issue is the low titers ( i.e. , concentrations ) that are achievable in the fermentation broth due to butanol toxicity .
researchers have attempted to increase tolerance with limited success , as reviewed previously ( 21 ) .
moreover , screening of known solvent - tolerant microorganisms revealed tolerance only up to 3% ( i.e. , 30 g / liter ) ( 22 ) . in order to reduce distillation energy consumption to one - third of the heat of combustion of butanol , broth concentrations would need to be greater than 4% ( 23 ) .
consequently , abe fermentation is a great candidate for alternative separation technologies , which as reviewed previously ( 23 ) include gas stripping , liquid - liquid extraction , adsorption , pervaporation , and combinations . speaking from our development experience
furthermore , some technologies can be integrated with continuous or semicontinuous fermentation processes , which increases capacity of capital equipment .
the question moving forward is whether such technologies are scalable and economically viable . in conclusion ,
given continual research , development , and investment into the three areas mentioned above , butanol s entrance into the advanced biofuel market could be accelerated .
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### Summary:
: abstract1-butanol is a large - volume , intermediate chemical with favorable physical and chemical properties for blending with or directly substituting for gasoline .
the per - volume value of butanol , as a chemical , is sufficient for investing into the recommercialization of the classical acetone - butanol - ethanol ( abe ) ( e. m. green , curr .
opin . biotechnol . 22:337343 , 2011 ) fermentation process .
furthermore , with modest improvements in three areas of the abe process , operating costs can be sufficiently decreased to make butanol an economically viable advanced biofuel .
the three areas of greatest interest are ( i ) maximizing yields of butanol on any particular substrate , ( ii ) expanding substrate utilization capabilities of the host microorganism , and ( iii ) reducing the energy consumption of the overall production process , in particular the separation and purification operations . in their study in the september / october 2012 issue of mbio , jang et al .
[ mbio 3(5):e00314 - 12 , 2012 ] describe a comprehensive study on driving glucose metabolism in clostridium acetobutylicum to the production of butanol .
moreover , they execute a metabolic engineering strategy to achieve the highest yet reported yields of butanol on glucose .
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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:
: functional community ambulation requires an ability to perform cognitive tasks while walking and an ability to adapt to extrinsic environmental factors that increase the complexity of mobility , such as obstacle avoidance ( e.g. , curbs ) and time - critical tasks ( e.g. , crossing the street within the time constraints imposed by traffic signals ) . a reduced capacity for dual - task walking may limit community mobility .
research has shown that healthy older adults experience significant decrements in gait speed when cognitive tasks are performed while walking , a phenomenon referred to as dual - task interference or cognitive - motor interference .
a limitation of the existing research on dual - task interference in aging is that it has focused predominantly on dual - task performance during unobstructed walking at preferred gait speed .
therefore , the effect of dual - task interference on gait and cognitive performance during more attention - demanding gait tasks remains largely unknown .
furthermore , because slowing down during unobstructed walking in the gait laboratory is inconsequential for successful completion of the motor task , individuals may place more importance on performing the cognitive task .
indeed , healthy young and older adults appear to place greater priority on the secondary ( nongait ) task in many dual - task situations [ 4 , 5 ] .
it seems reasonable to assume that when gait task complexity increases and there is a greater potential threat to stability , individuals would place more importance on completing the gait task safely .
bock et al . examined the dual - task costs of performing cognitive and gait tasks of varying difficulty in both young and older adults .
the authors concluded that in dual - task conditions , older adults were at greater risk for falls than young adults .
however , the effect of task difficulty on dual - task interference was not explicitly analyzed and remains unclear .
numerous studies have examined dual - task effects on gait during obstacle avoidance in older adults [ 615 ] , but none have directly compared the dual - task effects during obstacle negotiation to those during unobstructed walking .
recently examined the effects of walking task difficulty ( usual walking versus narrow - based walking ) on dual - task performance in young adults .
they found that walking task difficulty affected walking performance but not cognitive performance . because this study included only dual - task conditions with specific instructions to focus primarily on either the cognitive task or the gait task , it is not known what effect task difficulty has on a person 's default prioritization ; that is , the way in which the person chooses to allocate his attention in the absence of explicit instruction .
moreover , the study included only young adults , so age - related differences in the effects of task difficulty on dual - task interference are not currently known .
the purpose of this study was to determine the effect of gait and cognitive task difficulty on dual - task interference in healthy young adults and older adults .
we hypothesized that as the difficulty of the gait task increased , attention to gait would increase , resulting in smaller dual - task effects relative to simple walking ( unobstructed at self - selected speed ) .
we focus on gait speed as the measure of gait performance in dual - task conditions , since meta - analysis results show that cognitive - motor interference effects across a range of cognitive tasks are prominent in gait speed . furthermore , because research has shown that dual - task effects on gait vary according to the type of cognitive task , we explore our hypothesis in two different cognitive - motor dual - task combinations .
twenty young adults ( mean age 21.7 years , range 2027 ) and 15 older adults ( mean age 72.1 years , range 6684 ) were recruited through advertisements at northeastern university and local senior centers . to be included ,
participants had to be 1830 years or older than 65 years , be able to walk independently in the community for at least 50 meters , have intact cognition according to the mini - mental state exam ( score > 23 ) , and have normal or corrected - to - normal hearing and vision .
participants were excluded if they had a history of neurological disorders , any orthopedic conditions affecting gait , reported more than 2 falls in the past year , had an acute hospital stay within the last 3 months , or had a lower extremity amputation .
demographic information was collected for each participant , including age , gender , and education .
cognitive abilities of the participants were characterized using the mini - mental state exam , digit substitution test , stroop color - word interference test , comprehensive trail making tests , and the activities - specific balance confidence ( abc ) scale .
functional mobility was assessed using the timed up and go test ( tug ) .
each participant performed three gait tasks and two different cognitive tasks in isolation ( single - task conditions ) and each gait task in combination with each of the cognitive tasks ( dual - task conditions ) .
the cognitive tasks were the auditory stroop and the clock task . in the auditory stroop task , participants heard the words
high and low spoken in either a high pitch ( 360 hz ) or a low pitch ( 180 hz ) .
the participants were instructed to indicate the pitch of the word they heard ( ignoring the actual word presented ) by responding verbally high or
the participants heard a time ( e.g. , one - twenty - five ) and were required to determine whether the two hands of the clock at the given time were in the same half ( left / right ) or opposite halves .
yes ; if the hands were in opposite halves , the participants were asked to respond no .
there were no clock - task stimuli in which one of the hands was exactly on the twelve or six ( e.g. , one - thirty ) .
for each task , the participants completed at least two practice blocks of 30 trials while sitting .
single - task performance in each cognitive task was recorded in sitting and was always performed immediately before the dual - task conditions .
both the stroop and clock tasks were produced using directrt ( empirisoft , new york , ny , usa ) .
the stimuli were delivered through wireless headphones and participant responses were recorded through a wireless microphone ( logitech , newark , ca ) . for both cognitive tasks , we measured reaction time ( in milliseconds ) and accuracy ( percent of correct responses ) .
our assumption was that the clock task was more difficult because it required greater cognitive processing .
the three gait tasks were walking at self - selected speed ( ss ) , walking at fastest comfortable speed ( fc ) , and walking at fastest comfortable speed while stepping over an obstacle ( ob ) .
a critical assumption was that walking at fastest comfortable speed was more attention - demanding than walking at preferred ( self - selected ) speed , and that walking fast and stepping over an obstacle further increased the demands of the task . all gait tasks involved participants walking across a 6.1-meter platinum gaitrite walkway , which contains pressure activated sensors .
the participants started and finished each pass 2 meters beyond the end of the walkway so that only steady state gait data were captured .
participants completed 6 passes of the walkway for each condition and the average of the 6 passes was used for analysis . in the ob condition ,
a 15 cm high hurdle was placed at the 4.5 m mark of the gaitrite walkway .
the order of the three gait tasks was randomized , but was performed in the same order for the single - task and the two dual - task ( stroop , clock ) blocks .
block order ( single , stroop , clock ) was also randomized across participants .
to analyze the effect of task difficulty on dual - task interference , we calculated the dual - task effect ( dte ) on both gait speed and cognitive task performance ( reaction time and accuracy ) .
dual - task effects on gait speed ( dteg ) and clock and stroop - task accuracy ( dteacc ) were calculated as follows :
( 1)dte=(dual tasksingle task)single task100% . whereas a decrease in gait speed and accuracy represent performance decrement , an increase in reaction time ( i.e. , slower response ) represents performance decline , therefore dte on reaction time ( dtert )
thus , for each variable , negative values for dte indicate that performance deteriorated under dual - task conditions ( i.e. , dual - task cost ) , and positive values represent an improvement in the dual - task condition relative to single - task performance ( i.e. , dual - task benefit ) .
the young and older adults were compared on profile measures using independent t - tests . to verify whether the clock task required greater cognitive processing than the stroop task , we conducted paired t - tests on mean reaction times for the two tasks in the single - task ( sitting ) condition for each group . to determine whether participants increased their ss gait speed as instructed in the fc and ob conditions , we analyzed changes in gait speed across conditions with a 3 gait task ( ss , fc , ob ) 3 cognitive task ( single , stroop , clock ) anova for each group .
tukey 's post hoc tests were used as needed . to analyze the effects of gait and cognitive task difficulty on dual - task interference , we applied a 3 gait task ( ss , fc , ob ) 2 cognitive task ( stroop , clock ) 2 group ( young , older ) repeated measures ancova with education ( years ) as covariate to each dependent variable ( dteg , dtert , dteacc ) .
significant three - way interactions were followed up with two - way analyses and post hoc tests as needed .
the partial eta squared ( p ) is presented as a measure of effect size for each repeated measures ancova . by convention , 0.01 indicates a small effect size , 0.06 is moderate , and 0.14 represents a large effect . due to technical issues
three older adults and one young adult were missing gait data from one or more of the gait tasks . listwise deletion meant that these subjects were excluded from the analyses for gait variables , resulting in minor variations in degrees of freedom .
all analyses were performed using spss 18.0 ( spss inc . , chicago , il , usa ) .
the young and older adults did not differ in global cognition assessed using the mmse , but there were significant differences in specific cognitive domains , including executive function , inhibition of habitual response , and speed of processing ( table 1 ) .
the older adults also had significantly lower balance self - efficacy and took longer to complete the tug .
however , the differences between the groups on the cognitive and mobility measures were not considered clinically meaningful , since the older adults performed within normal limits for their age [ 21 , 27 , 28 ] . on average ,
the young adults had more years of education than the older adults ( table 1 ) .
the mean reaction time while sitting ( single - task ) for the clock task ( young adults m = 1403 ms , sd = 271 ; older adults m = 1889 ms , sd = 433 ) was significantly longer than that for the stroop task ( young adults m = 805 ms , sd = 109 ; older adults m = 956 ms , sd = 216 ) for both young adults , t(19 ) = 10.5 , p < .001 , d = 2.9 , and older adults , t(14 ) = 9.5 , p < .001 , d = 2.7 .
thus , consistent with our assumption , the clock task required greater cognitive processing than the stroop task . in both tasks ,
the mean gait speeds for young and older adults in each condition and each gait task are shown in table 2 .
participants significantly increased their walking speed when instructed to walk at their fastest comfortable speed . among young adults
, there were no significant differences in average gait speed between fc and ob for single - task or dual - task walking ( table 2 ) .
however , for older adults , average gait speed in ob was significantly slower than fc ( table 2 ) .
table 2 also illustrates that there were significant declines in gait speed during the stroop and clock tasks relative to single - task walking in both groups during the obstacle condition .
both groups had a significant reduction in fc walking speed for the clock task but not the stroop task .
in the ss condition , the older adults reduced their gait speed during stroop but not clock task .
young adults had no significant change in gait speed in either dual - task in ss .
these findings are corroborated by the significant gait task cognitive task group interaction effect on dteg , f(2,56 ) = 3.17 , p = .050 , p = .10 .
follow up two - way ancovas revealed that the three - way interaction occurred because the cognitive task group interaction was significant for the fc gait task ( p < .001 ; p = .39 ) , but not for ss ( p = .794 ; p < .01 ) or ob ( p = .376 ; p = .03 ) ( figure 1 ) . specifically , in fc , the dual - task cost ( negative dte ) on gait speed for the older adults during the clock task was significantly greater than that of young adults , and was also greater than dteg during the stroop task for either group ( figure 1 ) . in ss and ob , there was no effect of cognitive task on dteg for either group , although figure 1 shows a tendency for a larger dual - task cost in the clock task in ob among older adults .
young adults had mean accuracy of 99% ( sd 0.01 ) in the stroop task and 97.2% ( sd 0.1 ) in the clock task .
older adults , on average , were significantly less accurate than young adults ( p < .001 ) , with lower mean accuracy in the clock task ( m = 83.6% , sd = 0.2 ) than the stroop task ( m = 93.1% , sd = 0.1 ) ( p = .045 ) . mean values for dtert and dteacc for each gait task and cognitive task are presented in table 3 . after adjusting for education
, there were no significant main effects or interaction effects in the gait task cognitive task group ancova on dtert or dteacc . as illustrated by the wide confidence intervals in table 3
, there was large variability in the dual - task effects on both reaction time and accuracy for the stroop and clock tasks .
education was significantly related to dteacc in the ob condition ( r = .38 , p = .026 ) ; lower levels of education were weakly associated with larger dual - task costs in accuracy on the clock task during obstacle crossing . before adjusting for education ,
the three - way interaction on dteacc was significant due to a gait task cognitive task interaction for older adults but not young adults : dual - task cost on accuracy was significantly greater in the clock task during ob than in any other task among older adults ; the effect was not significant after adjusting for education .
the purpose of this study was to determine the effect of gait and cognitive task difficulty on dual - task interference in aging .
an important finding was that young adults were able to maintain fast walking speed in the obstructed condition with or without a simultaneous cognitive task , whereas older adults could not maintain fast walking speed in the obstructed condition even when no additional cognitive task was required .
however , fast - obstacle walking speeds for older adults were still significantly faster than self - selected gait speed during single - task and stroop task , but not in the clock task .
in other words , although older adults reduced their gait speed in the fast - obstructed condition relative to fast - unobstructed walking , they were still able to walk faster than their preferred speed , except when they had to perform the clock task while stepping over the obstacle .
this suggests that among older adults the attentional demands of performing a difficult cognitive task interfere with the attention processing requirements of negotiating an obstacle .
indeed , obstacle negotiation requires attention to spatial characteristics of gait in order to adjust strides and avoid hitting the obstacle .
it is likely that the older adults slowed down as an adaptive safety strategy to avoid making motor errors when stepping over the obstacle , and that this effect was exaggerated when the added cognitive task demanded greater attentional resources .
consistent with previous research , older adults demonstrated a significant dual - task decline in gait speed during the stroop task whereas young adults did not .
young adults , however , experienced a significant dual - task decline in gait speed during the stroop task in the fast - obstacle condition .
this finding suggests that in more attention - demanding gait tasks such as obstacle avoidance , a relatively simple cognitive task can impact gait speed , even in healthy young adults . whereas the stroop task affected walking speed in the fast - obstructed condition but not the fast - unobstructed condition , the clock task significantly reduced gait speed in both fast - obstructed and fast - unobstructed walking conditions .
thus , more difficult cognitive tasks may amplify dual - task interference in gait speed in easier gait tasks .
the three - way interaction on dteg corroborates the findings for gait speed and provides evidence for differential effects of gait and cognitive task difficulty on cognitive - motor interference during walking between young and older adults .
we hypothesized that increasing the attentional demands of gait would reduce the dual - task costs on gait speed due to increased allocation of attentional resources required for the gait task .
in contrast to our hypothesis , there was a tendency for dual - task effects on gait speed to increase with increasing gait task difficulty , although this was only significant for the older adults in the clock task in the fc condition ( see figure 1 ) .
it is possible that because we did not instruct the participants where to prioritize their attention during the dual - task conditions , they chose to slow down to optimize safety and/or to maintain performance on the cognitive task .
the large variability in the dual - task effects however , especially for cognitive task performance , implies that participants used a range of strategies to perform the dual - tasks .
future research should concentrate on identifying whether personal characteristics influence how individuals spontaneously allocate their attention during gait - related dual - task situations and whether particular subgroups of older adults are vulnerable to the effects of task difficulty .
an important finding from this study was the effect that controlling for education had on the dual - task interference effects on cognition .
analysis of the unadjusted means showed that the dual - task cost on accuracy in the clock task was significantly greater during obstacle avoidance than in any of the other gait conditions , but only for older adults .
however , after controlling for between - group differences in education , the cognitive task by gait task interaction for older adults was no longer significant .
the lack of significant interaction effects for cognitive variables after controlling for education suggests that education may play an important role in counteracting dual - task costs on cognitive task performance , especially accuracy .
it may be that more education leads to fewer errors in cognitive processing during dual - task walking , regardless of the difficulty of the gait or cognitive task .
that is , greater education may increase cognitive reserve and thereby reduce susceptibility to dual - task interference .
the idea that education contributes to cognitive reserve , and that increased cognitive reserve can limit clinical expression of cognitive changes is supported by strong evidence from the field of dementia research [ 29 , 30 ] .
although we tried to simulate the challenges of real - world walking demands by adding elements of speed and obstacle negotiation to our gait tasks , a limitation of this study is that the research was still conducted in a quiet research laboratory .
thus , it remains unknown how real - world environmental factors ( e.g. , noise , distraction ) affect dual - task interference .
furthermore , we assumed a hierarchical increase in gait task difficulty between walking at self - selected speed , walking at fastest comfortable speed , and walking fast while stepping over an obstacle .
however , we did not ask the participants of their perceptions of the tasks . finally , the findings from this study may be limited in their generalizability due to the small sample size and the predominance of women in the sample .
thus , the findings should be viewed as preliminary ; investigations involving larger , more representative samples are needed to examine the interactions between age group , gait task difficulty , and cognitive task difficulty on cognitive - motor interference . in the future , manipulating the timing of the onset of the stimulus in the obstacle negotiation path may provide more insight into the interactions between attentional processing associated with obstacle avoidance and the attention processing of an additional cognitive task .
in conclusion , the results of this study suggest that obstacle negotiation at fast walking speed , such as when stepping up a curb to avoid traffic , is highly attention - demanding for older adults and significantly compromises the ability to maintain walking speed .
this study provides evidence that gait task difficulty influences dual - task effects on gait speed , especially in older adults .
moreover , the effects of gait task difficulty on dual - task interference appear to be influenced by the difficulty of the cognitive task . education and/or cognitive reserve may be an important factor influencing cognitive - motor interference , especially in terms of performance of the cognitive task .
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### Summary:
: although gait - related dual - task interference in aging is well established , the effect of gait and cognitive task difficulty on dual - task interference is poorly understood .
the purpose of this study was to examine the effect of gait and cognitive task difficulty on cognitive - motor interference in aging .
fifteen older adults ( 72.1 years , sd 5.2 ) and 20 young adults ( 21.7 years , sd 1.6 ) performed three walking tasks of varying difficulty ( self - selected speed , fast speed , and fast speed with obstacle crossing ) under single- and dual - task conditions .
the cognitive tasks were the auditory stroop task and the clock task .
there was a significant group gait task cognitive task interaction for the dual - task effect on gait speed .
after adjusting for education , there were no significant effects of gait or cognitive task difficulty on the dual - task effects on cognitive task performance .
the results of this study provide evidence that gait task difficulty influences dual - task effects on gait speed , especially in older adults .
moreover , the effects of gait task difficulty on dual - task interference appear to be influenced by the difficulty of the cognitive task .
education is an important factor influencing cognitive - motor interference effects on cognition , but not gait .
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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:
: such clinicians should be reminded of the possibility of pbl when suspecting malignant bone tumors .
therefore , laboratory findings that help differentiate pbl from other primary bone tumors can play an important role .
serum soluble interleukin-2 receptor ( sil-2r ) levels in patients with common primary malignant bone tumors except pbl were reported not to be significantly elevated compared to those in healthy subjects in previous reports [ 1 , 2 ] .
reported sil-2r levels being significantly higher in pbl than in other malignant bone tumors and benign bone tumors / tumor - like lesions and commented that the sil-2r level is a valuable marker for diagnosing pbl .
however , we were not able to find reports discussing the changes in serum sil-2r levels during the clinical course in pbl . in this report , we present two pbl cases who had high serum levels of sil-2r on presentation and normalized serum levels after the treatments .
we show the clinical course of the two pbl patients and discuss the possible clinical significance of sil-2r levels in pbl .
in may 2007 a 52-year - old man visited the national hospital organization tokyo medical center ( ntmc ) with left buttock pain which had lasted for 6 months .
the radiograph showed osteosclerotic and osteolytic changes in the wing of the ileum and the acetabulum ( fig .
bone scintigraphy showed highly increased accumulation of 99mtc - hmdp in the left acetabulum and indicated sole bone lesion .
a whole - body ct scan and gallium scan revealed no evidence of visceral or lymph node involvement . from these results ,
a 67-year - old man with a 1-month history of right hip pain visited the ntmc due to difficulty in walking .
ct imaging showed moth - eaten pattern of destruction of the anterior part of the acetabulum and expanded soft tissue ( fig .
a whole - body ct scan , and bone and gallium scans were carried out .
thus , primary bone tumor of the right acetabular roof was suspected . in both cases ,
laboratory tests at hospitalization showed high levels of serum sil-2r [ case 1 : 2,880 u / ml , case 2 : 1,140 u / ml ( reference value : 188570 u / ml ) ] and slightly elevated levels of lactate dehydrogenase ( ldh ) [ case 1 : 263 u / l , case 2 : 241 u / l ( reference value : approx .
immunohistochemistry revealed positive staining for cd20 and leukocyte common antigen , and was negative for cd3 .
thus , both cases were diagnosed as pbl ( diffuse large b - cell lymphoma ) . according to the ann arbor staging system ,
both localized bone lesions were regarded as stage i. the chemotherapy [ r - chop ( rituximab , cyclophosphamide , doxorubicin , vincristine , prednisolone ) ; case 1 : 8 courses , case 2 : 6 courses ] was performed under the supervision of the hematology department . in case 1 , osteosclerotic changes increased and the pathological fracture line became unclear in radiographic images after the chemotherapy ( fig .
2a ) . new bone formation and increased osteosclerosis around the acetabulum as well as intrapelvic migration of the femur head were recognized in case 2 ( fig .
3a , b ) , and linked with radiological therapeutic response of the affected bones .
in may 2007 a 52-year - old man visited the national hospital organization tokyo medical center ( ntmc ) with left buttock pain which had lasted for 6 months .
the radiograph showed osteosclerotic and osteolytic changes in the wing of the ileum and the acetabulum ( fig .
bone scintigraphy showed highly increased accumulation of 99mtc - hmdp in the left acetabulum and indicated sole bone lesion .
a whole - body ct scan and gallium scan revealed no evidence of visceral or lymph node involvement . from these results ,
in august 2006 , a 67-year - old man with a 1-month history of right hip pain visited the ntmc due to difficulty in walking .
ct imaging showed moth - eaten pattern of destruction of the anterior part of the acetabulum and expanded soft tissue ( fig .
a whole - body ct scan , and bone and gallium scans were carried out .
thus , primary bone tumor of the right acetabular roof was suspected . in both cases ,
laboratory tests at hospitalization showed high levels of serum sil-2r [ case 1 : 2,880 u / ml , case 2 : 1,140 u / ml ( reference value : 188570 u / ml ) ] and slightly elevated levels of lactate dehydrogenase ( ldh ) [ case 1 : 263 u / l , case 2 : 241 u / l ( reference value : approx .
immunohistochemistry revealed positive staining for cd20 and leukocyte common antigen , and was negative for cd3 .
thus , both cases were diagnosed as pbl ( diffuse large b - cell lymphoma ) . according to the ann arbor staging system ,
both localized bone lesions were regarded as stage i. the chemotherapy [ r - chop ( rituximab , cyclophosphamide , doxorubicin , vincristine , prednisolone ) ; case 1 : 8 courses , case 2 : 6 courses ] was performed under the supervision of the hematology department . in case 1 , osteosclerotic changes increased and the pathological fracture line became unclear in radiographic images after the chemotherapy ( fig .
2a ) . new bone formation and increased osteosclerosis around the acetabulum as well as intrapelvic migration of the femur head were recognized in case 2 ( fig .
3a , b ) , and linked with radiological therapeutic response of the affected bones .
pbl is an extremely rare bone tumor ; its frequency is considered to be about 37% of all primary malignant bone tumors , approximately 3% of all extranodal lymphomas , and less than 1% of all malignant lymphomas [ 4 , 5 , 6 , 7 ] . according to who classification
, pbl can be categorized into two groups as follows : group 1 , lymphoma involving a single skeletal site , with or without regional lymph - node involvement , and group 2 , lymphoma involving multiple bones , without visceral or lymph - node involvement .
recently , several clinical reviews applying these criteria of pbl have been published [ 4 , 5 , 7 , 8 , 9 , 10 , 11 , 12 ] .
there was a slight male predominance and a tendency for senior adults to be affected more often , although pbl can occur at any age .
the pelvis or proximal part of the femur is the common site of the tumor .
most cases of pbl are reported to be non - hodgkin 's diffuse large b - cell lymphomas .
stage of disease , age , serum ldh levels , response to chemotherapy , and the use of combined modality therapy are considered to be prognostic factors in pbl .
radiographs and ct images of pbl usually present non - specific findings , mostly various patterns of osteolysis and osteosclerosis coexisting in the bone . as a result ,
radiological differential diagnosis of pbl from other types of primary bone tumors such as ewing 's sarcoma , osteogenic sarcoma , and chondrosarcoma is often difficult .
therefore , laboratory findings that help differentiate pbl from other common bone tumors are important .
so far , the significance of measuring sil-2r levels has been rarely reported in clinical reviews of pbl [ 4 , 5 , 7 , 8 , 9 , 10 , 11 , 12 ] .
in other primary malignant bone tumors including osteosarcoma , ewing 's sarcoma , chondrosarcoma , and malignant giant cell tumor , median serum levels of sil-2r are reported not to be significantly elevated compared with those of healthy controls [ 1 , 2 ] . recently , akahane et al . reported that the serum sil-2r level is valuable for differentiating pbl from other osteolytic malignancies or benign bone lesions that resemble malignant tumor radiographically . in our two pbl cases , the reduced sil-2r levels after r - chop therapy
were linked with the reduction of the tumor size and the osteosclerotic changes in the bone lesions . moreover ,
the changes in sil-2r levels were similar to those in ldh levels known as a prognostic factor of pbl .
the fact that sil-2r levels were associated with the clinical course of pbl means such measurements play an important role in the disease monitoring . adding to the recently reported results of the diagnostic significance of sil-2r in pbl
, our case study tentatively indicates the clinical significance of sil-2r levels as a tumor marker in pbl cases .
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### Summary:
: in two patients with primary bone lymphoma ( pbl ) treated in our clinic , serum levels of soluble interleukin-2 receptor ( sil-2r ) reflected the clinical course . in both cases ,
sil-2r levels were high before treatment and normalized with the therapeutic effects of chemotherapy , coinciding with the changes in lactate dehydrogenase levels and radiographic findings .
adding to the recently reported results of the diagnostic ability of sil-2r in pbl , our case study highlights the clinical significance of serum sil-2r levels as a tumor marker in pbl cases .
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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 period from october 2011 to april 2013 , 614 patients with critical limb ischemia were operated on with distal revascularization at the department of vascular surgery in kolding hospital , denmark .
a total of 354 received open surgical treatment and 260 were treated endovascularly . in 10 patients ,
no crural or pedal arteries were available for conventional bypass surgery . these patients were offered and accepted distal venous arterialization .
the group included eight males and two females , with a median age of 70 years .
eight had gangrene or painful ischemic ulceration of the foot , while two had ischemic rest pain .
half of the patients had earlier suffered above - ankle amputation of the contralateral leg .
comorbidity and risk factors included diabetes ( n=8 ) , renal insufficiency ( n=3 ) , hypertension ( n=7 ) , current or previous smokers ( n=7 ) . magnetic resonance angiography or digital subtraction angiography was applied to assess the arterial system and ultrasound examination was used for mapping of the venous system .
the operations were performed under regional anesthesia ( n=2 ) or general anesthesia ( n=8 ) .
the in situ technique was applied using a lemaitre valvutome ( le maitre vascular , burlington , ma ) to perform retrograde destruction of valves to the level of the ankle .
this was the common femoral artery ( n=6 ) , the superficial femoral artery ( n=1 ) , or the distal popliteal artery ( n=3 ) .
run - off was the dorsal pedal venous arch ( n=5 ) , the dorsal pedal venous arch and concomitant vein of the posterior tibial artery ( n=3 ) , or the dorsal pedal venous arch and a concomitant vein of the common plantar artery ( n=2 ) , depending on the location of the ischemic lesion according to the angiosomes theory .
an example of arterialization of both the dorsal pedal arch and a concomitant vein of the posterior tibial artery in a patient with gangrene of the medial calcaneal area and an ischemic wound at the base of the hallux is shown in fig .
the venous arterialization was an extension of an existing in situ bypass with insufficient arterial run - off . in eight cases ,
only venous material was used ( greater saphenous vein or small saphenous vein ) , while in two cases also 6 mm ringed , heparin - coated eptfe ( propaten , w. l. gore and associates , flagstaff , az ) , was interposed . in the pedal arch and deep pedal veins ,
it was possible to destroy the valves of the pedal arch retrogradely using a le maitre valvulotome via an extra incision .
the distal - most pedal veins that contained valves in need of destruction to obtain antegrade flow were the interosseous veins at the base of each toe .
in some cases , these veins were large enough for a mills antegrade valvulotome to be used for the veins of the first toe .
in other cases , and when we needed flow to other toes , smaller instruments were used , including knob needles , intravascular sheats , or guide wires . in one patient ,
supplemental valve destruction was performed endovascularly using a 0.035 guidewire , a 5 f sheat , and a van schie catheter ( cook medical , bloomington , in ) for valve destruction , and embolization of backflow was performed using trufill microcoils ( cordis , johnson & johnson , warren , nj ) ( fig .
access was gained through the graft via a puncture approximately 15 cm above the ankle . in eight cases , perioperative measurements of graft flow
example of angiosome - directed , combined deep and superficial venous arterialization in a patient with an ischemic wound at the toe and gangrene of the medial heel .
( a ) the great saphenous vein in situ , proximally anastomosed to the common femoral artery .
it can be noted from the color of the vein that arterial blood fills the vein proximal to the vascular clamps ( arrows ) .
( b ) at this stage , a posterior branch of the great saphenous vein has been transposed to a posterior tibial vein , allowing arterialization of the superficial venous arch toward the first toe and of the deep veins toward the heel .
( a ) digital subtraction angiogram showing antegrade filling of the pedal veins obstructed by a competent valve ( arrow ) .
( b ) after the valve has been destructed by means of a cutting balloon , distal filling has improved , but backflow is still prominent through an ascending vein ( arrow ) .
( c ) after placement of coils in the ascending vein ( arrows ) , backflow is partially obstructed .
follow - up was performed until : all wounds on the foot were healed with continuous epithelialization ; the operated limb was amputated above the ankle ; the patient died ; or the end of follow - up was reached on 25 august 2013 , whichever occurred first . in the cases when the patients were discharged before an endpoint was reached , follow - up was performed in an outpatient clinic .
in the period from october 2011 to april 2013 , 614 patients with critical limb ischemia were operated on with distal revascularization at the department of vascular surgery in kolding hospital , denmark .
a total of 354 received open surgical treatment and 260 were treated endovascularly . in 10 patients ,
no crural or pedal arteries were available for conventional bypass surgery . these patients were offered and accepted distal venous arterialization .
the group included eight males and two females , with a median age of 70 years .
eight had gangrene or painful ischemic ulceration of the foot , while two had ischemic rest pain .
half of the patients had earlier suffered above - ankle amputation of the contralateral leg .
comorbidity and risk factors included diabetes ( n=8 ) , renal insufficiency ( n=3 ) , hypertension ( n=7 ) , current or previous smokers ( n=7 ) .
magnetic resonance angiography or digital subtraction angiography was applied to assess the arterial system and ultrasound examination was used for mapping of the venous system .
the operations were performed under regional anesthesia ( n=2 ) or general anesthesia ( n=8 ) .
the in situ technique was applied using a lemaitre valvutome ( le maitre vascular , burlington , ma ) to perform retrograde destruction of valves to the level of the ankle .
this was the common femoral artery ( n=6 ) , the superficial femoral artery ( n=1 ) , or the distal popliteal artery ( n=3 ) .
run - off was the dorsal pedal venous arch ( n=5 ) , the dorsal pedal venous arch and concomitant vein of the posterior tibial artery ( n=3 ) , or the dorsal pedal venous arch and a concomitant vein of the common plantar artery ( n=2 ) , depending on the location of the ischemic lesion according to the angiosomes theory .
an example of arterialization of both the dorsal pedal arch and a concomitant vein of the posterior tibial artery in a patient with gangrene of the medial calcaneal area and an ischemic wound at the base of the hallux is shown in fig .
the venous arterialization was an extension of an existing in situ bypass with insufficient arterial run - off . in eight cases ,
only venous material was used ( greater saphenous vein or small saphenous vein ) , while in two cases also 6 mm ringed , heparin - coated eptfe ( propaten , w. l. gore and associates , flagstaff , az ) , was interposed . in the pedal arch and deep pedal veins ,
it was possible to destroy the valves of the pedal arch retrogradely using a le maitre valvulotome via an extra incision .
the distal - most pedal veins that contained valves in need of destruction to obtain antegrade flow were the interosseous veins at the base of each toe .
in some cases , these veins were large enough for a mills antegrade valvulotome to be used for the veins of the first toe .
in other cases , and when we needed flow to other toes , smaller instruments were used , including knob needles , intravascular sheats , or guide wires . in one patient ,
supplemental valve destruction was performed endovascularly using a 0.035 guidewire , a 5 f sheat , and a van schie catheter ( cook medical , bloomington , in ) for valve destruction , and embolization of backflow was performed using trufill microcoils ( cordis , johnson & johnson , warren , nj ) ( fig .
access was gained through the graft via a puncture approximately 15 cm above the ankle . in eight cases , perioperative measurements of graft flow
example of angiosome - directed , combined deep and superficial venous arterialization in a patient with an ischemic wound at the toe and gangrene of the medial heel .
( a ) the great saphenous vein in situ , proximally anastomosed to the common femoral artery .
it can be noted from the color of the vein that arterial blood fills the vein proximal to the vascular clamps ( arrows ) .
( b ) at this stage , a posterior branch of the great saphenous vein has been transposed to a posterior tibial vein , allowing arterialization of the superficial venous arch toward the first toe and of the deep veins toward the heel .
the color of the skin suggests successful revascularization . ( a ) digital subtraction angiogram showing antegrade filling of the pedal veins obstructed by a competent valve ( arrow ) .
( b ) after the valve has been destructed by means of a cutting balloon , distal filling has improved , but backflow is still prominent through an ascending vein ( arrow ) .
( c ) after placement of coils in the ascending vein ( arrows ) , backflow is partially obstructed .
follow - up was performed until : all wounds on the foot were healed with continuous epithelialization ; the operated limb was amputated above the ankle ; the patient died ; or the end of follow - up was reached on 25 august 2013 , whichever occurred first . in the cases when the patients were discharged before an endpoint was reached , follow - up was performed in an outpatient clinic .
seven of the operated limbs were amputated above the ankle after 23 ( 1256 ) days ( median , range ) .
the main reasons for amputation were lack of healing of either the original wound , of incisional wounds on the foot , or persisting pain at rest . in three cases ,
one patient with a patent graft chose amputation after 256 days although the wound was in a picture of slow healing .
patient characteristics and outcomes three patients had avoided amputation at the end of follow - up .
the original wound of the last patient , originating from amputation of the hallux , healed within 6 weeks , but before the healing of the incisions was complete , the patient had a plantar abscess that needed a surgical incision .
this incision showed slow healing and at the end of follow - up 309 days after surgery
the patient was in need of home - based wound care , but was ambulating . in one of the patients who experienced wound healing ,
the distal portion of the arterialized venous arch was thrombosed at the time when healing was complete . however , the proximal part of the bypass was open with run - off in a mid - crural fistula .
in our first experience with venous arterialization , amputation was avoided in 3 out of 10 patients . in a recent systematic review and meta - analysis ,
this analysis showed 71% limb salvage at 1-year follow - up , with the best results found in chinese and russian populations and better results in patients with buerger 's disease than in patients with obstructive atherosclerosis ( 6 , 8) .
the largest material from a western population was reported by lengua , who operated on 59 patients over a period of 26 years ( 5 ) .
although the present results of 30% limb salvage do seem disappointing compared to the few earlier published series , it must be suspected that a significant publication bias may be present , causing mainly good results to be published and disappointing results not to be reported . taking this into account , our results may be average rather than poor . also , since this is our initial experience , an effect of a learning curve may be suspected .
patient selection is of course a major concern when comparing outcome . as opposed to some other investigators who used no crural arteries as inclusion criterium ( 12 ) , we used arterial run - off for all patients where these were available , including plantar and dorsal pedal arteries , either as seen on preoperative angiograms or found by surgical exploration
. we also performed a high number of endovascular reconstructions including crural and pedal arteries .
venous arterialization was only used as ultimum refugium in cases with very extensive distal calcifications , or when arterial bypasses had already been attempted but had failed .
the results should , therefore , not be compared to the results of arterial bypass or pta , but rather with treatments like vasodilator antiplatelet prostacyclin , which has shown only a modest superiority over placebo in preventing amputation ( 13 ) , or lumbar sympathectomy , which may relieve symptoms but does not convincingly improve limb salvage ( 14 ) .
similar to other authors , we found poor healing of incisional wounds on the foot to be of importance for poor limb salvage .
this experience seems to favor using a more proximally located distal anastomosis combined with endovascular valve destruction and closure of arteriovenous fistula in a manner more similar to the technique originally described by alexandriescu ( 11 ) . for this initial group of patients ,
in retrospect , it would have been helpful to perform pre- and post - operative measurement of toe pressures and skin perfusion pressures , and we intend to do so in future cases .
we found the healing rate after venous arterialization to be slower than usually seen after arterial bypass surgery . in one case , where healing was evident , the patient lost patience and opted for amputation .
it is important , when consenting the patients for this type of surgery , to inform them thoroughly about a long expected recovery and venous arterialization should be reserved for patients who are willing to go through a long healing process which includes outpatient wound care and an uncertain final outcome .
it is also important that surgeons and caretakers are aware of the slower healing rate with venous compared to arterial revascularization
. this may prevent amputations in cases where slow healing causes disillusion . for the included patients
patients with peripheral arterial disease who undergo major limb amputation have a very poor prognosis , with almost 50% mortality within 1 year ( 15 ) .
patients who have had one leg amputated may be able to stay in their home , but after losing their second leg almost inevitably need to stay in nursing homes , causing loss of quality of life and large societal costs ( 16 ) .
hence , we find extensive attempts of limb salvage in this group of patients to be justified , given the patient is willing to undergo the treatment . in conclusion
, we found venous arterialization of the lower limb to be a possible alternative to primary amputation in cases where no other revascularizing options are present .
the operative technique may be improved by increasing the use of endovascular techniques of valve destruction and closure of fistula , and patient selection may be improved by thorough pre - consent information about expected prolonged wound healing .
the authors have not received any funding or benefits from industry to conduct this study .
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### Summary:
: backgroundpatients with critical lower limb ischemia without patent pedal arteries can not be treated by the conventional arterial reconstruction .
venous arterialization has been suggested to improve limb salvage in this subgroup of patients but has not gained wide acceptance .
we report our early experience after implementing deep and superficial venous arterialization of the lower limb.materials and methodsten patients with critical ischemia and without crural or pedal arteries available for conventional bypass surgery or angioplasty were treated with distal venous arterialization .
inflow was from the most distal unobstructed segment .
run - off was the dorsal pedal venous arch ( n=5 ) , the dorsal pedal venous arch and a concomitant vein of the posterior tibial artery ( n=3 ) , or the dorsal pedal venous arch and a concomitant vein of the common plantar artery ( n=2 ) depending on the location of the ischemic lesion .
venous valves were destroyed using antegrade valvulotomes , guide wires , knob needles , or retrograde valvulotomes via an extra incision.resultsseven of the operated limbs were amputated after 23 ( 1256 ) days ( median [ range ] ) .
the main reasons for amputation were lack of healing of either the original wound , of incisional wounds on the foot , or persisting pain at rest . in three cases ,
the bypass was open at the time of amputation .
two patients experienced complete wound healing after 231 and 342 days , respectively . by the end of follow - up , the last patient was ambulating with slow wound healing but without pain 309 days after surgery.conclusionvenous arterialization may be used as a treatment of otherwise unsalveable limbs .
the success rate is , however , limited .
technical optimization of the technique is warranted .
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: most of these patients have an igm dysglobulinemia and around 70% of those have anti - myelin associated glycoprotein ( mag ) antibody detected by enzyme - linked immunosorbent assay ( elisa ) .
indeed , it has long been demonstrated that mag behaves as a self - antigen in patients with polyneuropathy and igm monoclonal gammopathy . in the past 25 years
, numerous series have described anti - mag neuropathy as a homogeneous entity [ 3 , 4 ] .
the clinical picture of the disorder usually consists of a chronic sensory polyneuropathy with ataxia and tremor of progressive worsening .
motor involvement , if present , usually occurs lately in the course of the disorder .
nerve conduction studies display a demyelinating pattern with distally accentuated slowing of motor conduction , no conduction block , and a severe reduction of sensory nerve action potentials ( snaps ) .
when nerve biopsy is performed , it shows signs of demyelination on semithin sections and teased fiber studies , and electron microscopic examination usually displays the classic pattern of widening of myelin lamellae ( wml ) , which is considered the pathological hallmark of the disease .
this latter feature corresponding to deposits of the monoclonal igm on myelin sheath distinguishes pathologically anti - mag neuropathy from chronic inflammatory demyelinating polyradiculoneuropathy ( cidp ) . in the present study
, we show that anti - mag neuropathy is indeed a heterogeneous disorder as demonstrated by careful clinical , electrophysiological , and neuropathological analysis .
the data from all patients with a polyneuropathy associated with an igm monoclonal gammopathy and anti - mag antibodies seen in our neurology department over the previous 25 years were retrospectively reviewed .
age , gender , and duration of symptoms at the time of diagnosis were extracted from the medical charts . based on clinical evaluation
, patients were classified as having pure sensory neuropathy , ataxia with sensory neuropathy , and sensorimotor neuropathy .
ataxia was considered if patients had a positive romberg sign , subjective impression of balance loss , and visible balance disturbance when walking .
a sensorimotor neuropathy was defined by the presence of sensory loss on clinical examination and motor weakness at 4 or less on the medical research council ( mrc ) scale in any limb segment ( except if patients had weakness only in toe extensors ) . at the time of referral , 56 ( 93% )
bilateral motor conduction studies of median , ulnar , peroneal , and tibial nerves and sensory conduction studies of sural , median , and ulnar nerves were performed .
the nerve conduction data were considered sufficient for analysis when at least 2 motor nerves and one sensory nerve were examined in the lower limbs and 2 motor nerves and 2 sensory nerves in the upper limbs .
partial conduction block was defined by a reduction of compound muscle action potential ( cmap ) by proximal stimulation of at least 50% in the lower limb and at least 30% in the upper limb .
temporal dispersion was defined by a lengthening of cmap of at least 30% by proximal stimulation . the terminal latency index ( tli )
was calculated for the median and ulnar nerves as described . for the purpose of this study , patients were retrospectively classified as having typical anti - mag neuropathy : a grossly symmetric demyelinating neuropathy with distally predominant demyelination based on low terminal latency indexes , a severe decrease of sensory nerve action potential ( snap ) amplitudes in the lower limbs , and no conduction block or temporal dispersion , or a cidp - like pattern : fulfillment of the efns / pns criteria for cidp , normal tli in ulnar and median nerves and/or presence of conduction block and/or temporal dispersion in at least one nerve , and/or normal or near normal snaps in the lower limbs .
search for anti - mag antibodies was done several years ago for 4 patients by immunochromatography .
sera from most of the patients were tested for anti - mag antibodies by elisa ( bhlmann laboratories ag , schonenbuch , switzerland ) .
the cut - off positive value was considered above 1000 btu ( bhlmann titer unit ) according to the manufacturer 's instructions .
other sera were tested in the center of biology and pathology ( hospices civils de lyon ) for anti - mag antibodies and for antibodies to sulfate-3-glucuronyl paragloboside .
to confirm anti - myelin activity , we performed indirect immunofluorescence with the sera from 45 patients on normal human peripheral nerve as described earlier . in 15 patients
forty - three of the 60 patients underwent nerve biopsy after informed consent . depending on clinical and/or neurophysiological involvement , the sural , superficial peroneal or sensory branch of a radial nerve
a third fragment was frozen for direct immunofluorescence ( dif ) using specific antisera for igg , iga , igm , lambda and kappa light chains , and c3d conjugated to fluorescein , to reveal immunoglobulin deposits on the patients ' nerves .
qualitative data were expressed as percentages with their 95% confidence interval and quantitative data were expressed as mean sd .
statistical significance of differences between categorical variables was determined by means of or fisher exact test as appropriate and for differences between continuous variables by means of student 's t - test . statistical significance for all analyses
mean age at study was 67 10 years ( range 4687 ) and mean duration of symptoms at diagnosis was 35 44 months ( range 2204 ) .
nineteen ( 32% ) patients had the distal acquired demyelinating symmetrical ( dads ) phenotype .
symptoms and signs in these patients were mostly sensory and proximal segments of limbs were never involved by sensory and/or motor signs .
these patients had usually numbness or tingling limited to the feet and prominent ataxia and 3 of them had additional pain .
pain had the classical characteristics of neuropathic pain in these patients ( mainly burning , squeezing , and painful cold ) and was a prominent symptom in seven of those who used various analgesics ( clonazepam , gabapentin , amitriptyline , and pregabalin ) .
physical examination showed distal hypesthesia and tendon reflexes were variably impaired in this subgroup of patients ( ranging from diminished achilles reflexes to abolition of reflexes in all four limbs ) .
32 ( 53% ) patients had variable degrees of motor weakness leading to severe impairment in a minority of them .
mean duration of symptoms at diagnosis was 45.6 months in patients with sensorimotor neuropathy and 31.9 months in other patients although this difference did not reach significance .
the presence of any weakness was not statistically linked with the duration of symptoms when comparing patients with duration of disease below or above two years .
37 ( 66% ) patients had the typical anti - mag pattern as defined above .
most of them had a severe reduction of snaps in all four limbs , a distal pattern of demyelination as defined by low tlis in at least one nerve , and no conduction block .
most of these patients had conduction block and/or marked temporal dispersion and some had normal or near normal snaps in the lower limbs .
there was no correlation between the different clinical subtypes and the electrodiagnostic pattern of nerve involvement .
all patients had igm monoclonal gammopathy and anti - mag antibodies . for 51 ( 85% ) patients ,
the diagnosis was of a monoclonal gammopathy of undetermined significance ( mgus ) although 4 patients had waldenstrm 's macroglobulinemia , 2 patients had non - hodgkin 's malignant lymphoma , and 3 patients had chronic leukemia .
one patient with chronic lymphocytic leukemia had epineurial b cell infiltrates suggestive of lymphomatous transformation ( see below ) .
the titer of anti - mag antibodies was highly variable among patients , ranging from 1111 btu to > 70000 btu ( table 1 ) .
although quite strongly correlated with the neuropathological pattern and the electrodiagnostic findings , the biological data were not correlated with the clinical pattern as defined above .
this axonal loss was highly variable among patients , ranging from slight to severe . among patients who underwent nerve biopsy , 26 ( 60% ) had typical widening of myelin lamellae ( wml ) on electron microscopic examination ( figure 1 ) .
most of these patients had mild cellular infiltrates composed of lymphocytes ( anti - cd45 staining ) and macrophages ( anti - cd68 staining ) : 8 of these had macrophage - associated demyelination , a feature considered typical of cidp ( figure 2 ) .
one of the female patients ( 26 ) with mgus and wml had also prominent b cell infiltrates in the epineurium ( anti - cd20 staining ) suggesting the conversion of the gammopathy to a b cell lymphoma ( figure 3 ) .
all of these patients had features typical of a demyelinating neuropathy with onion bulb formations and/or completely demyelinated axons ( figure 4 ) .
additionally , macrophage - associated demyelination was encountered in all nerve samples from these patients .
thirty - five patients had indirect immunofluorescence ( iif ) to test reactivity of their serum against normal nerve .
iif failed to show any staining with anti - igm and/or anti - c3d in 9 patients and was mostly negative in patients with the cidp pattern and a low titer of anti - mag antibodies .
the details of the two subpopulations of patients according to the electrodiagnostic pattern are summarized in table 2 . among the 37 patients who had the typical anti - mag pattern on nerve conduction studies , 27 had nerve biopsy , of which 21 ( 78% ) showed typical wml ( p < 0.05 ) .
twenty - two of these 37 patients had iif , which was positive in 20 ( 91% ) cases . of note
, anti - mag antibodies were above 10000 btu in 32 ( 86% ) of the 37 patients with ncs suggestive of anti - mag neuropathy ( p < 0.05 ) . among the 17 patients who had nerve conduction studies consistent with cidp , 12 underwent nerve biopsy , which showed histological abnormalities suggestive of cidp , without wml on electron microscopic examination in 10 ( 83% ) cases ( p < 0.05 ) .
moreover , 10 of these 17 patients had anti - mag antibody titer below 10000 btu ( p < 0.05 ) .
four patients who had concordant nerve conduction and neuropathological findings suggestive of anti - mag neuropathy had low titers of anti - mag antibodies ( 11118663 btu ) but positive sgpg antibodies .
iif was carried out in 3 of these 4 patients and was positive in all .
the objective of this retrospective study was to reexamine the concept that polyneuropathy associated with anti - mag antibodies is a homogeneous entity .
nerve conduction studies usually show a symmetrical demyelinating neuropathy with distal accentuation and the phenotype is sometimes referred to as distal acquired demyelinating symmetric neuropathy ( dads ) .
the demographic features of our patients ( mean age at diagnosis of 69 years , sex ratio of 2.7 favoring males , and mean history of symptoms around two years before diagnosis ) do not differ from previous studies . similarly , the chronic progression of symptoms we observed in our patients is a classic feature of this condition [ 4 , 18 ] . in the present study
, 53% of the patients had a clinical sensorimotor neuropathy and the presence of motor signs was not associated with the duration of the disease .
we think this feature has not been emphasized previously . indeed , in the follow - up series of nobile - orazio et al .
, disability was mainly caused by prominent ataxia , although motor signs were not mentioned .
similarly , 28% of our patients had prominently sensory symptoms ( without ataxia ) that were sometimes painful suggesting small fiber involvement .
we did not check for small fiber loss by skin biopsy , as this technique was not yet available in our center at the time of the study .
this is in contrast with previous studies where ataxia was found in more than two - thirds of patients [ 6 , 19 ] .
the pattern of nerve conduction abnormalities in anti - mag neuropathy has been widely described in the literature and most authors have emphasized the distal accentuation of nerve conduction slowing [ 20 , 21 ] .
moreover , consensus diagnostic criteria for anti - mag neuropathy have been published and mostly rely on this feature along with severe reduction of snaps . in our series
, only two - thirds of patients had these typical electrodiagnostic features , while 30% of our patients had nerve conduction studies consistent with cidp .
moreover , most ( 83% ) of the patients with the cidp - like pattern who underwent nerve biopsy did not display the classic wml on electron microscopic examination .
widening of myelin lamellae ( wml ) was present in 78% of the patients who had nerve biopsy and nerve conduction studies typical of the dads phenotype .
wml is usually observed in the outer myelin lamellae and is caused by dissociation of the intraperiod lines by the monoclonal component and is a specific feature of anti - mag neuropathy . in our patients ,
wml constantly coexisted with macrophage - associated demyelination , a feature that is considered typical of cidp although it has been described by others in patients with demyelinating neuropathy and monoclonal gammopathy .
one patient in this series had prominent b cell infiltrates in the epineurium , a feature that prompted a change in her treatment . in this study , patients have been tested for the presence of anti - mag antibodies by elisa .
western blot ( wb ) analysis has long been the gold standard for detection of anti - mag antibodies and positive wb is present in approximately 50% of patients with igm monoclonal gammopathy and a demyelinating polyneuropathy .
the elisa method , which is much simpler , can be applied in most immunology laboratories . moreover
, a recent work has shown that it is valid and robust in detecting anti - mag antibodies in patients with igm mg and polyneuropathy . in this series ,
the elisa test with a cut - off value of 1500 btu was proven more sensitive than wb ( 71.2% versus 54% ) to detect anti - mag antibodies in patients with igm mg and a demyelinating polyneuropathy . in the present study
, we used a cut - off value of 1000 btu but only 2 patients had a titer below 1500 btu ( see table 1 ) so we think this has not significantly biased our results .
results of indirect immunofluorescence were highly correlated with electrodiagnostic studies and neuropathological data in our patients . indeed , among the ten patients who had an indirect immunofluorescence study in the cidp group , the test was negative in seven .
this was also correlated with a low titer of anti - mag antibodies , which was below 10000 btu in 10 out of 17 patients in this subgroup .
this feature was not surprising , as other authors have previously shown that sera from patients with low titers of anti - mag antibodies did not bind normal nerve , suggesting microheterogeneity of anti - mag antibodies .
conversely , the majority of patients with neurophysiological studies consistent with anti - mag neuropathy and high titers of anti - mag antibodies had a positive indirect immunofluorescence study .
this simple test has been reported as highly specific even in patients with no detectable igm gammopathy .
four patients ( 11 , 18 , 23 , and 29 ) in our series had a unique immunopathologic profile .
they had a low titer of anti - mag antibodies by elisa ( 1111 to 8363 btu ) and 2 of these had a negative western blot .
these 4 patients , who had electrodiagnostic testing suggestive of anti - mag neuropathy and typical wml for 3 of them , had positive sgpg antibody testing .
this may suggest that anti - sgpg antibody testing is more sensitive to detect a relationship between the polyneuropathy and igm monoclonal gammopathy in some patients , as previously outlined .
moreover , in the recent series by kuijf et al . , the positivity of anti - mag antibody and anti - sgpg antibody testing was highly correlated but 4 patients with a demyelinating neuropathy and igm gammopathy had negative anti - mag antibodies and positive anti - sgpg antibodies . in our patients with high ( > 10000 btu ) titer of anti - mag antibodies ,
nerve conduction studies were almost constantly suggestive of the dads phenotype although the clinical picture was heterogeneous . moreover , most of these patients had positive indirect immunofluorescence and wml .
these data point to a direct relationship between the monoclonal gammopathy and the demyelinating neuropathy , by contrast with some of the patients with the cidp - like profile .
additionally , 5 patients had positive anti - mag antibodies by immunochromatography without quantification and could not have elisa testing .
nevertheless , 4 of these patients had positive indirect immunofluorescence and 4 had nerve biopsy showing positive direct immunofluorescence and the presence of wml . in summary
, the data presented here clearly show the heterogeneity of polyneuropathy associated with anti - mag antibodies .
the clinical and pathological heterogeneity has already been emphasized recently , but we expand previous findings by demonstrating relationships between immunological , neurophysiological , and pathological profiles . in our series ,
clinical analysis suggests three main patterns of peripheral nervous system involvement : a sensory ataxic neuropathy , an almost purely subjective sensory ( sometimes painful ) neuropathy , and a sensory and motor neuropathy with variable degrees of weakness .
similarly , electrodiagnostic studies revealed that most of the patients had the phenotype referred to as dads , although at least one - third of the patients had a cidp - like presentation that may indicate a different pathophysiologic mechanism .
altogether , our data suggest that patients with anti - mag neuropathy based on elisa testing may be divided in two subgroups , according to nerve conduction studies , nerve biopsy findings , immunofluorescence data , and titers of anti - mag antibodies .
the first subgroup consists of patients with the typical anti - mag neuropathy who have a sensory or sensorimotor polyneuropathy with demyelinating features predominating in the distal segments of nerves , prominent alterations of sensory potentials , positive immunofluorescence studies , wml , and high titers ( above 810000 btu ) of anti - mag antibodies .
the second subgroup consists of patients with a cidp - like neuropathy , who have a sensory or sensorimotor neuropathy with demyelinating features involving intermediate or proximal segments of nerves , sometimes preserved sensory potentials , negative immunofluorescence studies , no wml , and low titers of anti - mag antibodies .
as the present study was retrospective , the phenotypes defined here were not taken into account at the time the patients were treated , and the care of the patients studied was considerably heterogeneous , from supportive treatment alone to the use of intravenous immunoglobulin , immunosuppressants , or monoclonal antibody ( rituximab ) .
we expect that our findings may have implications regarding the choice of therapy . indeed ,
as reviewed , immunomodulatory treatments like intravenous immunoglobulin ( ivig ) have demonstrated a short term and modest effect on patients with polyneuropathy and anti - mag antibodies and are not usually considered as a first - line treatment of this condition .
moreover , case reports have emphasized that a motor phenotype of anti - mag associated neuropathy could be linked to a good response to ivig .
similarly , open - label trials have shown that plasma exchange in combination with cyclophosphamide may be beneficial in the short term but does not provide any advantage over chlorambucil alone .
more recent studies suggest that rituximab is effective but in no more than half of the patients with polyneuropathy associated with anti - mag antibodies [ 33 , 34 ] .
we think these discrepancies may be partly due to the heterogeneity of this syndrome , which may involve different pathogenic mechanisms .
deciphering these mechanisms is challenging but may help finding the best targets to treat patients with a potentially disabling disease .
we have described a series of patients with polyneuropathy associated with igm monoclonal gammopathy and anti - mag antibodies .
anti - mag neuropathy is regarded as a homogeneous disorder characterized by a sensory ataxic neuropathy sometimes associated with tremor , but our personal experience is that this syndrome is characterized by more heterogeneity than was previously reported .
this study clearly demonstrates that anti - mag neuropathy is indeed a relatively heterogeneous entity and that this heterogeneity can be found at the clinical , neurophysiological , and pathological levels .
we suggest that this heterogeneity may be underlined by different pathophysiological mechanisms that remain to be elucidated .
if this assumption is true , it could have major therapeutic implications in this frequent and sometimes debilitating disorder .
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### Summary:
: polyneuropathy associated with igm monoclonal gammopathy and anti - myelin associated glycoprotein ( mag ) antibodies is an immune - mediated demyelinating neuropathy .
the pathophysiology of this condition is likely to involve anti - mag antibody deposition on myelin sheaths of the peripheral nerves and it is supposed to be distinct from chronic inflammatory demyelinating neuropathy ( cidp ) , another immune - mediated demyelinating peripheral neuropathy . in this series
, we have retrospectively reviewed clinical and laboratory findings from 60 patients with polyneuropathy , igm gammopathy , and anti - mag antibodies .
we found that the clinical picture in these patients is highly variable suggesting a direct link between the monoclonal gammopathy and the neuropathy .
conversely , one - third of patients had a cidp - like phenotype on electrodiagnostic testing and this was correlated with a low titer of anti - mag antibodies and the absence of widening of myelin lamellae .
our data suggest that polyneuropathy associated with anti - mag antibodies is less homogeneous than previously said and that the pathophysiology of the condition is likely to be heterogeneous as well with the self - antigen being mag in most of the patients but possibly being another component of myelin in the others .
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: rotator cuff disease is the most common cause of shoulder pain , particularly among the
middle - aged and elderly .
it is the most commonly diagnosed cause of shoulder dysfunction
being the causative factor in 74% of cases of shoulder pain . with increasing age , the
tendons that form the rotator cuff
undergo progressive degenerative changes which can lead
to partial or full - thickness tearing of the tendons , resulting in pain , weakness and
dysfunction in the rotator cuff and scapular muscles , tightness in the soft tissues , and
postural abnormalities1,2,3,4,5 .
rotator cuff disease can possibly be treated successfully with conservative management , but
this depends upon the gender of the patient and tear size as well as the degree of
atrophy2 .
conservative management aims
to control pain , improve patients range of motion ( rom ) , and enhance the scapulothoracic
rhythm and function .
conservative management also includes patient education and the use of
analgesics , non - steroidal anti - inflammatory drugs ( nsaids ) , and injections , functional
rehabilitation , and manual therapy along with physiotherapy modalities such as therapeutic
ultrasound ( us ) , which is used to promote healing and regeneration in inflamed tissue ,
reduce pain and muscle spasms , and improve rom1,2,3 , 6,7,8 .
however , some studies have found that the
use of us does not significantly improve shoulder problems3 , 7,8,9,10,11,12,13,14 .
the aim of this study was to evaluate the effects of therapeutic continuous us on pain ,
functional status , and isokinetic shoulder rotator strength in patients with shoulder pain
due to rotator cuff disease .
this prospective , randomized , double - blinded , placebo - controlled study involved of 22
patients with rotator cuff disease ( 11 males , 11 females ; age range , 5281 years ) who were
treated at the physical medicine and rehabilitation department of baskent university
hospital in adana , turkey .
a physiotherapist randomly assigned half of the patients to a
true us group and the other 11 to a sham us group .
these
assignments were unknown to both the patients and the physiatrist working with them .
this
study was approved by the local ethics committee of baskent university , and written informed
consent was obtained from all of the patients .
the inclusion criteria of the study were : the presence of unilateral shoulder pain and
limited active movement for at least four weeks prior to the study , normal passive shoulder
movement , a diagnosis of rotator cuff disease by magnetic resonance imaging ( mri ) , and no
physiotherapy for the shoulder in the four weeks prior to the study .
in addition , potential
study subjects needed to have at least two of the following positive impingement signs :
positive results in the speed , neer , or hawkins tests or the drop arm , lift - off , or
supraspinatus isolation tests ; a resistant , painful shoulder during internal and external
rotation ( ir and er ) ; or pain during the abduction of the shoulder with a painful arch8 , 15 , 16 . the consecutively referred patients who
met these criteria were informed about the details of the study .
patients were excluded if they had any of the following : a history of acute trauma , surgery
or a fracture to or in the proximity of the shoulders , rom limitation in the upper
extremities , a neurological deficit in the upper extremities , an underlying inflammatory
rheumatic disease , or signs of cervical pathologies that might be associated with shoulder
pain .
the rotator cuff pathologies were graded in three stages according to the results of mri ,
with stage 1 indicating acute inflammation with either tendonitis or bursitis , stage 2
signifying chronic inflammation either with or without degeneration , and stage 3
representing patients with a rupture of the cuff2 .
all the patients were evaluated before and immediately after
rehabilitation ( 20th day ) by the same physiatrist using the visual analog scale ( vas ) ,
university of california , los angeles ( ucla ) shoulder rating scale , and the constant - murley
shoulder outcome score as well as isokinetic measurements of the shoulder er and ir
muscles .
the constant - murley shoulder outcome score assesses the range of functional active movement
of a normal , diseased , or treated shoulder .
it is comprised of subjective assessments of
pain ( 15 points ) and activities of daily living ( adl ) ( 20 points ) together with objective
measures of rom ( 40 points ) and shoulder strength ( 25 points ) that are added and have a
maximum possible score of 10015 , 17 .
the ucla shoulder rating scale includes an evaluation of pain and a patient satisfaction
rating together with functional active forward flexion , and strength of forward flexion
assesment performed with manual muscle testing .
the maximum possible total score is 35
points , with higher scores indicating better shoulder function17 , 18 . to perform the isokinetic evaluation
, we used a biodex system 3 pro dynamometer ( biodex
medical systems , shirley , ny , usa ) to test the isokinetic strength of the shoulder er and ir
muscles at constant angular velocities of 60/second , and 180/second via a
concentric / concentric mode , and these tests were performed by the same physiatrist . to
standardize the measurements
, we created a new test protocol for the isokinetic mode menu of
the machine .
before the testing of each patient began , the dynamometer was calibrated , and
its position was established according to the standard measurement technique in which the
device was tilted 50 and oriented 20 and the seat was tilted 85 and oriented 15. in
addition , before the isokinetic muscle testing , 1 ml intra - articular 2% prilocaine was
injected into the affected shoulder to enable painless movement .
the patients were then
seated on a supine position in the isokinetic dynamometer chair at 80 hip flexion and 90
knee flexion with their ankles unrestricted .
their trunks and legs were stabilized using
straps across the chest , waist , and upper thighs .
muscle strength was tested with the
shoulder in a modified neutral position ( 45 abduction and 30 flexion ) , and the elbow
flexed at 90. the axis of rotation was adjusted with the axis alignment being longitudinal
through the head of the shaft of the humerus and the center of the glenohumeral joint in the
horizontal plane .
the elbow axis was aligned parallel to the entrance axis of the
dynamometer , and the neutral hand position was adjusted as indicated by the user s manual .
next , the movement range was set to a painless 90 shoulder rotation around the modified
neutral position ( 45 of ir and 45 of er ) .
all of these isokinetic protocols were performed exactly according to the
manufacturer s recommendations . after explaining the procedure to the patients , they were familiarized with it by
performing three submaximal and five maximal repetitions at each speed .
in addition , a
30-second rest period was provided between the familiarization trials and the testing .
the
isokinetic evaluation at 60/second and 180/second consisted of five and 10 repetitions of
maximal effort for each respective movement .
a 10-second rest period was allowed after each
measurement with a five - minute rest between the testing of the two shoulders .
we also measured the isokinetic strength at peak torque ( pt ) of er and ir at each speed and
used the highest torque value ( newton meters ) recorded during the isokinetic efforts in the
analysis .
the true us group received continuous us via a gymna combi 200 device for two - channel
electrotherapy ( gymnauniphy n.v .
bilzen , belgium ) operated at a frequency of 1.1 mhz and at
an intensity of 1.5 w / cm .
the transducer head had an area of 4.7 cm
and an effective radiating area of 4.1 cm .
while sitting on a table , the
patients placed an arm on their lap with their hand in a supinated position . using slow
circular movements ,
the physiotherapist applied the transducer head over the glenohumeral
joint , covering an area of approximately 10 cm for a five - minute period .
for the
sham us group , the intervention was performed with the same device set to the off mode ,
and the transducer head applied to the same area in the same way with the same transmission
gel .
afterwards , transcutaneous electrical nerve stimulation ( tens ) and hot packs were applied
to the patients of both groups for 20 minutes each , and then for 30 minutes , the patients
perfromed exercises that included active and passive shoulder rom , codmann exercises ,
capsular stretching , isometric and isotonic exercises for strengthening the rotator cuff ,
biceps , and deltoid muscles , and scapulohumeral stability exercises .
these exercises were
performed at the rehabilitation clinic and supervised by the same physiotherapist . at the
start of the therapy , or when a patient had severe pain or discomfort , passive restricted
rom exercises and gentle stretching were used . at a later phase or when discomfort or pain
had lessened , exercise shifted toward active rom exercises , and gradually isometric and
dynamic resistance exercises
tens ( stt-500 , stratek , korea ) was applied with a frequency of 100 hz and current
of 8.4 ma over the glenohumeral joint for 20 minutes .
statistical analysis was performed using spss statistics for windows version 17.0 software
program ( spss inc . ,
chicago , il , usa ) . for each continuous variable , distribution normality
was checked using the kolmogorov - smirnov and shapiro - wilk tests and histograms .
comparisons
between groups were performed using the mann - whitney u test for the data that was not
normally distributed .
in addition , the pre- and post - intervention data were analyzed via
repeated measures analysis , and p values of < 0.05 were considered to be statistically
significant .
the true and sham us groups were evaluated according to age , gender , affected extremity ,
stage of rotator cuff pathology , and duration of symptoms ( table 1table 1.clinical characteristics of the study populationcharacteristics true ultrasound groupsham ultrasound groupage ( years ) ( mean sd)52.9 11.157.1 15.0females/ males ( % ) 5/6 ( 45.5/54.5 ) 6/5 ( 54.5/45.5)stage 2/stage 3 radiological grade ( % ) 5/6 ( 45.5/54.50)6/5 ( 54.5/45.5)right / left affected extremity ( % ) 5/6 ( 45.5/54.5)9/2 ( 81.8/18.2)duration of symptoms ( months ) ( mean sd)27.5 37.018.1 33.1sd : standard deviation ) .
in addition , the
pre - intervention values of the vas , ucla shoulder rating scale , and constant - murley shoulder
outcome score , and the isokinetic muscle testing measurements of the affected extremity were
similar for both groups ( table 2table 2.vas , ucla shoulder rating scale , and constant - murley shoulder outcome scores and
isokinetic measurements of the study populationcharacteristics true ultrasound groupmedian ( min max)sham ultrasound groupmedian ( min max)pre - intervention vas7 ( 210)7 ( 59)pre - intervention ucla / total16 ( 626)16 ( 931)pre - intervention constant - murley / total63 ( 2589)72 ( 2679)pre - intervention constant - murley / adl12 ( 820)12 ( 620)pre - intervention affected extremity er pt 60/s
( nm)12.4 ( 4.6026.8)12.3 ( 8.619.8)pre - intervention affected extremity ir pt 60/s
( nm)20.4 ( 3.2025.3)17.6 ( 4.825.6)pre - intervention affected extremity er pt 180/s
( nm)9.0 ( 3.7019.8)11.5 ( 720.8)pre - intervention affected extremity ir pt 180/s
( nm)16.2 ( 3.8026.4)20.1 ( 4.331.2)unaffected extremity er pt 60/s ( nm)13.2 ( 6.523.2)15.4 ( 7.825)unaffected extremity ir pt 60/s ( nm)20.9 ( 7.227.3)21.7 ( 8.346.9)unaffected extremity er pt 180/s ( nm)13.2 ( 7.320.8)13.8 ( 8.627)unaffected extremity ir pt 180/s ( nm)13.8 ( 4.8026.8)22.3 ( 11.747)*min : minimum ; max : maximum ; vas : visual analog scale ; ucla : university of california ,
los angeles shoulder rating scale ; adl : activities of daily living ; rom : range of
motion ; er : external rotation ; pt : peak torque ; ir : internal rotation ; nm : newton
meters .
. furthermore , there was no significant correlation between the patients
pathology grades based on the mri and the pre - intervention values of their isokinetic muscle
strength , vas , constant - murley shoulder outcome , and the ucla rating scale scores
( p>0.05 ) .
sd : standard deviation min : minimum ; max : maximum ; vas : visual analog scale ; ucla : university of california ,
los angeles shoulder rating scale ; adl : activities of daily living ; rom : range of
motion ; er : external rotation ; pt : peak torque ; ir : internal rotation ; nm : newton
meters .
* p < 0.05 moreover , the pre - and post - intervention evaluation of the scores from the same instruments
showed statistically significant improvement in both the true and sham us groups , but the
differences in these scores between the two groups were not statistically significant
( p>0.05 ) .
the adl subgroup scores of the constant - murley shoulder outcome test remained
the same in the sham group , whereas those in the us group showed improvementbut the
difference was not statistically significant in the adl scores between the two groups
( p>0.05 ) .
moreover , when the pre- and post - intervention isokinetic measurements of the
affected extremity were compared , only the er pt 60/second score improved in the two
groups , but the difference was not at a statistically significant ( p>0.05 ) ( table 3table 3.pre- and post - intervention evaluations of the vas , ucla shoulder rating scale ,
constant - murley shoulder outcome , and isokinetic measurementscharacteristicstrue ultrasound group median
( min max)sham ultrasound group median
( min max)pre - interventionpost - interventionpre - interventionpost - interventionvas7 ( 210)2 ( 19)*7 ( 59)4 ( 17)*ucla/ total16 ( 626)26.5 ( 1333)*16 ( 931)28 ( 1033)*constant - murley / total63 ( 2589)54 ( 7293)*72 ( 2679)81 ( 3890)*constant - murley / adl12 ( 820)14 ( 1020)*12 ( 620)12 ( 1020)er pt 60/s ( nm)12.4 ( 4.66.8)10.8 ( 6.69.2)*12.3 ( 8.619.8)12.1 ( 5.628.4)*ir pt 60/s ( nm)20.4 ( 3.25.3)6.1 ( 15.129.8)17.6 ( 4.825.6)18.5 ( 7.531.1)er pt 180/s ( nm)9 ( 3.719.8)9.75 ( 621.2)11.5 ( 720.8)11.5 ( 6.618.3)ir pt 180/s ( nm)16.2 ( 3.826.4)13.85 ( 5.329.1)20.1 ( 4.331.2)20.9 ( 5.633.1)min : minimum ; max : maximum ;
vas : visual analog scale ; ucla : university of california ,
los angeles shoulder rating scale ; pt : peak torque ; adl : activities of daily living ;
rom : range of motion ; er : external rotation ; ir : internal rotation ; nm : newton meters .
min : minimum ; max : maximum ; vas : visual analog scale ; ucla : university of california ,
los angeles shoulder rating scale ; pt : peak torque ; adl : activities of daily living ;
rom : range of motion ; er : external rotation ; ir : internal rotation ; nm : newton meters .
several factors , such as poor posture , weakness and dysfunction of the rotator cuff and
scapular muscles , decreased rom in the shoulder complex , degeneration and inflammation of
tendons and bursae , acromial dysmorphology , capsular tightness , and glenohumeral
instability , are commonly believed to contribute to rotator cuff disease3 , 8 , 15 , 17 , 19 .
for this reason , the rehabilitation of
this disease aims to control pain , improve rom , and provide scapulothoracic rhythm and
function9 , 15 , 20 , 21 .
when evaluating the efficacy of physiotherapy programs for rotator cuff disease , joint
mobility and stretching , relaxation , and exercise programs are deemed to be beneficial for
strengthening the rotator cuff muscles9 , 22 . in our study , the physiotherapy
interventions led to improvements in the results of the vas , ucla shoulder rating scale and
constant - murley shoulder outcome test in both the true and sham us groups .
furthermore , the
results of our short - term intervention suggest that conservative management of rotator cuff
disease can lessen the patientspain , enhance their functionality , and increase their
satisfaction levels .
yldrm et al.23
performed us , infrared , and tens on patients with rotator cuff disease together with an
exercise program , and they also saw improvement in the same three evaluation
instruments .
therapeutic us is commonly used for the conservative treatment of rotator cuff disease and
is generally prescribed in conjunction with other interventions . when applied with
appropriate intensity and frequency , it increases the temperature in soft tissues with a
high protein density .
the physiological effects of us are increased blood flow , vascular
permeability , and local metabolism and enhanced fibrous tissue extensibility and muscle
relaxation7 , 8 , 13 .
however , in a review of
the biophysical effects of therapeutic us , baker et al.24 concluded that these effects were unlikely to be beneficial . in
addition
, they suggested that there was relatively little evidence to show that us had
beneficial effects in vivo , and , therefore , it was mere conjecture to conclude that us had
positive effects on patients with rotator cuff disease .
they also determined that any
changes that occur in an in vivo condition or in the extracellular fluid initiate a
protective reaction that minimizes the effects on cells , tissues , and organs and that these
protective mechanisms may at least be partly responsible for the discrepancy between the
results of in vitro us studies and the findings of a small number of high - quality ,
randomized , controlled trials .
the present study , continuous us resulted in no differential improvements in the vas ,
constant - murley shoulder outcome test , and ucla shoulder rating scale , with the exception of
the adl subgroup scores of the constant - murley outcome test , which increased in the us
group .
calis et al.3 compared the efficacy
of us , laser treatment , and exercise for 15 sessions with patients who had rotator cuff
disease and concluded that there were statistically significant improvements as a whole in
their rom , vas and constant - murley outcome scores . however
, their results did not
demonstrate that us was superior to the other interventions . in another study that evaluated
the use of us in conjunction with ice compresses , tens , and exercises in the treatment of
rotator cuff disease ,
celik et al.7 found
that us did not provide any additional improvement in rom , vas or constant - murley shoulder
outcome scores of the patients .
moreover , in a randomized , placebo - controlled trial , kurtai
et al.8 demonstrated that 10 minutes of us
provided no additional benefit when applied together with hot - packs , interferential current ,
and exercise interventions in the management of soft tissue disorders of the shoulder .
however , they did show that this combined therapy program improved the patient s pain and
rom and raised the shoulder disability questionnaire ( sdq ) and health assessment
questionnaire ( haq ) scores in the study population as a whole .
furthermore , in the review by
faber et al.21 , they found that adding us
to the treatment regimen did not change the functional levels of the patients , and some
studies have also demonstrated that there is little evidence for the effectiveness of
therapeutic us in the treatment of patients with musculoskeletal problems or for the
promotio of soft tissue healing25 , 26 .
isokinetic assessment of the rotator cuff is a common and reliable component of shoulder
muscle examinations .
additionally , because of the extensive mobility of the shoulder ,
various testing positions and articular planes can be used for isokinetic evaluation ; hence ,
finding a consensus protocol has been difficult . the test position plays a vital role in the
outcome measures , and the ability to reproduce the measurements depends on the selected
position27 . in this study , we evaluated
the isokinetic muscle testing based on the concentric / concentric protocol in the seated
position with the retracted shoulder in a modified neutral position .
while it is possible
that this was not the best position to evaluate the shoulder rotators , we believe that any
limitations this position might have caused were probably mitigated by the patients
remaininig in the same position throughout the isokinetic evaluations . in our trial , the er pt 60/second values increased in both the true and sham us groups ,
but the er pt 180/second values did not increase in either group .
the low angular component
of the isokinetic evaluation is usually the most painful and difficult for the patients . for
this reason ,
a decrease in pain after treatment may reflect as an improvement due to the er
pt measurement at the low angular velocity .
, the high angular velocity rates did not differ
between the pre- and post - physiotherapy sessions , but the ucla shoulder rating scale and
constant - murley shoulder outcome scores that are used for the functional evaluation of
patients improved .
these higher scores appear to contradict the results of the isokinetic
high angular velocity rates . in this study
, we also found that us was found to have no
effect on the isokinetic measurements of the er muscles at the end of the intervention , and
this was true at both the low and high angular velocity rates .
it was additionally found
that our physiotherapy program did not improve the isokinetic strength of shoulder ir at the
end of intervention in both the true and sham us groups . to the best of our knowledge ,
this is the first and only study to evaluate the effect of
therapeutic us on the isokinetic muscle strength of patients with rotator cuff disease .
our
findings demonstrate that continuous us therapy , when combined with other physiotherapy
interventions , provides no additional treatment benefits with regard to pain , functional
status , or isokinetic strength .
reduction of pain after physiotherapy may result in better
functioning of the shoulder in daily living activities and this may have helped to improve
muscle strength .
in addition , it is possible that the patients did not
understand the pre - intervention isokinetic testing of the control evaluations , and thus the
subsequent post - intervention testing , but this lack of understanding could not be measured .
another limitation was that the muscles of the rotator cuff were not isokinetically tested
during other movements .
furthermore , the long - term patient results are unknown , and we also
did not analyze our patients need for analgesics . finally , there is no accepted
standardized method for the physiotherapy modalities and rehabilitation interventions used
in this study . according to the results of our study , physiotherapy modalities may lower disability rates
by improving muscle strength and function while easing the pain of patients with rotator
cuff disease .
in addition , our findings indicate that therapeutic us does not provide any
additional healing effect when combined with other physiotherapy interventions .
|
### Summary:
: [ purpose ] the aim of this prospective , double - blind , randomized , placebo - controlled study
was to evaluate the effects of therapeutic continuous ultrasound ( us ) on patients with
rotator cuff disease .
[ subjects and methods ] twenty - two patients were treated with a
standard physiotherapy program consisting of a hot - pack , transcutaneous electrical nerve
stimulation ( tens ) , exercises , and us that was supervised by the same physiotherapist .
the
patients were randomly assigned to either a group that received true us ( n=11 ) or one that
received sham us ( n=11 ) .
[ results ] there were significant differences between the pre- and
post - intervention ucla shoulder rating scale and constant - murley shoulder outcome scores ,
vas , and external rotation ( er ) peak torque 60/second values for both the true and sham
us groups . however , the between - group differences were not statistically significant .
[ conclusion ] in patients with rotator cuff disease , physiotherapy interventions
effectively treat the pain , improve the clinical status , and increase the muscle strength
of the shoulder er at a low constant angular velocity , with functional improvement being
seen immediately after treatment .
however , at the end of the intervention , the us had
yielded no additional efficacy to the physiotherapy treatment regimen of the patients with
rotator cuff disease .
|
<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 prostate cancer accounts for 25% of all male cancer occurrences and 9% of the cancer death causes in the european union . .
only in 2008 , it was the most commonly diagnosed type , accounting for 25% of all cancers .
in germany , there are about 58,000 prostate cancer diagnoses each year . as for each cancer type ,
currently , several types of examination are used for screening potential patients : prostate specific antigen ( psa ) test , digital rectal examination ( dre ) and transrectal ultrasound ( trus ) .
those methods however , are not sensitive enough and the only secured diagnosis is the prostate biopsy with following histopathology examination . at present
the probe is introduced to the patient s rectum and free - hand navigated by the doctor .
the probe is equipped with a needle guide through which a needle is inserted after having established desired probe position towards the prostate area .
the first publications in this area recommended a 6 core systematic biopsy , but later studies showed that the number was insufficient [ 5 , 6 ] .
currently , the recommendation of the european urology association is at least 10 cores , whereas the exact number shall be adjusted according to the psa level and prostate volume . because of the fact that early cancer stages are invisible in the ultrasound images , the urologists are forced to take random biopsies without targeting specific cancer areas .
the biopsy procedure is limited by the 2d imaging , soft consistency and deformability of the prostate and instability of the manual probe navigation .
these factors significantly reduce the positioning accuracy and permit a reproducibility of the biopsy needle guidance .
30% . as a result , in around 40% of cases [ 79 ] a re - biopsy is needed .
this happens when the psa level increases in spite of negative result of the first biopsy . in the second examination ,
so - called saturation biopsy is performed with 20 - 40 cores again at random positions . in such circumstance
, the doctor ideally has to avoid taking the probes from the places that have been verified earlier as negative . with current standards
today , one tries to compensate the inaccuracy by an increased number of following cores , which in fact , increases patient s burden as well .
alternative approaches like mri - based techniques are developing fast and are truly promising , but they are much more expensive in comparison to an ultrasound and severely more time and resources consuming in terms of time pro biopsy core taken .
recent developments in morphologic , metabolic and physiologic 3d imaging typically mri - based are showing very good prospects for tumour localization within the prostate . unfortunately , those technologies are expensive ( about 2 - 3 million investment for a single site needed ) and their real - time capability is very restricted .
further , they provide a good localisation of suspicious lesions , however give no guidance to stereotactical biopsy of these locations .
to overcome these problems and increase biopsy success rate , we introduced a device combining every usable imaging information along with real - time ultrasound ( 1 ) .
the general idea is to use imaging to localize areas suspected of cancer and ultrasound to guide biopsy needles precisely to exactly those areas . the biopsee cart with the stepper fixation in our approach the user can fuse intraoperatively acquired 3d ultrasound on one hand with preoperatively acquired modalities , such as multi - parametric mri , pet , spect or any other 3d dataset available in dicom format to denote suspicious lesions and plan a targeted biopsy .
the real - time augmented reality ultrasound guidance improves greatly biopsy accuracy and reduces navigation time .
the system also provides means for the procedure documentation which is essential in follow - up examinations and some novel treatment methods like brachytherapy and focal therapy of the prostate .
additionally , by using the transperineal approach one reaches every prostate area , minimizes deformation , maximises reproducibility and reduces the risk of infection associated with bacteria from the rectum infiltrating the prostate during the rectal insertion process . a summary of the risks present during the conventional transrectal biopsy can be found in .
the presented device consists of a cart with a touch - screen and a pc with integrated ultrasound device and additional electronics for controlling position and orientation of the ultrasound probe .
the probe itself is a custom bi - plane endorectal design that is optimized for biopsy process : longer shaft optimized mechanical design , 165 transversal and 75 mm longitudinal field of view ( 2 ) .
each of the arrays consists of 128 elements , the maximum available frequency is 8 mhz for the transversal plane and 10 mhz for the longitudinal one .
this accounts for delivering superb quality images , which are also additionally filtered by the software .
the result is u / s images with de facto the best diagnostic quality available today .
the one - hole needle guidance device during the procedure , the probe is placed in a mechanical custom - made fixation device called the stepper(3 ) .
this is a 2dof set up : one can adjust probe depth within the patient s rectum and the rotation of the probe along its main axis .
both movement and rotation are tracked by 2 encoders which are connected to the aforementioned electronics inside the pc .
, one can image any plane of the prostate with very high accuracy and reproducibility , a fact impossible in the free - hand movement of the probe . the stepper - probe set - up for the needle insertion part we developed a dedicated movable needle guide that is attached to the stepper .
it has adjustable x and y coordinates enabling to drive a needle with mm accuracy to any location within the prostate .
the whole hardware set up is principally similar to the one used in a brachytherapy procedure , which gives the advantage that one could reuse certain equipment in both diagnosis and therapy .
however , our new positioning device allows among others to pinpoint any position within the prostate without gridding truncations .
however , the software supports also any kind of templates like those usually employed in brachytherapy procedures . on the software side ,
there is a kernel environment and each functional procedure step is mapped within a separate software module .
those include : ultrasound device control , u / s image filtering , stepper encoder control , u / s data acquisition , dicom data interface , volume fusion , contouring , biopsy planning , guiding , reporting and the dedicated patient database .
the user is free to perform different actions within the system , though a typical workflow for the navigated biopsy can be recommended and presented here .
the procedure can be split into planning the biopsy and guided removal of the tissue cores . in the first phase image ,
one can import different dicom image modalities and fuse them with on - board 3d ultrasound ( 4 ) .
3d u / s is acquired by recording a series of transversal or longitudinal 2d images while rotating or moving the probe along the z direction , resulting very similar dataset to ct scans , however generated with ultrasound instead of x - rays .
additional imaging modalities , typically multiparametric mri are imported through the dicom interfaces ( 5 ) .
both 3d volumes are then fused together using one of many available methods : manual , marker based or automatic .
this allows transferring organ and lesions usually visible on the diagnostic mri scan and delineated by a radiologist over the intraoperative ultrasound dataset . a 3d u / s dataset with contoured structures and a planned biopsy inside a marked lesion image fusion with mixed images ( mri u / s ) in the top row and ultrasound only in the bottom row finally , biopsy cores are placed virtually within the 3d data manually or automatically according to a pre - defined protocol .
the experience shows that doctors use predominantly a combination of stereotactic target based and statistical biopsy .
once a biopsy plan has been established , the first phase of the approach is completed typically within 10 - 15 minutes . during the following second ( navigation ) phase the user selects the desired biopsy core and first navigates the ultrasound probe to that position , i.e. the u / s transducer rotates until the longitudinal plane crosses the needle insertion line ( 6 ) .
next , the needle guide template is set to the planned coordinates by adjusting the x and y coordinates by the values given by the planning tool .
the inserted needle is slightly off the planned one for demonstration purposes the u / s image is overlaid by the organ and lesion contours as well as the planned needle position , thus a real - time navigation is established in a way that deviations from the target become immediately visible on the screen and can be corrected on - the - fly , enabling a positioning of the needle by very high accuracy of few mm from the desired target position .
organ shifts caused by the tissue deformation during needle insertion are equally visible and can be adjusted manually if necessary .
after each needle insertion , a screenshots is made and stored together with the position and orientation data for documentation purposes ( 7 ) .
the presented system has a custom designed patient database which allows saving any type of data used within the procedure .
our approach is the only one enabling complete and automatic documentation of the procedure without any user interaction .
all information ( images , contours , targets etc . ) can be exported via dicom - rt protocol to the therapy rtp system .
during the biopsy procedure one can mark the real needle position on the live ultrasound image . in order to measure the positioning accuracy ,
the preliminary assessment was comparing the distances between middle points of reconstructed biopsy cores and the planned ones . within a dataset of 1159 needles reconstructed during the first 50 biopsy procedures , the calculated mean error was 1.7 mm . with conventional transrectal biopsy
results with the first 50 patients ( submitted for publication ) have been performed for a typical cohort ( psa 9 7 , prostate 51 24 cm3 , age 42 - 77 ) . a saturation biopsy with an average of 24 cores was performed .
in addition to the random cores , stereotactic samples have been taken from mri suspicious areas .
cancer could be detected in 68% of the cases of first - time biopsies and 36% of re - biopsy after 1 - 3 initial negative 12-core trus biopsies .
in addition to the high detection rates , the principal benefit of our approach is its accuracy and reproducibility .
accuracy is needed for validating the mri findings and , thus , the mri method itself .
reproducibility means that since we track the needle location within the prostate accurately and we can reach effectively any prostate region , the biopsy cores are obtained guaranteed from different regions and by a regular scheme ensuring correct statistic coverage of the complete organ .
this is important in the case of repeated biopsy procedure : new cores can be taken from areas where no needle has been placed in the first procedure .
also , our method is of fundamental importance for focal therapy approaches in excluding multi - focal or non - visible lesions on the opposite prostate gland .
we presented a novel system for navigated prostate biopsy , which takes advantage of several computer graphics methods to enhance the examination procedure .
the image fusion along with different visualization modes enables easier organ and target lesion delineation and thus effective biopsy planning and exact and reproducible core samples under automatic documentation .
our experience shows that the needle and probe navigation feature together with combining live ultrasound imaging with virtual objects is essential for accurate and reproducible needle insertion .
the system has been clinically tested at the offenbach clinic and at the heidelberg university hospital .
tests in both hospitals with over hundred of patients confirmed the advantages of the image guided stereotactic prostate biopsy .
the implemented dicom rt protocol for transferring the biopsy cores localisation , enables treatment planning systems to consider these locations for local dose escalation protocols ( dose painting ) .
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### Summary:
: in the recent years , prostate cancer was the most commonly diagnosed cancer in men .
currently secure diagnosis confirmation is done by a transrectal biopsy and following histopathological examination .
conventional transrectal biopsy success rates are rather low with ca
. 30% detection upon the first and ca 20% after re - biopsy .
the paper presents a novel system for stereotactic navigated prostate biopsy .
the approach results into higher accuracy , reproducibility and unrestricted and effective access to all prostate regions .
custom designed ultrasound , new template design and integrated 2-axes stepper allows superior 2d and 3d prostate imaging quality and precise needle navigation .
dicom functionality and image fusion enable to import pre - operative datasets ( e.g. multiparametric mri , targets etc . ) and overlay all available radiological information into the biopsy planning and guiding procedure .
the biopsy needle insertion itself is performed under augmented reality ultrasound guidance .
each procedure step is automatically documented in order to provide quality assurance and permit data re - usage for the further treatment .
first clinical results indicates success rates of ca .
70% by first biopsies by our approach .
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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:
: cementless bipolar hemiarthroplasty using the anatomic medullary locking ( aml ) femoral stem ( depuy , warsaw , in , usa ) was performed on forty - five patients with intertrochanteric fractures , aged 70 and over , and were able to walk either with or without an aid prior to surgery at our institution between january 2000 and december 2005 . of these patients , 40 patients who could be followed up for 2 years
the surgical indications were severe osteoporosis ( grade 3 singh index8 ) ) and comminution of the medial cortical bone ( a2 according to the ao classification ) , which are associated with high rates of internal fixation failure .
the mean follow - up period was 40.5 months ( range , 24 to 62 months ) .
thirty - four patients ( 85% ) had combined diseases : 18 patients ( 45% ) had hypertension and the remaining patients had diabetes , cardiovascular diseases , cerebrovascular diseases , and lung diseases ( table 1 ) .
surgery was performed by the first author in all cases . under general or spinal anesthesia , a cementless aml 5/8 porous - coated femoral stem ( depuy )
a bipolar cup and a 28 mm femoral head ( depuy ) were used in all patients .
proximal fixation of the implant was reinforced with the additional fixation of trochanteric fragments around the proximal stem .
wires or nonabsorbable sutures were used for fixation depending on the size of the fragment .
quadriceps femoris muscle strengthening exercises were started from one day after surgery . in all patients ,
partial weight bearing with crutch walking and full weight bearing was started at 1 week and within 3 months after surgery , respectively .
postoperative occurrence of an embolism was confirmed in the patients presenting with chest pain or shortness of breath using blood tests including arterial blood gas analysis and chest computed tomography .
the harris hip scores9 ) at the last follow - up were classified into four categories ; excellent ( 90 to 100 ) , good ( 80 to 89 ) , fair ( 70 to 79 ) , and poor ( 60 to 69 ) .
the level of pain in the groin and thigh after surgery was divided into 3 grades ; mild , moderate , and severe .
the activities of daily living10 ) were graded into 4 categories ; excellent ( no pain or limitation of movement ) , good ( slight pain or limitation of movement not interfering with walking and personal hygiene ) , fair ( moderate pain or limitation of movement requiring assistance in walking ) , and poor ( severe pain , limitation of movement or poor general condition that made walking impossible ) . the initial fixation of the femoral stem was assessed in the proximal and isthmic areas on the radiographs taken immediately after surgery .
the proximal canal fit was rated good if the stem filled the proximal canal by more than 80% , and the press fit at the isthmus level was considered good when a gap of < 1 mm was noted between the stem and inner cortex.11,12 ) the femoral stem stability was classified into fixation by bone ingrowth , stable fibrous fixation , and unstable prosthesis according to the criteria of engh et al.13,14 ) the changes in the alignment and subsidence of the femoral components were measured from after surgery to the last follow - up ; 3 of valgus or varus and 5 mm longitudinal change were considered significant.3,10 ) the radiolucent line , bone resorption , endosteal new bone formation and osteolysis were examined in the seven zones described by gruen et al.15 ) a radiolucent line denoted the radiolucent area around the stem surrounded by radiodense lines , and was considered present if it occupied 50% of any zone.16 ) loosening of the femoral stem was defined as the appearance of a radiolucent line progressive or > 1 mm in all zones , or the presence of continuous subsidence or migration of the femoral stem .
cementless bipolar hemiarthroplasty using the anatomic medullary locking ( aml ) femoral stem ( depuy , warsaw , in , usa ) was performed on forty - five patients with intertrochanteric fractures , aged 70 and over , and were able to walk either with or without an aid prior to surgery at our institution between january 2000 and december 2005 . of these patients , 40 patients who could be followed up for 2 years
the surgical indications were severe osteoporosis ( grade 3 singh index8 ) ) and comminution of the medial cortical bone ( a2 according to the ao classification ) , which are associated with high rates of internal fixation failure .
the mean follow - up period was 40.5 months ( range , 24 to 62 months ) .
thirty - four patients ( 85% ) had combined diseases : 18 patients ( 45% ) had hypertension and the remaining patients had diabetes , cardiovascular diseases , cerebrovascular diseases , and lung diseases ( table 1 ) .
surgery was performed by the first author in all cases . under general or spinal anesthesia , a cementless aml 5/8 porous - coated femoral stem ( depuy )
a bipolar cup and a 28 mm femoral head ( depuy ) were used in all patients .
proximal fixation of the implant was reinforced with the additional fixation of trochanteric fragments around the proximal stem .
wires or nonabsorbable sutures were used for fixation depending on the size of the fragment .
quadriceps femoris muscle strengthening exercises were started from one day after surgery . in all patients ,
partial weight bearing with crutch walking and full weight bearing was started at 1 week and within 3 months after surgery , respectively .
postoperative occurrence of an embolism was confirmed in the patients presenting with chest pain or shortness of breath using blood tests including arterial blood gas analysis and chest computed tomography .
the harris hip scores9 ) at the last follow - up were classified into four categories ; excellent ( 90 to 100 ) , good ( 80 to 89 ) , fair ( 70 to 79 ) , and poor ( 60 to 69 ) .
the level of pain in the groin and thigh after surgery was divided into 3 grades ; mild , moderate , and severe .
the changes in walking ability from before to after surgery were investigated . the activities of daily living10 ) were graded into 4 categories ; excellent ( no pain or limitation of movement ) , good ( slight pain or limitation of movement not interfering with walking and personal hygiene ) , fair ( moderate pain or limitation of movement requiring assistance in walking ) , and poor ( severe pain , limitation of movement or poor general condition that made walking impossible ) .
the initial fixation of the femoral stem was assessed in the proximal and isthmic areas on the radiographs taken immediately after surgery .
the proximal canal fit was rated good if the stem filled the proximal canal by more than 80% , and the press fit at the isthmus level was considered good when a gap of < 1 mm was noted between the stem and inner cortex.11,12 ) the femoral stem stability was classified into fixation by bone ingrowth , stable fibrous fixation , and unstable prosthesis according to the criteria of engh et al.13,14 ) the changes in the alignment and subsidence of the femoral components were measured from after surgery to the last follow - up ; 3 of valgus or varus and 5 mm longitudinal change were considered significant.3,10 ) the radiolucent line , bone resorption , endosteal new bone formation and osteolysis were examined in the seven zones described by gruen et al.15 ) a radiolucent line denoted the radiolucent area around the stem surrounded by radiodense lines , and was considered present if it occupied 50% of any zone.16 ) loosening of the femoral stem was defined as the appearance of a radiolucent line progressive or > 1 mm in all zones , or the presence of continuous subsidence or migration of the femoral stem .
the mean harris hip score at the last follow - up was 80.6 9.3 .
better than fair results were obtained in 27 patients ( 67.5% ) ; excellent in 8 ( 20.0% ) , good in 19 ( 47.5% ) , fair in 9 ( 22.5% ) , and poor in 4 ( 10.0% ) . groin pain and thigh pain
were noted in 7 patients ( 17.5% ) and 5 patients ( 12.5% ) , respectively , but significant pain requiring medication was noted in one patient in each area ( 2.5% ) .
of the 40 patients , 11 ( 27.5% ) and 29 ( 72.5% ) patients could walk with and without support before surgery , respectively .
of the 29 patients , 17 could still walk without support after surgery , but 11 required assistance and one was unable to walk .
of the 11 patients who could walk with support before surgery , six showed no difference after surgery , four patients who had used a cane before surgery became more dependent on walking aids and one could not walk due to a poor general condition after surgery .
overall , 24 ( 60% ) out of 40 patients regained their preoperative walking ability ( table 2 ) .
twenty - three patients ( 57.5% ) could carry out their daily living activities and personal hygiene after surgery ; 6 ( 15.0% ) , 17 ( 42.5% ) , 13 ( 32.5% ) , and 4 ( 10% ) patients had excellent , good , fair and poor results , respectively .
according to the radiological findings , a press - fit was achieved either at the proximal area or the isthumus in all patients ; the proximal canal fit , the press fit at the isthmus and both were achieved in 18 ( 45% ) , 12 ( 30% ) and 10 ( 25% ) patients , respectively ( fig .
the stability of the femoral stem at the last follow - up according to the criteria of engh et al.13,14 ) was fixation by bone ingrowth in 23 patients ( 57.5% ) and stable fibrous fixation in 17 patients ( 42.5% ) ; there were no unstable prostheses .
a radiolucent line was observed in five patients ( 12.5% ) and mainly in gruen zones 1 and 7 ; in zone 1 in three patients ( 7.5% ) and in zone 7 in four patients ( 10% ) ( table 3 ) .
endosteal new bone formation was observed in 15 patients ( 37.5% ) , mainly in gruen zones 2 , 3 , 4 , 5 , and 6 : two ( 5% ) , seven ( 17.5% ) , twelve ( 30% ) , nine ( 22.5% ) , nine ( 22.5% ) , six ( 15% ) , and one patient ( 2.5% ) in zones 1 , 2 , 3 , 4 , 5 , 6 , and 7 , respectively ( table 3 ) .
bone resorption was noted in 23 patients ( 57.5% ) and mostly in gruen zones 1 , 2 , 6 and 7 : six ( 15% ) , four ( 10% ) , two ( 5% ) , one ( 2.5% ) , five ( 12.5% ) , and eight patients ( 20% ) in zones 1 , 2 , 3 , 4 , 5 , and 7 , respectively ( table 3 ) . with regard to the changes in the alignment of the implant
the degree of subsidence of the femoral stem was 1 , 2 , and 3 mm in ten , six and five patients , respectively .
a superficial infection occurred as a postoperative complication in three patients ( 3.8% ) , which was treated with local wound care and antibiotics .
no case of death during the hospital stay or other complications , such as joint dislocation , deep infection and embolism , were encountered .
. anatomic reduction of the fractures is difficult to achieve and maintain , often leading to malunion or reduction failure.2 ) in addition , postoperative early ambulation may not be feasible , and the rates of postoperative complications and mortality are high due to combined disorders . accordingly , postoperative early ambulation and rehabilitation should be taken into account when considering treatment options , and hemiarthroplasty is regarded as one of the most effective primary treatment methods for unstable intertrochanteric fractures.3,4,17,18 ) cemented fixation is advantageous for achieving initial implant stability and rapid rehabilitation in cases of unstable fractures with poor bone quality.17,19,20 ) cementless implants can be used to prevent cement - related problems , but implant migration due to bone ingrowth failure , thigh pain and bone resorption as a result of increased stiffness can be problematic.21,22 ) there are recent reports showing that implant migration can be avoided by promoting the osteointegration of cementless femoral components.21,23 ) in particular , the osteointegration rates are high even in elderly patients with osteoporosis and there has been no increase in the implant failure rates.7,22 ) in the current study , initial press - fit fixation was achieved in all patients either at the proximal canal or isthmus , and fixation by bone ingrowth or fibrous stable fixation were observed after a more than two year follow - up , even though 1 mm , 2 mm , and 3 mm subsidence were observed in 10 , 6 , and 5 patients at the 1st postoperative year .
this indicates that the osteointegration rate in the diaphysis can be high in osteoporotic elderly patients with a singh index less than grade 3 after the insertion of aml implants .
therefore , the use of cementless implants can lead to satisfactory results , even in elderly patients with osteoporosis .
there were no postoperative complications , such as femoral stem loosening , significant alignment changes and progressive subsidence .
kang et al.11 ) reported that the loss of bone density in the proximal femur after arthroplasty using aml implants was not associated with the clinical symptoms , even though it occurred at a significant level in zone 7 . in this study ,
bone resorption was observed primarily in the proximal area , such as zones 1 , 2 , and 7 , but this did not lead to a fracture or loosening during the follow - up period .
early ambulation within 2 to 3 weeks after surgery is important for preventing complications that can be caused by long - term bed rest in elderly patients with a poor general condition and combined diseases.24 ) the achievement of initial press - fit fixation is essential for early ambulation and rehabilitation . in one study
, hemiarthroplasty produced better postoperative results than internal fixation in terms of limping and the use of a walking aid in patients with limited walking ability before surgery.18 ) considering that press - fit fixation in the proximal femur is difficult to achieve in elderly patients with unstable fractures , the use of a cylindrical implant that can be fixed to the isthmus or diaphysis can be helpful .
the aml implant is effective in improving the initial rotational stability owing to its broad triangular shape in the proximal portion .
in addition , it can provide initial and late stability25 ) owing to the cylindrical shape in the middle , which is congruent with the shape of the femoral diaphysis making isthmic level or diaphyseal fixation possible regardless of the dorr type.26 ) in this study , initial press - fit fixation was achieved in the isthmus in 12 patients ( 30% ) in whom proximal fixation was not possible .
the prevention of complications associated with long bed rest or those requiring intensive treatments , such as fat thrombosis or lung embolism , was attributed to the achievement of initial press - fit fixation , the initiation of quadriceps femoris muscle exercise and wheel chair ambulation immediately after surgery , and walking exercise at 1 week after surgery .
the functional outcomes after hemiarthroplasty tend to worsen over time due to the decrease in activity caused by the aggravation of preexisting diseases.4 ) in this study , the postoperative walking ability became worse compared to the preoperative one in 16 ( 40% ) of the 40 patients .
this was attributed to muscle weakness and a decrease in balancing ability during the postoperative period , which are common in elderly patients .
the overall postoperative functional recovery was satisfactory , because all patients could walk with or without support except for two ; one patient with worsening cerebrovascular disease and the other with a poor general condition .
similarly , twenty - three patients ( 57.5% ) could carry out their daily activities without assistance , such as walking and washing .
ambulation became worse due to pain in 2 patients but there were no abnormal findings , such as implant loosening or 2 cm lower limb - length discrepancy .
cemented fixation is associated with the highest death rate in arthroplasty patients,27 ) which can be a concern for elderly patients in whom combined diseases and poor general condition are common .
a short - term follow - up study showed that bipolar hemiarthropasty using a tapered femoral stem for displaced femoral neck fractures in more than 70-years - old patients produced clinically and radiologically satisfactory outcomes.28 ) in this study , cementless fixation of cylindrical implants for the treatment of intertrochanteric fractures resulted in satisfactory results due to the avoidance of cement toxicity and the sufficient initial fixation strength provided by the press - fit fixation at either the proximal or isthmic levels .
accordingly , the patients could achieve early ambulation and rehabilitation , and the stability could be secured with endosteal new bone formation postoperatively .
the short - term results of cementless bipolar hemiarthroplasty in elderly patients with unstable intertrochanteric fractures demonstrated satisfactory results .
these results are expected to be useful for further studies with a long - term follow - up .
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### Summary:
: backgroundbipolar hemiarthroplasty for unstable intertrochanteric fractures in elderly patients is a viable option that can prevent the complications of an open reduction , such as nonunion and metal failure .
this study evaluated the clinicoradiological results of cementless bipolar hemiarthroplasty for unstable intertrochanteric fractures in elderly patients.methodsforty hips were followed for more than 2 years after cementless bipolar hemiarthroplasty using a porocoat aml hip system .
the mean age was 78.8 years and the mean follow - up period was 40.5 months .
the harris hip score and postoperative hip pain were analyzed clinically .
the radiological results were assessed using a range of indices.resultsat the last follow - up , the mean harris hip score was 80.6 points .
there were one case of hip pain and one case of thigh pain .
twenty - four cases ( 60% ) showed no decrease in ambulation capacity postoperatively .
radiologically , there were 23 cases ( 57.5% ) of fixation by bone ingrowth and 17 cases ( 42.5% ) of stable fibrous fixation .
there were no cases of osteolysis .
eleven cases ( 27.5% ) of new bone formation were found around the stem .
all stems were stable without significant changes in alignment or progressive subsidence.conclusionsthe short - term results of cementless bipolar hemiarthroplasty in elderly patients with unstable intertrochanteric fractures were satisfactory .
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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 authors have investigated three species of clupeidae such as herring ( clupea pallasii ) , korean anchovy ( coilia nasus ) and large - eyed herring ( harengula zunashi ) , belonging to the order clupeiformes .
the fish is also indigenous to some parts of the southern regions of the yellow sea .
fishes are the most popular marine products in korea because of their taste and nutritional value , and koreans consume them in large quantities .
especially , korean anchovy and large - eyed herring are widely distributed in the entirety of brackish - water habitats and seawater areas of the yellow sea in the korean peninsula , as well as in several areas in china . however , in spite of their economic and scientific consequences , a little information currently exist regarding the taxonomical ( kim et al . , 2001 ) , physical ( an et al . , 2013 ) and nutritional ( heu et al . , 2012 ) levels only of clupeid species in korea . during the last two decades , environmental contamination and various environmental disruptions by industries and city sewage ,
have threatened the coastal fisheries , and then reduction of individual number of this fish is an increasing trend in the 2000s .
this study attempt is to elucidate the genetic distances and variations within and between herring , korean anchovy and large - eyed herring species from the yellow sea of the korean peninsula .
muscle tissues were obtained separately from individuals of three clupeid species such as herring ( c. pallasii ) , korean anchovy ( c. nasus ) and large - eyed herring ( h. zunashi ) from the yellow sea of the korean peninsula , respectively .
three species of fish muscle was collected in sterile tubes , placed on ice immediately , and stored under refrigeration until needed .
genomic dna was extracted and purified under the conditions described previously ( yoon & kim , 2004 ; song & yoon , 2013 ) . the dna pellets were incubation - devrepied for 2 hrs , held at 40c until analysis , and then dissolved in the te buffer ( 10 mm tris- hcl , ph 8.0 ; 1 mm edta ) .
the concentrations of the extracted genomic dna samples were estimated based on the absorbance at 260 nm by a spectrophotometer ( beckman coulter , buckinghamshire , uk ) .
pcr analysis was performed on dna samples extracted from a total of 21 individuals using seven decamer primers .
seven oligonucleotides primers ( bion-07 , bion-10 , bion-11 , bion-18 , bion-25 , bion- 27 and bion-40 ; bioneer co. daejeon , korea ) were displayed to generate the shared loci , specific loci , unique shared loci to each species and shared loci by the three species which could be obviously scored .
the degree of variability was calculated by use of the dice coefficient ( f ) , which is given by the formula : f = 2 nab / ( na+nb ) , where nab is the number of bands shared between the samples a and b , na is the total number of bands for sample a and nb is the total number of bands for sample b ( jeffreys & morton , 1987 ; yoke - kqueen & radu , 2006 ) .
euclidean genetic distances within- and between - species were also calculated by complete linkage method with the support of the hierarchical dendevrepogram program systat version 13 ( spss inc . , chicago , il , usa ) .
the genomic dna isolated from herring ( c. pallasii ) , korean anchovy ( c. nasus ) and large - eyed herring ( h. zunashi ) in the yellow sea , respectively , were amplified several times by pcr reaction , as shown in fig .
similarity matrix including bandsharing values ( bs ) and genetic differences was calculated using nei and li 's index of the similarity of clupeid individuals from the yellow sea of the korean peninsula , respectively . the band - sharing value between individuals no .
03 was 0.976 within the herring species ( c. pallasii ) , which was the highest value identified among the three species ( unpublished data ) . in the present study , averagely ,
an oligonucleotides primer generated 40.3 amplified products per primer in the herring species , 37.9 in korean anchovy species and 39.3 in large - eyed herring species , as demon - strated in table 1 . here ,
the seven oligonucleotides primers bion-07 , bion-10 , bion-11 , bion-18 , bion-25 , bion-27 and bion-40 were used to generate the unique shared loci to each species and shared loci by the three species , as illustrated in table 2 .
259 unique shared loci to each species , with an average of 37 per primer , were observed in the herring species , and 217 loci , with an average of 31 per primer , were observed in the korean anchovy species . as regards average bandsharing value ( bs ) results , indi - viduals from herring ( c. pallasii ) species ( 0.920 ) exhibited higher bandsharing values than did individuals from korean anchovy ( c. nasus ) species ( 0.872 ) ( p<0.05 ) , as illustrated in table 3 .
dna fragments attained by seven decamer primers ranged in size from 50 bp to 2,200 bp in the three clupeid species , as displayed in fig .
2 . the higher fragment sizes ( > 1,000 bp ) are much more observed in the herring species .
many researchers studied the sizes of dna fragments in the pcr profiles of barramundi ( lates calcarifer ) ( partis & wells , 1996 ) , four species of the mullidae family ( mamuris et al . , 1999 ) , the eastern pacific yellowfin tuna ( thunnus albacares ) ( diaz - jaimes & uribe - alcocer , 2003 ) , five species of korean catfish ( silurus asotus ) ( yoon & kim , 2004 ) , venus clam ( gomphina aequilatera ) ( kim et al . , 2006 ) and the turtle leg ( pollicipes mitella ) ( song & yoon , 2013 ) .
multiple comparisons of average bandsharing values among herring ( c. pallasii ) , korean anchovy ( c. nasus ) and large - eyed herring ( h. zunashi ) species , respectively , were generated according to the bandsharing values cp : clupea pallasii , cn : coilia nasus , hz : harengula zunashi values with different superscript are significantly different , p<0.05 each value is a result of three different experiments .
the number of unique loci to each species and number of shared loci by the three species generated by pcr analysis using 7 oligonucleotides primers in herring ( c. pallasii ) , korean anchovy ( c. nasus ) and large - eyed herring ( h. zunashi ) species , respectively cp : clupea pallasii , cn : coilia nasus , hz : harengula zunashi the number of average loci per lane and specific loci by pcr inquiry using 7 oligonucleotides primers in herring ( c. pallasii ) , korean anchovy ( c. nasus ) and large - eyed herring ( h. zunashi ) species cp : clupea pallasii , cn : coilia nasus , hz : harengula zunashi
pcr - based electrophoretic profiles of c. pallasii ( lane 1 - 7 ) , c. nasus ( lane 8 - 14 ) and h. zunashi ( lane 15 - 21 ) , respectively , from the yellow sea of the korean peninsula , amplified by oligonucleotides primers bion-07 ( a ) , bion-10 ( b ) , bion-11 ( c ) , bion-18 ( d ) , bion-25 ( e ) , bion- 27 ( f ) and bion-40 ( g ) .
each lane shows differrent individual dna samples used . amplified products were electrophoresed on a 1.4% agarose gel and detected by staining with ethidium bromide .
100 bp ladder markers were used as a dna molecular size marker ( m ) .
distribution of fragment sizes of herring ( c. pallasii ) , korean anchovy ( c. nasus ) and largeeyed herring ( h. zunashi ) species , respectively .
the fragment numbers in each size interval have been computed from the pooled fragments obtained with all the primers .
the higher fragment sizes ( > 1,000 bp ) are much more observed in the hz species .
the hierarchical dendevrepogram indicates three main branches : cluster 1 ( pallasii 01 , 02 , 03 , 04 , 06 and 07 ) , cluster 2 ( nasus 08 , 09 , 10 , 11 , 12 , 13 and 14 ) , and cluster 3 ( zunashi 15 , 16 , 17 , 18 , 19 , 20 , 21 and pallasii 05 ) ( fig .
the genetic distance among the three clupeid species ranged from 0.018 to 0.318 . in three clupeid species ,
the shortest genetic distance displaying significant molecular difference was between individual pallasii no . 03 and pallasii no .
the values of the pairwise comparisons of unbiased genetic distance between the populations of the indian major carp ( catla catla ) from the combined data for the four primers , ranged from 0.025 to 0.052 ( islam et al . , 2005 ) .
they reported that the padma and the jamuna populations were separated from each other with the lowest genetic distance ( d = 0.025 ) .
the genetic distance between the indian ocean lobster and the korean slipper lobster species ranged between 0.040 and 0.612 ( park et al . , 2005 ) .
they suggested that this genetic technique could be used to discriminate between different river populations of major carp .
hierarchical dendevrepogram of genetic distances , accomplished from three clupeid species . the related construction among different individuals from herring ( pallasii ) , korean anchovy ( nasus ) and large - eyed herring ( zunashi ) species , respectively , was created according to the bandsharing values and similarity matrix .
consequently , pcr analysis generated on the genetic data displayed that the herring ( c. pallasii ) species was widely separated from korean anchovy ( c. nasus ) species .
reversely , individuals of korean anchovy species were properly closely related to those of large - eyed herring species , as shown in the hierarchical dendevrepogram of genetic distances .
as stated above , the potential of genetic analysis to identify diagnostic markers for the identification of three clupeid species has been demonstrated ( mccormack et al . , 2000 ) .
generally speaking , this pcr analysis method has been applied to identify specific markers particular to line , species and geographical population , as well as genetic diversity / polymorphism in diverse species of organisms ( mccormack et al .
, 2000 ; kim et al . , 2006 ; yoon & kim , 2004 ) .
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### Summary:
: in this study , seven oligonucleotides primers were shown to generate the shared loci , specific loci , unique shared loci to each species and shared loci by the three species which could be obviously calculated .
euclidean genetic distances within- and between - species were also calculated by complete linkage method with the sustenance of the hierarchical dendevrepogram program systat version 13 . the genomic dna isolated from herring ( clupea pallasii ) , korean anchovy ( coilia nasus ) and large - eyed herring ( harengula zunashi ) , respectively , in the yellow sea ,
were amplified several times by pcr reaction .
the hierarchical dendevrepogram shows three chief branches : cluster 1 ( pallasii 01 , 02 , 03 , 04 , 06 and 07 ) , cluster 2 ( nasus 08 , 09 , 10 , 11 , 12 , 13 and 14 ) , and cluster 3 ( zunashi 15 , 16 , 17 , 18 , 19 , 20 , 21 and pallasii 05 ) . in three clupeid species , the shortest genetic distance displaying significant molecular difference was between individual pallasii no . 03 and pallasii no .
02 ( 0.018 ) .
individual no .
06 of pallasii was most distantly related to nasus no .
11 ( genetic distance = 0.318 ) .
individuals from herring ( c. pallasii ) species ( 0.920 ) exhibited higher bandsharing values than did individuals from korean anchovy ( c. nasus ) species ( 0.872 ) ( p<0.05 ) .
as a result , this pcr analysis generated on the genetic data displayed that the herring ( c. pallasii ) species was widely separated from korean anchovy ( c. nasus ) species .
reversely , individuals of korean anchovy ( c. nasus ) species were a little closely related to those of large - eyed herring ( h. zunashi ) species .
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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 common feature of epithelial tissues such as the epidermis , small intestine , lung , and mammary gland is the coexistence of multiple distinct adult stem cell populations ( van keymeulen and blanpain , 2012 ; rock and hogan , 2011 ) . in some of these tissues such as the epidermis and intestine ,
the stem cell heterogeneity is well characterized , but its functional consequences in terms of tissue maintenance and response to injury or insult remain poorly understood ( barker et al . , 2012 ; jaks et al . , 2010 ) .
in other tissues like the mammary gland and prostate , distinct stem cell populations are responsible for maintaining the luminal and basal compartments independently during homeostasis ( van keymeulen et al . , 2011 ;
the epidermis forms the outer protective layer of the skin and comprises the interfollicular epidermis ( ife ) with associated adnexal structures such as the pilosebaceous unit .
the pilosebaceous unit includes the hair follicle ( hf ) and the sebaceous gland ( sg ) and is attached to the ife via the infundibulum . here
the ife is maintained by a combination of long - lived stem cells ( scs ) and committed progenitors ( clayton et al .
scs in the lower permanent bulge region of the pilosebaceous unit ( hair follicle stem cells , hf - scs ) are responsible for hair regrowth and express markers such as gli1 , lgr5 , keratin 15 , keratin 19 , and cd34 ( jaks et al . , 2010 ) .
the isthmus , which forms the lower portion of the upper pilosebaceous unit , contains multiple partly overlapping populations marked by the expression of lgr6 , plet1/mts24 , and lrig1 ( jensen et al . , 2009 ; nijhof et al . , 2006 ;
adjacent to the isthmus at the junctional zone ( jz ) region is the sg , which forms during development from an early population of lrig1 expressing precursor cells and is subsequently maintained by blimp1-expressing cells ( jensen et al . , 2009 ; frances and niemann , 2012 ; horsley et al . , 2006 ) .
fate mapping based on inducible - marker expression is the preferred method for delineating cell behavior in vivo ( alcolea and jones , 2013 ; van keymeulen and blanpain , 2012 ) .
this technique has formed the basis for understanding how complex tissues are maintained . with the use of lineage tracing ,
it has been possible to identify stem cells that contribute to most epidermal components , but it has so far been impossible to determine whether the epidermis is maintained in a hierarchal manner or as independent compartments governed by higher - order structural arrangements .
moreover , the population responsible for the maintenance of the uppermost part of the pilosebaceous unit , the infundibulum , remains elusive .
hf - scs have been reported to replenish the other epidermal sc niches and therefore act as multipotent master scs at the top of a cellular hierarchy ( morris et al . , 2004 ; petersson et al . ,
similarly , progeny of multipotent lgr6-expressing scs in the isthmus are detected both in the sg and ife ( snippert et al . , 2010 ) .
in sharp contrast , additional studies have shown that the pilosebaceous unit including the infundibulum is maintained independently of the ife in the absence of wounding ( ghazizadeh and taichman , 2001 ; levy et al . , 2005 ;
the extent of contribution from each epidermal sc population to the different epidermal lineages and the overall arrangement of tissue maintenance remain unresolved .
genetic perturbation and changes in the local microenvironment affect cell behavior and the lineage commitment of epidermal scs ( owens and watt , 2003 ) .
this is evident from the role of epidermal scs upon injury ( plikus et al . , 2012 ) .
recent evidence from fate - mapping studies demonstrates that otherwise slowly proliferating scs are the cells within the ife that make the major contribution to wound repair ( mascr et al . , 2012 ) .
scs from the pilosebaceous unit are also mobilized to participate in repair of the ife ( ito et al . , 2005 ) . however , once in the ife , the cellular origin within the pilosebaceous unit appears to influence the capacity to be maintained long term ( jaks et al . , 2010 ) .
it remains to be understood whether certain sc progeny are selectively retained in the wound or whether loss of sc progeny from the wound site after healing is a stochastic process .
lrig1 is one of multiple markers associated with scs in the upper pilosebaceous unit ( jaks et al . , 2010 ;
, 2009 ) , as well as in other tissues ( wong et al . , 2012 ; lu et al . , 2013 )
in the epidermis , these cells are capable of contributing to all epidermal lineages in skin - reconstitution assays ( jensen et al . , 2009 ) ; however , their exact lineage potential during normal homeostasis and the functional relevance of the observed epidermal sc heterogeneity remain unresolved . in this study
we address sc heterogeneity within the epidermis with the aim to ( 1 ) determine whether sc populations have distinct features ; ( 2 ) assess the hierarchal relationship between scs during steady - state homeostasis ; and ( 3 ) investigate how sc identity affects cell behavior upon tissue perturbation .
in order to investigate the properties and physical relationship of distinct sc populations in epidermal homeostasis , we utilize a mouse model with egfp - ires - creert2 inserted at the translational start site in exon 1 of the lrig1 locus ( lrig1 knockin [ ki ] ; figure s1a available online ) .
this mouse model , in combination with validated antibodies , enables us to assess the physical overlap of scs populations in the pilosebaceous unit ( figure 1a ) .
importantly , the lrig1 ki model faithfully reproduces the expression of endogenous lrig1 protein ( figures 1b1d ; figures s2a
lrig1 is expressed by cells in the upper isthmus and sg distinct from cd34 hf - scs ( figure 1e ) .
lrig1-egfp cells express reduced levels of sca1 , a protein expressed highly by cells in the ife ( figure 1f ; jensen et al . , 2008 ) . during the growth ( anagen )
phase of the hair cycle , lrig1 expression extends into the outer root sheath and hair germ ( figure 1 g ; jensen et al . , 2009 ) .
similar to the intestinal tract , lrig1 is here coexpressed with lgr5 ( wong et al . , 2012 ) .
in order to restrict our analysis to lrig1-expressing cells in the upper pilosebaceous unit , all subsequent experiments have been carried out in telogen back skin .
this analysis is supported by data from tail epidermis , where the hair cycle is asynchronous .
the upper pilosebaceous unit contains multiple sc populations marked by lrig1 , plet-1/mts24 , lgr6 , and blimp1 expression ( horsley et al . , 2006 ; nijhof et al . , 2006 ; jensen et al . , 2009 ; snippert et al . ,
we show that lrig1 and plet1/mts24 are expressed in the same location ( figure 1h ) .
the expression of lgr6 is more widespread and can be detected in the hf - sc niche , in the ife , and in the sg in addition to the reported expression in the isthmus ( figure 1i ; figures s1c and s1d ; snippert et al . , 2010 ) . here ,
similar coexpression is observed in the sg ( figure 1i ) . these lrig1-egfp cells in the basal layer of the sg are distinct from blimp1 cells , which are suprabasal and have a pronounced differentiated morphology as previously reported ( figure 1j ; cottle et al . , 2013 ) .
the pattern of marker expression is further substantiated by coexpression of lrig1 and plet1/mts24 at the rna level ( figure 1k ) .
we conclude that lrig1 and plet-1/mts24 are expressed by cells in the same location in the upper isthmus , and that these cells are distinct from cells expressing blimp1 in the sg .
in addition , lgr6 expression is not restricted to the isthmus as previously reported ( snippert et al . , 2010 ) ,
given that scattered lgr6-egfp cells are present throughout the entire epithelium . in order to assess whether lrig1-expressing cells are molecularly distinct from hf - scs and basal cells in the epidermis , lrig1-egfp cells , cd34 hf - scs , and itga6lrig1cd34 cells , which primarily represent basal undifferentiated ife cells , were isolated for transcriptional analysis ( figures 2a and 2b ; table s1 ) .
principal component analysis identifies the three different subsets of cells as distinct ( figure 2c ) .
hierarchal clustering of differentially expressed genes shows that lrig1-egfp cells are more related to ife cells than to the hf - sc ( figure 2d ) .
there is , however , a subset of 92 probe sets associated with 58 annotated genes , which are shared between the two sc populations including markers previously identified as hf - sc markers ( figures 2e and s1 g ; table s2 ) . a set of 73 probes corresponding to 49 annotated genes is specifically associated with the lrig1 compartment .
interestingly , these include ccl2 and ccl7 , which are two inflammatory cytokines previously associated with the stressful environment in the upper pilosebaceous unit ( nagao et al . , 2012 ) .
gene ontology ( go ) analysis of lrig1-expressing cells versus ife cells reflects the functionality of the two populations . here
, cells in the ife express genes associated with lipid metabolism , which is integral to barrier formation , whereas lrig1 cells have elevated expression of genes associated with receptor protein kinase signaling , cell adhesion , and migration , as well as various development pathways ( table s3 ) . in line with the clustering analysis and the individual comparison of the three populations ( figures 2d and 2e ) ,
the majority are associated with development and morphogenetic and differentiation pathways ( table s3 ) .
comparison of lrig1 with cd34-expressing cells reveals a strong enrichment for genes associated with proliferation in the lrig1 compartment .
moreover , lrig1-egfp cells show altered expression of genes regulating growth when compared to basal ife cells ( table s3 ) .
this suggests that there is a difference in their basic behavior in vivo that may reflect tissue - specific requirements for replenishment . in support
, we observe a large number of ki67 cells in the lrig1-expressing compartment , and during a short pulse with bromodeoxyuridine ( brdu ) , a much higher proportion of lrig1-egfp cells incorporate the label , when compared to both cd34 hf scs and ife cells ( figures 2f and 2 g ) .
the highly proliferative nature of lrig1-expressing cells is strikingly similar to the behavior of lrig1 cells in the small intestine ( wong et al . , 2012 ) .
interestingly , unlike hf - scs , epidermal lrig1-egfp cells show significant transcriptional overlap with lrig1 cells from the small intestine , which might underpin certain behavioral similarities ( figure s1h ) .
we conclude that the upper pilosebaceous unit contains a distinct population of cells marked by lrig1 , which , based on their expression profile and incorporation of nucleoside analogue , represents one of the most proliferative cell compartments in telogen back skin . based on the highly proliferative phenotype of lrig1 cells , we hypothesize that these cells play an active role in tissue maintenance . in order to address the behavior of these cells in vivo , lrig1 ki mice were crossed with rosa26-lsl - tdtomato mice , and lrig1 cells were labeled genetically with tdtomato during the resting phase of the hair cycle with a single administration of tamoxifen . without the administration of tamoxifen , we do not detect tdtomato cells ( figure s2 g ) .
analysis of back - skin samples taken 3 days after labeling revealed that the majority of tdtomato cells are found either as single cells or as two cells in the jz ( figures 3a and 3b ) .
less frequently , labeled cells are also seen in the sg , and rarely in the lower hf ( figure 3b ) . over time , labeled progeny from the jz expand upward to fill the entire infundibulum , where they persist for at least 1 year without migration into the ife ( figures 3c3 g ) .
based on the long - term maintenance and expansion of labeled clones , we conclude that the infundibulum is maintained as an independent compartment by lrig1-expressing scs .
although the tail is asynchronous in its hair cycle , the observations from back skin are reiterated here ( figures s2h s2l ) .
approximately 20% of the labeling events were initially observed within the basal layer of the sg .
this proportion remains constant over time , indicating that resident cells in the sg are capable of long - term maintenance of this compartment ( figures 3b , 3i , and 3j ) .
initially , labeled lrig1 cells were negative for the marker blimp1 ; however , over time tdtomato - labeled lrig1 progeny became blimp1 , supporting the notion that blimp1 marks terminally differentiated sebocytes ( figures 3k and 3l ; cottle et al . , 2013 ) .
given that 30% of follicles have more than one labeled cell and less than 5% of pilosebaceous units have labeling in both the sg and infundibulum 6 months after labeling , we conclude that lrig1 cells at the single - cell level contribute only to the infundibulum or the sg ( figures 3a , 3b , and 3h ) .
hf - scs have previously been proposed as the master sc population at the top of a cellular hierarchy ( petersson et al . , 2011 ) .
in order to assess the autonomy of epidermal compartmentalization , we investigated the relationship between the upper and lower pilosebaceous compartments .
our fate - mapping data from the year and 1 year time points from lrig1 cells demonstrate that labeled cells are confined to the pilosebaceous unit and make no contribution to the ife ( figures 3a3l ; figures s2i
s2l ) . as the fraction of labeled clones in the lower part of the pilosebaceous unit
is reduced over time , this strongly suggests that cells from the isthmus do not contribute to hf maintenance ( figure 3b ) . in order to determine whether hf - scs repopulate the upper pilosebaceous compartment , as has been suggested for k15-expressing cells ( morris et al . , 2004 ; petersson et al . ,
2011 ) , we utilize lineage tracing from the lgr5-egfp - ires - creert2 and k19creer mouse models to specifically mark the hf - sc compartment . as previously reported , labeled cells are confined to this compartment at time points up to 1 year ( figures 3m3p ; figure s2 ; jaks et al . , 2008 ; youssef et al . , 2010 ) .
this demonstrates that the upper and lower compartments of the pilosebaceous unit , as well as the ife , are maintained in autonomous manners .
ife scs have been shown to be the major contributor to tissue regeneration following injury ( mascr et al . , 2012 )
; however , evidence from hairless mice and lineage tracing from pilosebaceous scs supports a role for these cells in the regenerative response ( brownell et al .
, 2011 ; ito et al . , 2005 ; langton et al . , 2008 ; snippert et al . ,
it has also not been clear to what extent cells were specifically retained in the ife following tissue repair based on their ancestry ( plikus et al . , 2012 ) .
this is pertinent when considering the plasticity of scs in vivo . in order to address the role of different defined cellular compartments in tissue regeneration , we investigated the behavior of tdtomato - labeled lrig1 and hf - scs following skin wounding using serial imaging of live anaesthetized animals .
one to two weeks after wounding , labeled cells from both pilosebaceous sc compartments were detected in a radial pattern in the wound area ( figures 4a4c and 4g4i ; figures s3a
s3c ) . progeny are subsequently retained up to 1 year in the ife ( figures 4d4f and 4j4l ) .
this imaging technique allows quantitative analysis of labeled cells during the repair process in individual mice .
this reveals a substantial reduction in the proportion of labeled cells 3 weeks after wounding ( figure 4 m ) , which corresponds to the reduction in hyperplasia of the newly regenerated epidermis ( figures s3d and s3e ) .
the reduction in labeled cells following 3 weeks is reminiscent of reported observations for progeny of keratin-15-expressing hf - scs ( ito et al . , 2005 ) .
previous studies have focused on the tail epidermis , which facilitates high - resolution imaging . in order to investigate early events and whether there are significant differences between back and tail skin , we analyze three - dimensional ( 3d ) reconstructions of epidermal - tail whole mounts .
two days following tail wounding , progeny of lrig1 cells appear at the wound margin more than 200 m from the originating pilosebaceous unit ( figure 4n ; figure s3f ) .
analysis of hf - scs shows delayed recruitment , given that labeled cells at day 2 were still retained in the lower pilosebaceous unit ( figure 4o ; figure s3f ) . although the role of pilosebaceous scs in tissue repair of the tail epidermis has been disputed ( mascr et al . , 2012 ) , we show here that they contribute to tissue repair irrespective of the population of origin ( figures 4p4r ; figures s3g
this demonstrates that regional differences dictate whether cells are primed for an early or late regenerative response but do not impact their lineage plasticity in vivo .
recent evidence from studies of hf - scs and their progeny implies that oncogenic responses upon k - ras activation depend on the proliferation status and sc potential ( white et al . , 2011 ) . in order to probe the response from highly proliferative lrig1-expressing cells upon oncogenic stimulation
, we utilized a cre - inducible model for constitutive activation of k - ras ( tuveson et al . ,
expression of k - ras ( g12d ) causes increased phosphorylation of the downstream erk kinase in the upper pilosebaceous unit and sg hyperplasia ( figures s4a s4i ) . in line with the increased levels of erk activation , there were significant changes to the structure and proliferation within the infundibulum , but we observed no tumor development and very little effect to the ife on back skin ( figures s4a s4e and s4g s4i ) .
mice subsequently developed benign papillomas in lip epidermis from 4 months following the induction of k - ras ( g12d ) , as described for other cre drivers ( figure 5a ; lapouge et al . , 2011 ;
2011 ) . in order to understand the difference in epidermal - tumor susceptibility between the two sites
sg hyperplasia was also evident in the lip epidermis after k - ras activation ( figure s4f ) .
as in back skin , lrig1 expression was detected in highly proliferative cells in the pilosebaceous unit and never in the ife ( figures 5b and 5c ) .
similarly , fate mapping showed that labeled cells were initially found in the upper isthmus ; however , at later time points , tdtomato cells were detected in the ife , and always in association with fully labeled infundibula ( figures 5d and 5e ) .
basal cell carcinomas , which are driven by aberrant shh signaling , only form from cells in the ife ( youssef et al .
, 2010 ; kasper et al . , 2011 ; wong and reiter , 2011 ) .
in order to test whether mobilization of scs from the pilosebaceous unit is sufficient for tumor induction , mice expressing the oncogenic k - ras mutation in lrig1-expressing cells were treated with the tumor promoter 12-o - tetradecanoylphorbol-13-acetate ( tpa ) .
tpa induces a robust inflammatory response , which stimulates migration of lrig1-expressing cells into the ife ( figure 5 g ) .
however , this is not sufficient to induce tumor formation ( figure 5f ) . instead
, a more abrasive approach was adopted wherein the oncogenic mutation was combined with full - thickness wounding .
this drives very rapid and efficient papilloma formation in back skin from the lrig1 compartment ( figure 5f ) .
the tumors are similar to those forming from the lips and display a high number of proliferating cells , as well as a differentiated compartment ( figures 5h5 m ) .
we conclude that oncogenic mutations in scs perturb normal behavior within the tissue , and that wounding in addition to simple migration out of the natural compartment is required for tumor initiation .
in this study we define the cellular networks that underlie epidermal homeostasis as founded in the existence of subsets of scs with distinct tissue contributions . here , the lower part of the pilosebaceous unit , the infundibulum , the sg , and the ife are maintained as independent compartments .
the normal boundaries are broken upon wounding , and cells are rapidly recruited into the wounded region , where they subsequently contribute long term to tissue homeostasis , irrespective of their ancestry . wounding is also the auxiliary signal required for inducing tumor formation from lrig1-positive scs expressing oncogenic k - ras .
the upper pilosebaceous unit contains multiple overlapping populations of scs ; however , it has been difficult to rectify differing observations between expression studies , lineage - tracing studies , and reporter models ( horsley et al . , 2006 ;
, 2005 ; snippert et al . , 2010 ; brownell et al . ,
careful examination of individual markers has enabled us to dissect this relationship . here , we show that plet1/mts24 and lrig1 are both expressed in the upper isthmus .
the expression of lgr6 in multiple compartments makes fate mapping from lgr6-expressing cells very difficult to interpret , because labeled progeny might arise from lgr6 cells in the different structures rather than from a single source as previously suggested ( blanpain , 2010 ) . a much simpler model for tissue homeostasis is consequently emerging , wherein during homeostasis ,
lineage - specific amplification by defined sc populations is beginning to emerge as a general mechanism for tissue replenishment ( van keymeulen and blanpain , 2012 ) .
the best examples are the mammary gland and prostate , wherein the luminal and myoepithelial compartments are maintained independently throughout life ( van keymeulen et al . , 2011 ; ousset et al . , 2012 ; choi et al . ,
we demonstrate that the different functional components of the epidermis are maintained in a similar manner during steady - state homeostasis , and we propose that this represents a general mechanism for the maintenance of complex cellular systems .
this enables the tissue to respond to specific requirements of individual regions . in this manner
, the epidermis can simultaneously cater to the requirements for cyclic growth of the hf and the constant maintenance of the sg and ife .
our study identifies lrig1-expressing cells in the upper isthmus as a highly proliferative sc population responsible for maintenance of the infundibulum .
one major feature of the infundibulum is the mechanical stress exerted from the hair shaft as it protrudes out through the skin . in agreement with the increased stress levels
, we do observe expression of proinflammatory cytokines such as ccl2 and ccl7 specifically in lrig1 cells . by having a dedicated compartment of stem cells ,
it is possible to specifically respond to the requirement of the infundibulum for constant repair .
lrig1 has been characterized as a negative regulator of proliferation both in vivo and in vitro ( gur et al . , 2004 ;
the proliferative behavior of lrig1-expressing stem cells in vivo is , however , analogous to their counterparts in the small intestine , where lrig1 controls sc proliferation by modulating the amplitude of erbb signaling ( wong et al . , 2012 ) .
in both cases the inductive signals for proliferation must either overcome its inhibitory effects or utilize pathways that are not regulated by lrig1 .
future analysis of the genes identified as differentially expressed in lrig1 cells is likely to shed light on gene networks responsible for the unique behavior of these cells .
an important function of scs in adult tissues is to contribute to wound repair following injury ( plikus et al . ,
a major difference between scs and more committed progeny within the epidermis is the ability of scs to be retained once the tissue is healed ( mascr et al . , 2012 ) .
ife - derived stem cells were recently shown to be the predominant contributor to tissue repair ( mascr et al . , 2012 ) ; however , evidence from hairless mice and the long - term retention of cells from the pilosebaceous unit suggest that these cells are likewise involved ( langton et al . , 2008 ; ito et al .
the observation that cells can move across boundaries upon wounding shows that cells are not lineage restricted , but that the microenvironment , rather than cellular ancestry , dictates cell behavior in vivo .
moreover , the apparently proportional retention of all pilosebaceous sc progenies supports the notion that this is a stochastic rather than a hard - wired process .
experimental evidence demonstrates that epidermal scs have the potential to initiate tumor formation ( lapouge et al . , 2011 ;
white et al . , 2011 ) ; however , tumors formed upon expression of oncogenic k - ras are generally associated with areas of abrasion ( van der weyden et al . , 2011 ) .
we observe that expression of k - ras g12d in lrig1-expressing cells drives sg and infundibula hyperplasia without affecting the ife significantly .
the speed and the reproducibility with which these tumors form following wounding strongly suggest that additional mutations are not required .
we expect that in the future this model will provide an attractive platform for the identification of genes involved in tumor formation .
it is evident that loss of p53 combined with k - ras activation drives malignant progression ( caulin et al .
2011 ) , and it is very probable that such combinations will not need additional wound - associated signals to initiate tumor formation from lrig1-expressing cells . in summary , we have identified lrig1 as a marker of the sc compartment responsible for independent maintenance of the infundibulum and sg .
a picture is now emerging in which the epidermis is compartmentalized during homeostasis , and this provides a functional explanation for the sc heterogeneity in the pilosebaceous unit .
we predict that it will be possible to observe similar compartmentalized patterns in other complex organs .
this is potentially a general method for controlling tissue homeostasis , in that it provides a simple solution to cater for regional differences in the requirement for tissue replenishment .
lrig1-egfp - ires - creert2 mice were generated by knocking an egfp - ires - creert2 cassette into the endogenous lrig1 locus in c57bl6 embryonic stem cells .
lgr5-egfp - ires - creert2 , k19creer , k - ras - lsl - g12d , and rosa - lsl - tdtomato mice have been described previously ( barker et al .
. injections of tamoxifen dissolved in corn oil ( lrig1 , 100 g ; lgr5/ki9 , 3 mg ) .
activation of k - ras was achieved by topical application of 100 g 4-hydroxytamoxifen in acetone .
wound biopsies were carried out with a circular biopsy punch on the dorsal ( 5 mm ) or tail ( 2 mm ) skin . for tpa treatment ,
1 g of tpa in acetone was applied topically to back skin on days 1 , 4 , 8 , and 11 .
all in vivo experiments were performed under the terms of a uk home office license .
immunohistochemistry was performed using the immpress polymer detection kit ( vector labs ) . for immunofluorescence staining ,
samples were blocked in 0.5% bsa , 0.5% fish skin gelatin , and 0.1% triton x-100 before overnight incubation in primary antibody as listed in table s4 .
primary antibodies were detected with appropriate alexa - fluorophore - conjugated secondary donkey antibodies ( invitrogen ) .
whole mounts of tail epidermis , tissue preparation , and images were acquired as described previously ( jensen et al . , 2009 ) .
keratinocytes were isolated and sorted from mouse back skin as previously described ( jensen et al . , 2010 ) .
flow cytometry was carried out using a cyan adp ( beckman coulter ) and an lsrfortessa ( bd biosciences ) flow cytometer , and cell sorting was carried out on a facsaria ( bd biosciences ) and a moflo legacy cell sorter ( beckman coulter ) . an apc brdu flow kit ( bd pharmingen )
total rna was isolated from flow - sorted cells using the purelink rna micro kit with on - column dnase digestion ( invitrogen ) .
complementary dna was synthesized and analyzed by quantitative pcr ( qpcr ) as described previously ( wong et al . , 2012 ) . for global gene - expression
profiling , rna was preamplified ( ovation rna amplification system , nugen ) and hybridized to mousewg-6 v.2 beadchips ( illumina ) .
raw data from the mousewg-6 v.2 beadchips were processed using the r package lumi ( du et al . , 2008 ) .
a variance - stabilizing transformation , quantile normalization , and quality control were performed on the expression data .
nonexpressed probes ( detection p value 0.01 in all samples ) were removed from downstream analysis . to test for differential expression ,
multiple testing correction on all probes and across contrasts was performed by controlling the false discovery rate .
strategy was used to adjust the f statistic p values to find probes that were differentially expressed in at least one sample .
probes were considered significant if the adjusted p value was 0.05 and the log fold change was 0.5 . for gene - set enrichment analysis ,
expressed probes were ranked according to their association with lrig1-gfp and -gfp cells in the small intestine . identified gene signatures associated with epidermal scs were subsequently analyzed for their association with lrig1-gfp or -gfp cells in the intestine ( http://www.broadinstitute.org/gsea/index.jsp ; mootha et al . , 2003 ) .
go analysis for biological processes was carried out on differentially expressed gene sets using the david bioinformatics resource ( huang et al . , 2009 ) .
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### Summary:
: summarythe complex anatomy of the epidermis contains multiple adult stem cell populations , but the extent to which they functionally overlap during homeostasis , wound healing , and tumor initiation remains poorly defined . here , we demonstrate that lrig1+ve cells are highly proliferative epidermal stem cells .
long - term clonal analysis reveals that lrig1+ve cells maintain the upper pilosebaceous unit , containing the infundibulum and sebaceous gland as independent compartments , but contribute to neither the hair follicle nor the interfollicular epidermis , which are maintained by distinct stem cell populations .
in contrast , upon wounding , stem cell progeny from multiple compartments acquire lineage plasticity and make permanent contributions to regenerating tissue .
we further show that oncogene activation in lrig1+ve cells drives hyperplasia but requires auxiliary stimuli for tumor formation . in summary ,
our data demonstrate that epidermal stem cells are lineage restricted during homeostasis and suggest that compartmentalization may constitute a conserved mechanism underlying epithelial tissue maintenance .
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: medullary thyroid carcinoma ( mtc ) represents 3% to 10% of most institutional series of thyroid cancers ; hereditary mtc accounts for 25% to 30% of these patients ( 1 , 2 ) .
hereditary mtc is divided into three clinical subtypes depending on the presence or absence of tissue - specific tumors , phenotypic characteristics and the number of affected family members : familial mtc ( fmtc ) , multiple endocrine neoplasia ( men ) type 2a and men type 2b ( 3 , 4 ) .
it is defined as the presence of mtc in a kindred with four or more affected members , and with no clinical or biochemical evidence of adrenal or parathyroid gland involvement either in the affected members or in the available first degree relatives ( 5 ) .
fmtc represents a less aggressive form of hereditary mtc , and it has a corresponding older age at onset , often between 20 and 40 , compared to men 2a and men 2b ( 6 , 7 ) .
hereditary mtc is caused by autosomal dominant gain - of - function mutations in the ret proto - oncogene ( 8) .
a germline mutation in the ret proto - oncogene , which encodes for a transmembrane tyrosine kinase receptor , predisposes individuals to develop mtc .
an identifiable ret mutation can be detected in about 85% of fmtc families ( 9 ) .
the majority of germline mutations in fmtc have been found in exons 10 and 11 of the ret proto - oncogene , specifically within the cysteine codons 609 , 611 , 618 , 620 , and 634 .
in addition , mutations in the intracellular domain of the protein have been described at : 768 , 790 , 791 in exon 13 , v804 m , 844 in exon 14 , 891 in exon 15 , and 912 exon 16 ( 3 , 7 , 10 ) .
mutations at codons 532 , 533 ( exon 8) , 768 , 844 , and 912 have been identified only in families with fmtc ( 10 - 12 ) .
many studies of ret mutations in heritable mtc have been published in different countries . however , there are few reports of these mutations in korean families with fmtc . in this study we screened members of a large korean family that had a history of fmtc by genetic analyses , and
five patients were diagnosed with mtc before genetic testing ( ii-1 , ii-4 , iii-2 , iii-8 , iii-14 ) .
other three patients were diagnosed after genetic testing and clinical screening ( ii-2 , iii-1 , iii-13 ) .
the index case was a 67-yr - old woman ( ii-1 ) who had a total thyroidectomy with modified radical neck dissection bilaterally , at the age of 48 yr , for an anterior neck mass that presented 10 yr earlier .
the histological examination showed the presence of mtc in both lobes and microscopic metastatic disease in 14 lymph nodes in the central and both lateral compartments .
there was no clinical or biochemical evidence of pheochromocytoma , parathyroid disease or other associated clinical features attributed to men2 . on her last follow - up visit , 23 yr after her initial diagnosis
, there was no radiological evidence of recurrent or metastatic disease , despite an elevated serum calcitonin level of 593.5 pg / ml ( normal range , < 10 pg / ml ) . the index patient and at - risk family members had ret mutation genetic screening . prior to obtaining the samples , all individuals included in the study
however , they refused further biochemical testing and agreed only to thyroid ultrasound examinations . for identification of ret germline mutations
, genomic dna was purified from peripheral blood lymphocytes using the qia quick pcr purification kit ( qiagen , hiden , germany ) .
dna of the index case ( ii-1 ) was first screened by looking for ret proto - oncogene mutations in exons 10 , 11 , 13 , 14 , 15 , and 16 , where most of the ret mutations are found in fmtc . for the rest of the individuals ,
genomic dna was amplified by the polymerase chain reaction with oligonucleotide primers for exons 10 , 11 , 13 , 14 , 15 , and 16 .
single - strand conformation polymorphism analysis and direct sequencing were performed on an automated dna sequencer ( abi prism 310 , perkin elmer , foster city , ca , usa ) .
for identification of ret germline mutations , genomic dna was purified from peripheral blood lymphocytes using the qia quick pcr purification kit ( qiagen , hiden , germany ) .
dna of the index case ( ii-1 ) was first screened by looking for ret proto - oncogene mutations in exons 10 , 11 , 13 , 14 , 15 , and 16 , where most of the ret mutations are found in fmtc . for the rest of the individuals ,
genomic dna was amplified by the polymerase chain reaction with oligonucleotide primers for exons 10 , 11 , 13 , 14 , 15 , and 16 .
single - strand conformation polymorphism analysis and direct sequencing were performed on an automated dna sequencer ( abi prism 310 , perkin elmer , foster city , ca , usa ) .
genetic analysis of the index case revealed a missense tgcagc mutation at codon 618 in exon 10 of the ret protooncogene .
2 ) . direct sequencing of the ret exon 10 polymerase chain reaction products , from genomic dna of family members , showed that 11 of 29 members were carriers for this mutation , and 18 were unaffected .
eight ( ii-1 , ii-2 , ii-4 , iii-1 , iii-2 , iii-8 , iii-13 , and iii-14 ) of them underwent surgery and one ( iii-12 ) has been scheduled for surgery .
the mean age at surgery was 37 yr ( range , 18 to 67 ) . the youngest patient to present with mtc and lymph node metastases was 18-yr old .
median follow - up period was 10 yr . there was no case with disease recurrence or death during follow - up .
the brother of the index case ( ii-5 ) exhibited increased serum calcitonin in response to pentagastrin stimulation and underwent a total thyroidectomy at 45 yr of age ; the histology examination showed normal thyroid tissue .
two family members positive for the ret mutation , a 37-yr - old man ( iii-3 ) and a 12-yr - old girl ( iv-3 ) , are asymptomatic and have no evidence of disease by thyroid ultrasound ; they have refused further biochemical investigation .
we report a ret mutation in exon 10 , codon 618 that causes substitution of a cysteine by a serine in the cysteinerich domain of the ret receptor in a three - generation fmtc family composed of 30 members with 11 carriers .
approximately 85% of families with fmtc have an identifiable ret mutation ( 9 ) . in general , fmtc patients have the same mutations as patients with men2a , but they are more evenly distributed among cysteines 618 , 620 , and 634 each accounting for 25% to 35% of the mutations .
five percent to 10% of fmtc patients have a mutation in an intercellular domain , that is , in codons 768 , 804 or 891 ( 9 , 12 - 15 ) .
it has been established that specific ret mutations predict the phenotypic expression of the disease .
it has been reported previously that mutations at codon 618 are associated with men2a , fmtc and hirschsprung disease ( hscr1 ) .
mutations in this codon are associated with low transforming activity of ret and may be associated with milder forms of the disease ( 16 , 17 ) . in the kindred that we have described here , all of the affected patients had mtc as the sole clinical finding and did not have any evidence of adrenal or parathyroid involvement on screening .
the median age at surgery was 27 yr ( range , 18 to 67 ) .
the median age at the time of the development of mtc , in this study in fmtc patients , was similar to the age reported for previous fmtc families . among eight patients with mtc ,
the fmtc with cysteine ret mutations found in the korean population is consistent with the clinical pattern reported worldwide ; to date there have been no ethnic differences identified for fmtc .
( 3 ) reported that ret mutations can be stratified into three groups ( levels 1 to 3 ) based on the biological aggressiveness of mtc observed in patients with these mutations .
level ii mutations are considered high risk , and correspond to men2a and some fmtc mutations , including codons 611 , 618 , 620 , and 634 .
carriers of high - risk ret mutations develop mtc starting from the age of one year ( codon 634 ) and five years ( codon 611 , 618 , and 620 ) , lymph node metastasis from the first decade ( codon 634 ) and the second decade ( codon 611 , 618 , and 620 ) , and distant metastases generally from the third decade ( 18 ) .
current guidelines for the treatment of patients with level two , high - risk group mutations , recommend prophylactic total thyroidectomy before the age of five years . no agreement has been reached about the need for additional central lymph node dissection in patients with these mutations .
the 12-yr - old granddaughter ( iv-3 ) in this family is being carefully monitored at the time of preparation of this report to determine the appropriate timing of thyroidectomy .
such surgery has not yet been performed because of the potential risks and complications associated with a thyroidectomy , the lack of radiological signs of development of mtc , and the possibility of slow growth of mtc associated with a codon 618 mutation .
the other family members positive for the ret mutation , a 37-yr - old man ( iii-3 ) , is asymptomatic and have no evidence of disease by thyroid ultrasound .
we have recommended prophylactic thyroidectomy , however , to date they have refused the procedure . in summary , we report here an extracellular mutation of the ret proto - oncogene that was identified in a large korean family with fmtc . the mutation substituted a cysteine for a serine in codon 618 of exon 10 ( c618s , tgc to agc ) .
our results suggest that this genetic profile might be associated with usually aggressive clinical course with regional lymph node metastasis but late onset of mtc .
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### Summary:
: familial medullary thyroid carcinoma ( fmtc ) is caused by autosomal dominant gain - of - function mutations in the ret proto - oncogene .
an identifiable ret mutation can be detected in about 85% of fmtc families .
the majority of germline mutations in fmtc have been found in exons 10 and 11 of the ret proto - oncogene , specifically within the cysteine codons 609 , 611 , 618 , 620 , and 634 .
we screened members of a large korean family that had a history of fmtc by genetic analyses , and propose a therapeutic approach for managing the disorder .
we report a ret mutation in exon10 , codon 618 that causes substitution of a cysteine by a serine in the cysteine - rich domain of the ret receptor in a three - generation fmtc family composed of 30 members with 11 carriers .
nine of the gene carriers were clinically affected .
the fmtc with cysteine ret mutations found in the korean population is consistent with the clinical pattern reported worldwide ; to date there have been no ethnic differences identified for fmtc .
our results suggest that this genetic profile might be associated with usually aggressive clinical course with regional lymph node metastasis but late onset of mtc .
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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 challenge for x - ray radiation therapy is that the therapeutic doses used can damage neighboring normal cells .
other than designing better beam techniques , a variety of radiosensitizers ( including chemicals , ions , and nanoparticles ) have been used to enhance the efficacy of radiation therapy .
because nanoparticles can be functionalized to target ligands expressed at tumor cell surfaces , nanoparticles of heavy atoms have been proposed as promising radiosensitizers for radiation therapy .
owing to high x - ray attenuation coefficient and biocompatibility , gold nanoparticles have been intensively studied as promising candidates to enhance radiation doses.13 secondary electrons and photons released when a photon is incident on a metallic surface are the cause of sensitization .
several interactions can take place between a photon and a metallic surface based on the energy of the photon .
compton scattering and photoelectric effects dominate when metallic nanoparticles are used as imaging contrast agents.4,5 as photoelectrons and auger electrons are released due to the photoelectric effect , they travel through the cell and hydrolyze water molecules creating free radicals that interact with dna causing dna damage , and eventually cell death.6,7 analytical and monte carlo methods have been used to calculate the production of secondary electrons in terms of the dose enhancement factor ( def).8,9 the def is defined as the ratio of the average radiation dose absorbed by the tumor when it is loaded with nanoparticles to the dose absorbed without the nanoparticles .
previous analytic calculations were carried out for a single nanoparticle and scaled to account for the total number of nanoparticles attached to a cell surface .
the probability of photoelectric interactions , energy balances , and particle transport equations are analytically solved to determine the amount of energy deposited within the cell .
the simulation assumes that the nanoparticles are evenly distributed on the cell surface , each nanoparticle has the same probability of interacting with a photon and producing a photoelectron , there are no interactions between secondary electrons and neighboring nanoparticles , and for every electron that leaves the cell , another one enters creating a lateral equilibrium.10 analytical methods yield solutions that are exactly reproducible between different runs and allow flexibility in changing parameters for any given application .
in addition , computations take much less time , milliseconds , compared to monte carlo methods , which can take up to hours per run based on geometry complexity
. however , analytical techniques are mostly limited to one - dimensional ( 1-d ) space and errors are not easy to estimate .
the monte carlo method treats the electron or photon trajectory as a sequence of random steps .
each step is presumed to end in an interaction , chosen through another random sampling .
the interactions can cause a change in direction , energy loss , or creation of secondary particles.11,12 all types of physical interactions between matter and radiation can be modeled using monte carlo methods for 1-d , 2-d , and 3-d applications .
for deep penetration problems or for regions where too few particles contribute to the solution , variance reduction techniques can be used to improve accuracy , but even then the statistical error may be unacceptable.13 several software packages are available for radiation transport in matter such as geant4 , mcnp5 , and egsnrc .
mcnp5 is a radiation transport code distributed by the radiation safety information computational center at oak ridge national laboratory . written in fortran 90
, this transport code uses a condensed history model.14,15 egsnrc is a free open - source software package distributed by the national research council of canada .
written in c++ , it has an exact boundary crossing algorithm that is used in conjunction with the presta - ii transport code.14 geant4 is another open - source package written in c++ originally intended for high - energy physics.16 because of the broad range of applications of geant4 , the user must supply a physics list that outlines the details of the model.14,17 egsnrc was decided upon due to it being free open - source software , with its ease of use for user input files , customizable material files , geometry visualization , and documentation .
an issue of these activities is that the results obtained in each group using different methods are largely different .
since each group models a different parameter , it is difficult to compare the soundness of each simulation method . given the importance of simulation in guiding experiments , it is imperative to find a reliable simulation method with minimum requirements on empirical data .
this study intends to compare an analytical simulation based on a 2010 paper10 and a monte carlo simulation based on a 2005 paper.18 this study aims to provide , for the first time , a head - to - head comparison between analytical solutions vs monte carlo simulations for radiation dose enhancement .
it will look into how def differs with source energy , nanoparticle materials , and concentration for both analytical and the monte carlo simulation .
a cell is modeled as a slab of tissue with a single nanoparticle attached to its surface ( figure 1 ) .
an analytical and a monte carlo simulation were compared for various source energies , nanoparticle materials , and concentrations .
endothelial cell lines of tumor vasculature are more likely to be exposed to nanoparticles . for both simulations ,
an endothelial cell was modeled as a 10102 m slab composed of 10% hydrogen , 11% carbon , 2% nitrogen , and 76% oxygen according to the international commission on radiation units and measurements .
x - ray energies from 10 to 900 kev were chosen to model the low - energy photon beam .
nanoparticle concentrations of 5 , 10 , 15 , and 20 mg / g of tissue , evenly distributed through the cell , were chosen based on their usage in literature .
the analytical simulation modeled a single nanoparticle with radius of r , at the center of a cell .
dose enhancement was calculated using the equations presented in the 2010 ngwa et al paper and the 2012 hossain and su paper.9,10 for these equations , a base dose , dw = 2 gy , chosen based on its clinical relevance , and a monoenergetic beam were used to calculate the photon fluence ( ) :
=dwe(en)e(1)and the number of photons interacting with a single nanoparticle , nph = **r , where ( en/)e is the mass absorption of coefficient of water at a given photon energy e , and r is the nanoparticle radius .
on the basis of the probability of a photoelectric interaction , p ( pe/)e*np*dnp , where dnp is the average distance a photoelectron travels through the nanoparticle , np is the nanoparticle density , and ( pe/)e is the photoelectric absorption coefficient of the nanoparticle at energy e. the total number of photoelectrons produced per nanoparticle is calculated using the following equation :
npe = nph*p(2 ) based on the energy of the photoelectron , epe = e eedge , the maximum distance traveled through the cell is :
rt=0.0431(e+0.367)1.770.007(3 ) the energy deposited within the cell , per photoelectron is calculated using the following equation :
eec = habccxby2*habcrrt[3.316(rtx+0.007)0.435 + 0.0055(rtx)0.33]dx,(4)where habc = 2**r(0.5*t)2 , cxby = 2**rt*(rt 0.5 t ) , with t being the thickness of the cell . this equation assumes evenly distributed nanoparticles and equilibrium between secondary electrons leaving and entering the cell .
this is then scaled by the total number of photoelectrons released , npet = npe*nnp , where nnp is the total number of nanoparticles in the cell , to get the total energy deposited in the cell , eect = eec*npet .
the def is then
def = dw+dnpdw,(5)where dnp = eect / mcell is the dose deposited from the photoelectrons .
egsnrc provided by the national research council of canada was used as the basis for the monte carlo simulation .
egsnrc is an electron transport code that comes equipped with electron transport in matter , tracking for individual electrons and photons . using tutor7pp as a base , the code was modified to allow for photoelectric interactions , atomic relaxations resulting in auger electrons , and compton interactions .
tutor7pp is a standard code with the egsnrc distribution that uses analog scoring to calculate energy deposition in each region along with energy reflected and transmitted through the geometry.14 the code was modified to tag and track photoelectrons , auger electrons , compton photons , or compton electrons .
if the tracked particle deposited its energy within the cell , its type and energy was outputted to a file and the energy was scored in a bin based on its type .
after the simulation was complete , the code exported the energy deposited by compton photons and electrons , auger electrons , photoelectrons as well as the total energy deposited in the cell .
four - component international commission on radiation units and measurements tissue was used as the base material for the cell , and the composition and density were altered for the different concentrations .
the beam cross - section was 1010 m , had a full width at half maximum of 10 , and varying mean energies .
the global electron cutoff energy was set to 0.7 mev , and the global photon cutoff energy was set to 0.01 mev .
def was calculated for each energy by dividing energy deposited in the cell with nanoparticles by energy deposited in the cell without nanoparticles for the same number of photon instances .
the number of photon instances that provided a base dose of 2 gy was used for each photon energy .
the analytical simulation modeled a single nanoparticle with radius of r , at the center of a cell .
dose enhancement was calculated using the equations presented in the 2010 ngwa et al paper and the 2012 hossain and su paper.9,10 for these equations , a base dose , dw = 2 gy , chosen based on its clinical relevance , and a monoenergetic beam were used to calculate the photon fluence ( ) :
=dwe(en)e(1)and the number of photons interacting with a single nanoparticle , nph = **r , where ( en/)e is the mass absorption of coefficient of water at a given photon energy e , and r is the nanoparticle radius .
on the basis of the probability of a photoelectric interaction , p ( pe/)e*np*dnp , where dnp is the average distance a photoelectron travels through the nanoparticle , np is the nanoparticle density , and ( pe/)e is the photoelectric absorption coefficient of the nanoparticle at energy e. the total number of photoelectrons produced per nanoparticle is calculated using the following equation :
npe = nph*p(2 ) based on the energy of the photoelectron , epe = e eedge , the maximum distance traveled through the cell is :
rt=0.0431(e+0.367)1.770.007(3 ) the energy deposited within the cell , per photoelectron is calculated using the following equation :
eec = habccxby2*habcrrt[3.316(rtx+0.007)0.435 + 0.0055(rtx)0.33]dx,(4)where habc = 2**r(0.5*t)2 , cxby = 2**rt*(rt 0.5 t ) , with t being the thickness of the cell . this equation assumes evenly distributed nanoparticles and equilibrium between secondary electrons leaving and entering the cell .
this is then scaled by the total number of photoelectrons released , npet = npe*nnp , where nnp is the total number of nanoparticles in the cell , to get the total energy deposited in the cell , eect = eec*npet .
the def is then
def = dw+dnpdw,(5)where dnp = eect / mcell is the dose deposited from the photoelectrons .
egsnrc provided by the national research council of canada was used as the basis for the monte carlo simulation .
egsnrc is an electron transport code that comes equipped with electron transport in matter , tracking for individual electrons and photons . using tutor7pp as a base , the code was modified to allow for photoelectric interactions , atomic relaxations resulting in auger electrons , and compton interactions .
tutor7pp is a standard code with the egsnrc distribution that uses analog scoring to calculate energy deposition in each region along with energy reflected and transmitted through the geometry.14 the code was modified to tag and track photoelectrons , auger electrons , compton photons , or compton electrons .
if the tracked particle deposited its energy within the cell , its type and energy was outputted to a file and the energy was scored in a bin based on its type .
after the simulation was complete , the code exported the energy deposited by compton photons and electrons , auger electrons , photoelectrons as well as the total energy deposited in the cell .
four - component international commission on radiation units and measurements tissue was used as the base material for the cell , and the composition and density were altered for the different concentrations .
the beam cross - section was 1010 m , had a full width at half maximum of 10 , and varying mean energies .
the global electron cutoff energy was set to 0.7 mev , and the global photon cutoff energy was set to 0.01 mev .
def was calculated for each energy by dividing energy deposited in the cell with nanoparticles by energy deposited in the cell without nanoparticles for the same number of photon instances .
the number of photon instances that provided a base dose of 2 gy was used for each photon energy .
low - energy beams , 200 kv , with a penetration depth of 5 mm have limited applications and are mainly used for surface treatment of the skin .
medium energies 200 kv1 mv ( orthovoltage and supervoltage x - rays ) are used for shallow treatments , while greater high - energy beams from 1 to 25 mv are used for treating deeply buried ( > 2 cm in depth ) tumors.19 figure 2a shows the results from analytical simulation , where defs as a function of source energy for copper , silver , gold , and bismuth nanoparticles are calculated .
x - ray beams used for medical treatment are polyenergetic where the high - energy spectra have a low - energy component . at lower energies ,
x - ray matter interactions are dominated by the photoelectric effect , whereas the high - energy component interacts with matter by compton scattering .
the photoelectric effect is most effective until the photon energy from the external beam reaches a certain maximum that depends on the specific material under consideration . the interaction probability between the source photons and the nanoparticles , as well as the energy transfer coefficient in the medium , increases with decreasing source energy and increasing atomic number of the nanoparticles .
the photoelectric cross - section varies as z or z , where z is the atomic number of the nanoparticle and is enhanced by an increased absorption by electron shells ( k , l , m , etc ) at low energies .
the photoelectric effect is followed by the emission of an x - ray photon or an auger electron .
the auger effect is mostly seen in z<15 materials and is almost absent in materials with z>60.19 in materials with higher atomic numbers , such as gold and bismuth , there are two peaks corresponding to the k and m edge energies .
silver only has one peak , which corresponds to the l edge energy , while copper does not have these peaks .
the peaks occur when the photon energy exceeds the edge energy and begins ionizing a different electron shell .
peaks near the edge energies support the theory that at low energies , photoelectrons and auger electrons have a shorter trajectory in tissue , and therefore are more likely to deposit all of their energy in the cell . for high energies ,
the analytical simulation predicts a def of 1 , ie , no enhancement , for all materials .
figure 2b shows the results from the monte carlo simulation , where def varies as a function of energy for copper , silver , gold , and bismuth . for the energies of interest
, the monte carlo simulation predicts a gaussian distribution for the def , with a maximum at around 90 kev for gold and bismuth and 50 kev for silver and copper .
the monte carlo simulation also predicts that at high energies the def levels out around 1.2 for copper and upward of 1.6 for gold .
this is because the z - dependent probability of the photoelectric effect gets smaller at the higher mev ranges , where the compton interaction starts to dominate . in compton scattering , which is independent of z ,
the scattered photon , depending on its energy , can further induce the photoelectric or compton effect as well as generate secondary electrons .
secondary electrons generated by kev x - rays from the nanoparticle surface have lower energy , a shorter trajectory , and higher energy transfer rate to the surroundings , which in turn results in a higher def value .
figure 3a d shows a direct comparison between the analytical and monte carlo simulation for various materials at a concentration of 20 mg / g . for each material ,
one major difference is at high energies where the analytical simulation does not predict an enhancement ( def = 1 ) , the monte carlo simulation does .
since the monte carlo takes a random sampling for each trajectory step , it accounts for interactions with neighboring nanoparticles .
these interactions could change the trajectory of the photoelectrons and auger electrons , reduce the electrons energy , or cause another photoelectron or auger electron to be ejected . in all the cases
, the monte carlo simulation would continue to track its trajectory until all the energy is deposited within the cell .
the analytical simulation on the other hand assumes a linear trajectory of the electron with a set probability of depositing the energy within the cell .
the discrepancy at low energies may be due to the analytical simulation not accounting for recombination .
finally , def was calculated as a function of energy for various concentrations of gold nanoparticles .
figure 4a shows the results from the analytical simulation , while figure 4b shows the results from the monte carlo simulation .
both simulations predict an increase in def as the concentration increases , although the increase in the monte carlo simulation is larger than the increase in the analytical simulation for larger energies . at 10 kev ,
this may be due to several factors including recombination , which is accounted for in the monte carlo simulation .
nanoparticles of high atomic number elements could be used to enhance x - ray radiation therapy .
although both analytical and the monte carlo simulations predict an increase in dose enhancement in the presence of nanoparticles , the two methods do not give comparable results for few reasons .
the monte carlo simulation takes into account energy deposited by photoelectrons , auger electrons , compton photons and compton electrons , and source photons , while the analytical one calculates energy deposited by source photons and photoelectrons.the monte carlo simulation accounts for electron
hole recombination while the analytical simulation does not.monte carlo simulation randomly samples the photon or electron path and accounts for particle interactions , while the analytical simulation assumes a linear trajectory .
the monte carlo simulation takes into account energy deposited by photoelectrons , auger electrons , compton photons and compton electrons , and source photons , while the analytical one calculates energy deposited by source photons and photoelectrons .
monte carlo simulation randomly samples the photon or electron path and accounts for particle interactions , while the analytical simulation assumes a linear trajectory .
this work demonstrates that for varying nanoparticle material , concentration , and x - ray beam conditions , the monte carlo simulations present a more comprehensive approach to calculate defs .
future works should involve improving the analytic simulation by adding in the auger electron spectrum , taking into account the relaxation effects , and simulating discrete nanoparticles within the cell .
validation of the two simulations should be conducted through experiments carried out in phantoms or mice .
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### Summary:
: analytical and monte carlo simulations have been used to predict dose enhancement factors in nanoparticle - enhanced x - ray radiation therapy .
both simulations predict an increase in dose enhancement in the presence of nanoparticles , but the two methods predict different levels of enhancement over the studied energy , nanoparticle materials , and concentration regime for several reasons .
the monte carlo simulation calculates energy deposited by electrons and photons , while the analytical one only calculates energy deposited by source photons and photoelectrons ; the monte carlo simulation accounts for electron
hole recombination , while the analytical one does not ; and the monte carlo simulation randomly samples photon or electron path and accounts for particle interactions , while the analytical simulation assumes a linear trajectory .
this study demonstrates that the monte carlo simulation will be a better choice to evaluate dose enhancement with nanoparticles in radiation 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:
: unesco estimates that about 10 - 15 % of children around the world are counted under the category of children with special needs , and about 8 % of them are those with learning disorder ( 1 ) .
national consultancy committee , in the case of disabled children , gives the following definition for learning disabilities :
children with learning disability show their disability in one or more basic psychological processes related to understanding or using oral or written language .
representations of this disability may appear in the form of disorders in listening , thinking , speaking , reading , writing , spelling , or calculating .
these disorders are found to be as consequences of circumstances such as perceptual flaw , brain lesion , minimal brain dysfunction , dyslexia , dysphasia , etc .
their disability in learning is not the one primarily related to vision , listening , motor deficiencies , mental retardation , affective distress and lack of environmental equipment ( 2 ) .
considering the above definition
, learning disabilities can be divided into three main categories : dyslexia , dyscalculia , dysgraphia ( 3 ) .
students with specific learning disability , from this point of view , are reported to constitute 4 to 12 % of all students ( 4 ) .
some students have normal intelligence but are disabled in reading , writing , speaking , mathematical perception , etc . and come to a weak overall educational function .
children with learning disability are in middle to top level of intelligence , but face apparent problems in learning some skills .
they also have some other abnormal signs including perceptual disorders in one or more sensual dimension , disability in unifying received sensual information , and disorder in sensual - motor coordination .
most of these sensual - motor and perceptual disorders are in direct relationship with learning difficulties ( 5 ) . according to d.s.m iii r , expressive writing disorder is a disorder in skill learning that is characterized by weak function in writing and composing ( spelling ) ( 6 ) .
the classification of psychological disorders dsm iv points to the overlap of this disorder with educational affairs that demand composing written texts ( e.g. editing and rewriting sentences , and justified paragraphs ) and also the significant lower position of writing skills than assessed intelligence and education which is expected from a certain age ( apa , 1994 ) .
one of the well - known theories in clarifying learning disabilities is visual - motor model by getman ( 7 ) .
he focuses on motor development and believes that it 's the basis for perceptual and cognitive development .
he believes that a learning program for children could be useful when it moves them to cognitive level after passing motor and perceptual levels successfully . if these programs do not look at those levels as their basis , they would not work and learning in cognitive level remains volatile ( 2 ) .
he related most of the learning difficulties to inappropriate senso - motor development and neurological organization .
it means that children who do not correctly sense the world ( not to see or hear appropriately ) , do not have enough efficiency in human properties like intelligence , speech , etc .
; and this appropriate sensation is highly affected by performing moves such as crawling and creeping in the right time and correctly ; and simultaneous and concordant development of these moves with the five senses results in appropriate and perfect development of brain .
therefore whenever stages of nervous development have not been passed correctly and there have not been coordination and cooperation between moves and senses the individual would face learning difficulties ( 8) .
clements discusses a characteristic which is most related to minor brain damage , one of which is special learning disabilities ( reading and writing ) ( 1 ) . in taylor 's ( 9 ) view damage to motor cortex not only causes average deficiencies in motor control , but may lead to other complications like slow - wittedness and weak learning in children ( 10 ) .
sherrington has renounced that motor system is the first nervous system that develops and prepares a basis for later perceptual development ( 11 ) .
some specialists in learning disorders focus on perceptual development , delicate movements and visual - motor coordination and believe that writing is a composition of visual and motor skills in form of an integrated whole .
in fact delay in concordant development of visual - motor aspects leads to writing disability ( 12 ) .
many researchers have confirmed the important role of perceptual- motor skills in child development and announced that senso - motor skills make up the basis for mental development as are indicated in the literature briefly .
in this research ,
ewd or writing disability is one of learning disabilities that students show apparent educational weakness in dictation . in this
disorder students commit errors by misplacing letters , mistaking punctuations , reversing letters and works , and wrong spelling .
such students also commit grammatical errors in writing compositions .
assessing and analyzing the mentioned theories and studies need time and full view .
it is simplistic to accept that brain damage is the only cause of learning disorder . as in many cases
in other words , maybe interplay of various biological , psychological and socio - cultural factors play a role in formation of psychological phenomena .
another analysis is that maybe brain damage has a primary role in occurrence of learning disability and affects the function of cognitive acts , but other peripheral factors aggravate disorder and make more problems in function of psychological activities .
during last century
human s knowledge have been increased about learning disabilities , but in clarifying causes of this disabilities theme remain great shortage of information , and research in this field is going on .
the purpose of present paper is to study on these disorders with emphasis on role of senso - motor aspects and brain damage .
considering present theories and themes , we attempt to find answers to questions of is there any relationship between delayed visual - motor development and ewd and is brain damage in students with ewd more than students without ewd
participants , sample , and sampling : the type of present research is causal - comparative .
population of research is a sample of male and female students in second and third grade elementary school in karaj city .
there were 43 children ( 26 m , 17f ) in first group with ewd and second group , without ewd , had 46 students ( 27 m , 19f ) .
first of all , 4 elementary schools were chosen accidentally , then , by regular sampling , students were chosen accidentally form the list of classes ( one out of every five student ) , so that totally 77 students in second and third grade were chosen from those four elementary schools .
in second stage ,
43 students were selected who had normal intelligence ( according to intelligence tests ) and had 1.5 standard deviations lower than the mean . considering the other selection criterion which was having at least 3 mistakes in dictation , they were selected as the sample and underwent visual - motor bender - gestalt development test .
another 46 students who had relatively letter dictation scores ( considering class quizzes ) were selected as normal students without dictation problems and also underwent bender - gestalt test . for choosing them we used all elementary schools in karaj as sampling .
second and third grade teachers in every school were asked to introduce their students who have not dictation problems .
a ) visual - motor gestalt test ( 13 ) : the most important instrument used in this research is visual - motor gestalt test .
this test has been used for diagnosing brain damages , selecting children as they are ready to enter school , diagnosing reading and learning difficulties , assessing emotional problems , studying developmental disabilities , and also as a nonverbal intelligence test ( 14 ) . test reliability through test retest according to koppitz ( 15 ) system is 0.53 to 0.90 .
bender - gestalt test has been applied for two purposes in this study : first , for investigating visual - motor perception development and then for diagnosing brain damage subjects .
the scores that subjects get in bender - gestalt test according to brain damage index is based on number of errors , i.e. if the student shows four or more than four determined errors of his / her old layout in bender - gestalt test , he / she is brain damaged and the score that subject gets in bender - gestalt visual - motor test on the basis of 30 criteria of koppitz shows visual - motor perception development of subject .
b ) raven test : this test is applied in measuring individual s intelligence in three ability levels .
children 's special form is used in present research that is applied for 5 - 10 years old children .
this form can be applied either individually or collectively , but here it is applied individually to the subjects ( 16 ) .
c ) goodenough test : goodenough painting test as an intelligence test can be administered either individually or in a group and here it is administered individually .
goodenough ( 17 ) designed this test in 1926 and heris ( 18 ) revised and completed the plan .
this test is more valid and accurate in measuring intelligence in children aged 5 - 10 . in present study it is used as on auxiliary and complementary instrument .
integration index of this test with stanford - binet test is reported 0.74 ( 18 ) .
d )
wechsler test ( 1991 ) :
wechsler intelligence test for children is made of two parts : verbal and applied .
the average of internal consistency of general intelligence for 11 age groups is reported 0.96 ( 19 ) , verbal part 0.94 and practical part 0.90 conformity index has been reported to be at least 0.70 and at most 0.86 .
validity indices for verbal subtests ( 0.77 to 0.86 ) were reported to be a bit more than those of practical subtests ( 20 ) .
e ) dictation test : dictation test is a researcher made test . in present study , dictation test has helped to separate weak students form average and excellent students .
this result has gained through computing integration index between average of class scores , teachers ' assumed score , and score of administered dictation test ( synchronic validity ) .
the students , who their scores were 1.5 standard deviations below the average , were separated according to have 3 signs of dictation errors ( considering class dictation scores and administered dictation test ) and underwent the intelligence test .
formation and administration of dictation test is as follows : first , a text for dictation test is extracted from farsi text book of second and third grade elementary school , with help of experienced teachers .
numbers of words in texts for second and third grade were 136 and 126 respectively . in each test 4 or 5
words were put exactly like the words in text book , in order that weak students in dictation can be found more accurately .
first hypothesis was that , if the student has learned well about letters and spelling , he / she should be able to write words , which are similar to his / her text book and of same stems , correctly .
second hypothesis was that , one student may be weak in dictation , but he / she can write the correct spelling due to a big deal of practice , rehearsing , and continually seeing the words , then the test can not exactly indicate his / her weakness in dictation .
after primary evaluation of scores ( assessing level of difficulty , discrimination , scores distribution ) the test was administered to 77 male and female students in second and third grade elementary school .
first hypothesis : according to bender - gestalt test , visual - motor perception of students with ewd is lower than students without ewd . in order to test the hypothesis , resulted averages of the two groups ( with and without disorder ) in visual - motor perception development are compared and examined by use of student's t test for independent groups .
second hypothesis : brain damage in students with ewd is more than students without ewd . in order to compare brain damage in the two groups , with ewd and without ewd ,
yates correction formula and c test ( chi - square ) were used .
in order to compare state of visual - motor development in students with and without ewd ,
average of raw scores ( scores of bender - gestalt visual - motor development test ) ca nt be used , because tested students have various ages .
it is possible that two subjects in different ages get equal scores in bender - gestalt test while they are different in development .
in other words maybe assessment of developmental sample for each of them by considering the norm of his age group indicates an acceptable and normal development or an abnormal and delayed one .
therefore , in order to have an accurate comparison of two group s development state , and take into consideration their peers , first , bender - gestalt scores should be converted to standard z scores , then z scores should be converted to balanced t scores , in order to delete negative signs and decimal figures and have a better understanding and interpretation of z scores
average and standard deviation of visual - motor development for each group had calculated based on balanced t scores and results of statistical calculations are briefed in table 2 .
first hypothesis : according to bender - gestalt test , visual - motor perception of students with ewd is lower than students without ewd . in order to test the hypothesis , resulted averages of the two groups ( with and without disorder ) in visual - motor perception development are compared and examined by use of student's t test for independent groups .
second hypothesis : brain damage in students with ewd is more than students without ewd . in order to compare brain damage in the two groups , with ewd and without ewd ,
yates correction formula and c test ( chi - square ) were used .
in order to compare state of visual - motor development in students with and without ewd ,
average of raw scores ( scores of bender - gestalt visual - motor development test ) ca nt be used , because tested students have various ages .
it is possible that two subjects in different ages get equal scores in bender - gestalt test while they are different in development . in other words
maybe assessment of developmental sample for each of them by considering the norm of his age group indicates an acceptable and normal development or an abnormal and delayed one .
therefore , in order to have an accurate comparison of two group s development state , and take into consideration their peers , first , bender - gestalt scores should be converted to standard z scores , then z scores should be converted to balanced t scores , in order to delete negative signs and decimal figures and have a better understanding and interpretation of z scores .
average and standard deviation of visual - motor development for each group had calculated based on balanced t scores and results of statistical calculations are briefed in table 2 .
in present study , diagnosis of ewd is determined by a score at least 1.5 standard deviation below the average score in dictation test .
as indicated in table 1 , average dictate score of second grade students is 123.85 and its standard deviation is 11.02 , and average dictate score of third grade students is 116.66 and its sd is 7.94 . hence based on table 1 , those with scores 1.5 sd below the average were separated and underwent other tests .
based on fig .
1 , comparison of the two group s curves shows that :
percentile concentration curve for healthy subjects and subject with ewd in bender - gestalt test .
scores of disordered group in one percentile point is more than the healthy group in that point .
domain of the group with ewd in bender - gestalt test is more than healthy group ( 38 - 92 ) .
minimum and maximum scores in the group with ewd are more than min and max scores in healthy group .
figure 1 shows the delayed visual - motor development of students with ewd compared with normal students .
this can be understood by comparing percentages of two groups compared to the average ( score 50 based on t scale ) :
in healthy group about 78% scored below 50 and 22% scored above 50 .
as the calculated t score ( 5.15 ) is bigger than t 1% ( 2.33 ) in single domain test , the null hypothesis is rejected and it is concluded , with 99% confidence , that there is a significant difference between the compared average so it can be concluded that visual - motor perception development of students with ewd is lower than students without ewd ( p<0.01 ) .
in order to assess whether the observed frequency distribution ( brain damage ) is formed by chance or not , a c text should be applied . because the calculated c ( 2.25 ) is smaller than table c ( 3.84 ) in 5% level , the null hypothesis is not rejected and there is n't any significant difference between healthy students and those with ewd in terms of brain damage ( p>0.05 ) ( table 3,4 ) .
the first research hypothesis , saying that " students with ewd have a more delayed visual - motor development than healthy students " was confirmed , and it was concluded with 99% confidence that there is a significant difference between compared averages .
the above conclusion indicates that there is a relationship between visual - motor perception and expressive writing ability . in other words ,
this confirms that one of the effective factors in learning is quality of development in visual perception , motor activities ( general and specific ) and the coherence and coordination between them .
it is to say that those who have passed a normal process in motor development levels and have combined these movements with their perception , in appropriate time and place , are more successful in understanding things .
in fact , such individuals , by means of making secured connection between visual perception system and motor perception system and integrating these two , can rely on information received by each one in future and give meaning to them in formation .
when the individual can trust perceptional or motor system , he / she can process the information with confidence and represent it as a motor action ( like writing ) when it is necessary .
it is important to notice that writing dictation is rather an audio - motor activity than visual - motor one .
therefore , this question is raised that , what kind of relationship there can be between visual - motor development and expressive writing ?
it seems to be a sophisticated procedure , yet these two are suggested to have similar mechanisms . actually , combination of perceptional data and motor information is important in adjusting and contrasting these two kinds of received information .
generally any perceptual ( visual or auditory ) or motor activity has a complementary role in learning functionality .
it is very important that the person can attend to two subjects simultaneously and make the required coordination and coherence .
a child who can make appropriate connection between vision and movement , and has appropriate motor response to external stimuli when required , this ability can also probably be generalized to other skills such as making good connection between auditory stimuli and motor responses .
also in relation with the above mentioned problem of " how to connect two processes , visual - motor or auditory - motor " , another important subject can be explained that is " stream of adjusting two phenomena - sound and vision - or how to fit hearings and seeing " not to imagine and learn one stimulus visually and auditory at the same time can play a role in learning it . this way
the connection between seeing and hearing breaks and the child writes expressively what he hears .
therefore , there is an indirect relationship between dictation writing and visual - motor development .
another important point involving researcher 's mind is absence of relationship between dictation test scores and bender - gestalt test scores in children with ewd .
a small group of subjects got acceptable scores in bender - gestalt test in spite of their disability in dictate writing .
this indicates that some other factors are involved in creation and formation of the disorder .
that is , maybe the children who have got normal scores in bender test but are extremely weak in dictation , are more of visual encoding type than auditory , and because it is easier to learn and recall words auditory , children are unable to recall images of words by hearing .
many researches are carried out about the relationship between visual - motor development ( perceptual - motor ) and educational ability .
the results show that children , who are motor - visually developed , are more successful in education ( 15,21,22 ) .
meanwhile , malinger and longley ( 23 ) carried out a research similar to the present study in 1988 .
they administered bender - gestalt test to 20 normal kids and 20 children with learning disabilities , which was administered and scored by koppitz method .
results showed that number of errors in children with learning disability is significantly more than number of errors in normal kids .
in present study , after analyzing collected data , it was found that the number of errors in drawings made by students with ewd ( according to 30 criteria of koppitz ) is significantly more than normal students .
similar findings of different researches on this case indicate that there is a direct relationship between learning disability and visual - motor coordination .
the second hypothesis , saying that brain damage in students with ewd is more than healthy students , was rejected and the null hypothesis was confirmed .
according to the conclusion above it is understood that there is no relationship between brain damage and disability in expressive writing . in other words , students with expressive writing disability have a healthy neural system and there is no lesion in their brain .
this result is on the contrary with some theories and findings and so the research gets some ambiguities , because various theories introduce different causes for learning disorder .
others notice the attention limitation , ways of information processing , motor development and so on .
therefore , on one hand the present result is an approval to theories opposing the brain damage view , but on the other hand puts an obvious paradox in research findings . because some of the conducted researches are indicating neural signs in children with learning difficulties ( reference ( 25 ) leads to general acceptance of learning disabilities as a sort of minor brain damage ) .
hence it is difficult to make a distinct interpretation and conclusion of the present study , and the following should be taken into consideration :
scholars hold various views about diagnostic ability of bender - gestalt test in brain damage .
others believe that bender - gestalt visual - motor test does not give detailed information on damages ; it is limited to identifying major brain damage in right hemisphere and is unable to help diagnose minor brain damage and left hemisphere damages ( 26 ) . although bender considers his test a suitable instrument for diagnosing neural disorders and brain damages and believes that visual - motor perception is an integral action of the individual 's whole personality that is controlled by cerebral cortex , he suggests that it should be used with caution when it is taken as a device for diagnosis of brain damage .
things such as answering time , repeated erasing , and long hesitations should be taken into consideration as well as method of administration and marking , individual 's background evaluation , and use of neural and other specialized tests ( 27 ) .
the last point is that sometimes it is difficult to diagnose brain damage exactly as it is because both organic and functional disorders lead to mistakes in drawing test images ( 14 ) .
the present research has tried to shed light on theories of causes of learning disabilities and purify previous research findings with emphasis on role of senso - motor aspects and brain damage in these disorders .
expressive writing disorder ( ewd ) has made the basis for work . based on our findings
it could be concluded that normal children have higher visual - motor coordination compared with children with ewd .
it indicates that those who are relatively more developed than their peers , in terms of visual - motor perception , are more successful in education , especially in expressive writing .
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### Summary:
: background learning disability is one of the most noticed subjects for behavioral specialists .
most of thelearning difficulties are caused by senso - motor development and neurological organization .
the main purposeof the present research is to examine the role of delayed perceptual - motor development and brain damage inorigination of expressive writing disorder ( ewd).methods the studied sample is 89 pupils divided into two groups , one of which is pupils with expressivewriting disorder ( n=43 ) and the other is pupils without expressive writing disorder ( n=46 ) , consisted of secondand third grade elementary school students .
first of all , students with ewd are selected through dictation testand intelligence test , and then the two groups , students with and without ewd , would take the bender gestalttest .
the average score of perceptual visual - motor development and brain damage of two groups is comparedusing t test for independent groups and 2 test.results results show that there is a significant difference in perceptual visual - motor development betweenstudents with ewd and students without ewd ( p<0.01 ) . based on the results , perceptual - motor development ofstudents with ewd is lower than students without ewd .
there is no significant difference in brain damagebetween those with ewd and healthy people , ( p > 0.05).conclusionbased on our findings it could be concluded that those who are relatively more developed thantheir peers , in terms of visual - motor perception , are more successful in education , especially in expressive writing .
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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:
: successful local anesthesia is important for pain control . fear and anxiety associated with endodontic treatment
it was found that the anesthesia of mandibular molars with irreversible pulpitis was more difficult than the healthy pulps .
the reason for difficulty in pulpal anesthesia of teeth with irreversible pulpitis were described in previous studies .
however in mandibular teeth due to the thickness of buccal cortical bone buccal infiltration technique is not as effective as nerve block techniques .
pulpal anesthesia of posterior mandibular teeth with irreversible pulpitis is most frequently achieved by the inferior alveolar nerve block ( ianb ) injection technique .
the failure rate is between 44% and 81% as was described in various clinical studies . due to the failure rate of ianb
when the conventional ianb fails , supplemental injections ( with different techniques and/or types of anesthetic ) are frequently required in patients with irreversible pulpitis to achieve complete anesthesia .
supplemental techniques such as the intraosseous , intraligamentary , and infiltration injections technique have been studied to raise the anesthetic success .
the intraosseous injection requires special equipment for drilling the cortical bone and injecting the anesthetic solution thus is not a preferred technique .
. it would be useful to have results produced by these techniques be achieved with simpler options such as infiltration technique .
infiltration injection increases the success of ianb injection and is used very often as the supplemental injection technique . the present systematic review compared and evaluated the anesthetic success rates of ianb injection technique alone or along with supplemental infiltration ( si ) technique when used for pulpal anesthesia of mandibular posterior teeth with irreversible pulpitis .
the search was done in pubmed and medline ( twease ) and google search engine .
ianb and irreversible pulpitis , infiltration in mandibular teeth and irreversible pulpitis .
the search was done till march 2014 . the inclusion and exclusion criteria for selecting the studies for the systematic review were listed in table 1 .
the abstract of 159 studies were then assessed depending on the predetermined criteria , to identify 14 relevant studies and 145 studies were excluded .
the full texts of the 14 relevant studies were further analyzed and found only 6 studies were eligible , which were meeting the defined specific criteria .
the structured question was is there any difference in the anesthetic success rates of ianb injection technique used alone compared with the combination of ianb and si injection technique when used for pulpal anesthesia of mandibular teeth with irreversible pulpitis .
the pico analysis was performed where the population was represented by patients with irreversible pulpitis in posterior mandibular teeth .
the primary outcome was a percentage of successful pulpal anesthesia in the block alone or along with the si technique with the help of heft parker visual analog scale ( hp - vas ) method while performing the endodontic procedure .
hp - vas with a 170-mm line marked with various terms describing the levels of pain was used for this purpose .
the millimeter marks were removed from the scale , and the scale was divided into four categories : no pain corresponded to 0 mm ; faint , weak , or mild pain corresponded to 0 - 54 mm ; moderate
pain 55 - 114 mm ; and strong , intense , and maximum possible
study design of the included studies the list of excluded studies with reason for exclusion was shown in table 3 .
studies with reason for exclusion the comparison of percentage of patients with successful anesthesia with ianb alone and si technique ( no pain or weak / mild pain during endodontic access preparation and instrumentation ) was presented in table 4 .
the comparison of percentage of patients with successful anesthesia with ianb ( block ) and ianb and si inferior alveolar nerve block alone gave 14 - 39% success rate .
the difficulty regarding adequate pain control in the posterior region of the mandible during dental procedures has been reported .
the reduced efficacy of ianb has been associated with various factors such as the thickness of cortical bone , overlying soft tissue and accessory innervations .
success rate of ianb in an uninflamed pulp was reported to be 70% compared with 30% in patients with irreversible pulpitis .
it was also reported that the failure of local anesthesia in patients with irreversible pulpitis was found to be 8 times more with respect to normal patients .
thus , the present study was undertaken to compare the success rates of ianb alone or along with the si technique in irreversible pulpitis .
first , the inflamed tissue has a lowered ph as a result of which the amount of the base form of the anesthetic required to go through the nerve sheath and membrane has reduced .
this leads to decreased ionized form of the anesthetic within the nerve with resultant decreased anesthesia .
second , altered resting potentials and lowered thresholds of excitability of the nerves in the inflamed tissue . as a result of lowered threshold of excitability of these nerves ,
third , there were anesthetic resistant sodium channels and upregulation of sodium channels in pulp with irreversible pulpitis .
the patients in the included studies of the review were actively experiencing pain in mandibular posterior teeth and were diagnosed with irreversible pulpitis .
the subject was asked to rate the pain before the treatment and during the treatment using a hp - vas .
profound lip numbness was the subjective criteria selected for the inclusion of the subjects in all the studies .
lip numbness was used as subjective criteria for the inclusion of the subjects in the study .
it should be noted that all the patients included in the study had subjective symptoms of lip numbness , but the anesthesia was not successful in all cases .
patient 's age , gender , posterior tooth type , initial pain in the included studies were not significantly different between the two groups .
furthermore , patients included were not premedicated , had no systemic conditions such as diabetes , heart disease , high blood pressure .
therefore , it can be assumed that the results of this study are not affected by these factors as a result of which the two groups can be compared on their respective anesthetic success . in all the selected studies , anesthetic response of the patient
was taken 15 min after ianb and 5 min after the si as this time period was previously reported to obtain complete anesthesia .
the hp - vas was used in the included studies to rate the pain to measure the degree of pulpal anesthesia .
however , two methods have been used to assess the efficacy of local anesthetic injections in previous studies .
some investigators have used pulp sensibility tests such as electric pulp tester ( ept ) or the cold test , whereas others have used the hp - vas .
hp - vas was selected in the inclusion criteria of the review for measuring pain level .
found in their study that 42% of the patient who received anesthesia despite giving a negative response to ept experienced pain during treatment .
various methods have been used for assessing pulpal anesthesia bjorn was the first to correlate a negative response to the maximum output of electrical pulp stimulation to painless dental treatment . however , negative response to ept does not produce profound anesthesia . also , lip numbness is not the indication of pulpal anesthesia .
therefore , the preparation of access cavity and extirpation of pulp was used to measure effectively the success of pulpal anesthesia using hp - vas .
randomization of patients in the two groups and blinding of the anesthetic agent was performed to eliminate any bias .
the anesthetic success was clinically evident with si injection technique as compared to ianb injection technique , but was not statistically significant in the studies .
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### Summary:
: aim : to systematically review the anesthetic success rates of inferior alveolar nerve block ( ianb ) injection technique alone with that of combination of ianb and supplemental infiltration ( si ) technique when used for pulpal anesthesia of mandibular posterior teeth with irreversible pulpitis during endodontic treatment.settings and design : the study follows a longitudinal study design involving original research.materials and methods : electronic databases were systematically searched for randomized controlled clinical studies .
studies were selected by predefined inclusion and exclusion criteria.statistical analysis used and result : the statistical analysis used was based on the results of the original research .
all the included studies showed that there is the difference in the values comparing the two techniques , but the data are not statistically significantly different.conclusion:based on this review , the better anesthetic efficacy of the si was observed .
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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:
: sometimes , pathogens may reach the bone directly during a neurosurgical operation , e.g. lumbar discectomy .
rarely , vertebral discitis is reported as a complication of laparoscopic operations with fixating sutures on the promontory .
three weeks later , she presented with increasing back pain without neurological signs and symptoms or fever .
due to elevated c - reactive protein ( crp ) , a deep - seated surgical site infection was suspected .
computed tomography ( ct ) scan and magnetic resonance imaging ( mri ) of the pelvis were normal besides presacral seroma .
however , one of four blood culture bottles was positive with pseudomonas aeruginosa and the patient was treated with piperacillin / tazobactam for 14 days .
three months after the initial operation , the patient presented with severe back pain radiating to both legs .
the lower lumbar spine was highly tender on percussion , but the neurologic examination revealed only a slight loss of muscle strength in the big right toe .
the mri of the spine now revealed vertebral discitis without epidural abscess formation ( fig . 1 ) .
culture of ct - guided needle biopsy was positive with p. aeruginosa and antibiotic therapy with 6 1 g ceftazidime i.v . per day
the loss of muscle strength in the big right toe persisted and was interpreted as stenosis of right s5 foramina due to infective destruction which did not require neurosurgical decompression .
it is also possible that after the operation the presacral seroma was not the primary infectious site but got infected during the pseudomonas sepsis .
spinal tuberculosis and brucellosis mainly occur in endemic areas , but should also be suspected in migrants .
most patients present with back pain , but motor weakness and sensory changes are only found in a minority .
a high level of suspicion is required in patients with opioid - dependent back pain and an unexplained inflammatory response .
leucocyte counts may be elevated or normal , whereas crp levels are increased in 58 to 82% of patients .
if a vertebral discitis is suspected , an mri of the affected area should be performed .
this is the gold standard with sensitivity , specificity and accuracy of 96 , 92 and 94% , respectively . typically , mri shows decreased signal intensity of vertebral bodies in t1-weighted images and increased disc signal intensity in t2-weighted images
. however , mri may be negative early in the disease course and should be repeated after 714 days if the diagnosis is still likely . in the absence of positive blood cultures with a typical microorganism ct - guided biopsy for microbiology and histology
if microbiological culture of a representative biopsy remains negative for > 5 days , broad spectrum bacterial dna amplification may help to identify a causative microorganism , particularly if antibiotics had been administered before biopsy . if empirical therapy is needed before the availability of first microbiologic results , the choice of antimicrobials is dependent on likely pathogens , individual patient history and local resistance patterns .
however , intravenous therapy with high doses of antimicrobials sufficiently covering staphylococci and other gram - positive bacteria are the first priority to rapidly reach bactericidal drug levels in bone , disc and epidural space . in regions and/or situations with a low pre - test probability for mrsa
empirical treatment for gram - negative bacteria including pseudomonas is usually reserved for patients with additional risk factors .
the switch to oral therapy depends on oral bioavailability , drug susceptibility , individual patient parameters and on a good clinical response .
blood counts , liver and kidney function tests should be used to guide optimal dosage and monitor adverse events of prolonged and high - dose antimicrobial therapy .
routine follow - up imaging is not recommended unless disease progression or treatment failure is suspected based on clinical and laboratory assessment .
surgical debridement is usually needed in the case of epidural abscess formation or disease progression despite adequate antimicrobial therapy .
a review of the literature in medline revealed only a few case reports of vertebral discitis after fixation on the promontory .
a fixation on the promontory can be a trauma of the spine leading to a locus of minor resistance to subsequent infection .
only straight forward diagnostic followed by a consequent therapy can avoid unnecessary postoperative morbidity by persistent neurological deficits because of this rare complication .
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### Summary:
: vertebral discitis usually arises from haematogenous spread of pathogens to the discs and bones .
vertebral discitis can rarely occur as a complication after laparoscopic operations with fixating sutures on the promontory .
we report the case of an 81-year - old woman who underwent a laparoscopic resection rectopexy because of rectal prolapse .
weeks after the operation , the patient developed lower back pain with radiation to both legs not responding to symptomatic therapy .
two months later , a magnetic resonance imaging of the lumbar spine showed vertebral osteomyelitis and discitis .
a fixation on the promontory may be sufficiently traumatic to the spine to pave the way for subsequent infection .
a high index of suspicion should be raised in patients with persistent , severe back pain .
anamnesis , imageing and an adequate specimen from the affected area for microbiological analysis are crucial for timely diagnosis and appropriate management involving targeted and prolonged antimicrobial 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:
: dental study models are essential records for orthodontic diagnosis , planning , and treatment evaluations .
however , the plaster models are prone to damage and loss , require storage space , and are inefficient in terms of retrieval and transfer .
recent advances in digital technology have led to the replacement of the plaster casts with digital models to eliminate the drawbacks of plaster models.1 the most popular method of fabricating digital dental models is optical or laser scanning of a plaster cast obtained from an alginate impression .
more recently , direct scanning of alginate impressions using cone - beam computed tomography ( cbct ) has been introduced to eliminate the need for plaster pouring .
their results proved that the cbct technique is accurate enough for the measurements in orthodontic diagnosis .
naidu et al.2 reported that tooth width measurements from digital models obtained by cbct scanning of alginate impressions were as reproducible as those obtained from plaster models with calipers .
white et al.3 studied 16 sets of maxillary and mandibular vinylpolysiloxane and alginate impressions that were converted into cbct scanned dental models to evaluate the accuracy of intra- and interarch measurements .
the results indicated that digital orthodontic models obtained from cbct scanning of both alginate and vinylpolysiloxane impressions provided dimensionally accurate representations of intra - arch relationships for orthodontic evaluation .
wiranto et al.4 assessed the validity of digital models obtained from the cbct scanning of alginate impressions in tooth width measurements in 22 subjects , and concluded that tooth - width measurements on digital models did not differ significantly from those on plaster models .
although all these studies showed the validity of cbct scanning of alginate impressions , the impressions were sent to the laboratory for the scan .
all these studies used digimodel ( orthoproofusa , albuquerque , nm , usa ) , which is currently the main provider of this service .
orthoproof uses an industrial cbct to digitize alginate impressions.234 however , with the recent popularity of dental cbct , many practitioners now have access to cbct scanners in clinics , negating the need to send impressions to a remote laboratory .
no published study has evaluated the accuracy of digital dental models obtained from a dental cbct scanner . on the other hand , another new alternative for digital dental model fabrication
is direct scanning of the dentition with an intraoral scanner.5678 however , the validity of the intraoral scan data has not yet achieved consensus among professionals , particularly when they are scanned in vivo , whereas scanning plaster models in vitro shows relatively reliable accuracy.9 furthermore , this system still requires a long duration to scan the entire dentition , although some research has demonstrated a reduction in scanning time.10 a recent study8 assessing the time and patient acceptance of an intraoral scanner concluded that alginate impressions are still the preferred method with respect to chair time and patient acceptance . in cases where successive laboratory work using an actual dental model , such as fabrication of indirect bonding trays , is needed
, additional three - dimensional ( 3d ) printing should be performed to create a physical model from virtual images . however , with cbct scanning of the alginate impression , both the digital model and actual plaster cast can be obtained from a single impression , which results in a marked reduction in clinical workload .
in addition , there is no need to use an extended - pour alginate material when impressions are scanned using the cbct scanners in clinics . regarding the accuracy of digital dental models , few studies dealt with the models made from traditional alginate materials .
torassian et al.11 used traditional alginates together with alginate substitute materials in a study assessing the dimensional accuracy of digital models . in their study , the impressions for each material were taken and sent to the laboratory for digital model fabrication 72 hours later .
the results showed that digital models were significantly smaller in all dimensions compared with plaster models .
although significant changes were found in the impressions , the authors could not evaluate when the change occurred within the experimental time period because the impressions were sent to the laboratory for the scan .
no published study has evaluated the dimensional accuracy of digital models on a consecutive hourly basis after the impression was taken .
the purpose of this study was to investigate the dimensional accuracy of a digital dental model obtained from a cbct scan of alginate impressions according to the time elapse .
twenty adults ( 8 men and 12 women ; mean age , 26.5 years ) with normal occlusion and no missing teeth were enrolled in the study . all subjects provided informed consent to participate in this study .
three different alginate impression materials were selected including two traditional alginates and one extended - pour alginate : 1 ) alginoplast ( heraeus kulzer gmbh , hanau , germany ) , 2 ) cavex impressional ( cavex holland bv , haarlem , the netherlands ) , and 3 ) cavex colorchange ( cavex holland bv ) .
cavex colorchange was used as the extended - pour alginate material . after mixing the 3 types of alginate impression materials according to their respective manufacturer 's instructions , maxillary impressions of each subject
were taken using a plastic impression tray ( president impression tray system ; coltene / whaledent ag , altstatten , switzerland ) .
any impurities and saliva were rinsed away under running water and excess material beyond the impression tray was trimmed without damaging the cervical areas of the dentition . with a gentle air blow , water collected on the surface of the impression was removed .
each obtained impression was then stored in a room that reflected an ordinary clinical situation where the temperature ranged from 16 to 21 and humidity ranged from 45% to 55% relative humidity ( rh ) without any sealing device .
each alginate impression was scanned with a cbct scanner ( alphard vega ; asahi roentgen ind .
co. , kyoto , japan ) immediately after taking the impression , and after 1 , 2 , 3 , 4 , 5 , and 6 hours under the following conditions : 80 kv ; 5 ma ; voxel size , 0.2 0.2 0.2 mm ; field of view ( fov ) , 102 102 mm .
the reason why the scanning time was extended up to 6 hours was that the extended - pour alginate material was used together with the traditional alginates .
the data scanned immediately after taking the impression , which was obtained within 5 minutes after impressions , were used as controls in this study .
the digital imaging and communications in medicine ( dicom ) file obtained from the cbct was reconstructed into 3d images and then converted to stereolithography ( stl ) format using v - works program ( version 4.0 ; cybermed , seoul , korea ) with application of identical hounsfield unit ( -175 ) to each image .
then , the images were imported into a 3d reverse engineering software program ( rapidform2006 ; inus , seoul , korea ) .
the negative of the alginate impression image was transformed to a positive image by using the reverse normal function in the program ( figure 1 ) .
using the image scanned immediately after impression taking as the reference image , all images taken according to the time elapse were reoriented to obtain a consistent 3d orientation using the surface registration function of the program .
three linear measurements were made on each digital model with the use of rapidform 2006 software in three dimensions : anterior - posterior , transverse , and vertical .
the anterior - posterior dimension was evaluated by measuring the incisor to molar from the mesiobuccal cusp tip of the upper right first molar to the maxillary midline .
the transverse dimension was measured using the intermolar width , the line between the mesiobuccal cusp tip of the upper right first molar and the same point on the upper left first molar .
the vertical dimension was evaluated using the incisor height , which was measured from the incisal edge at the midline of the maxillary right central incisor to the gingival margin ( figure 2 ) . in order to assess the measurement errors ,
20 images were selected randomly , and the measurements were obtained twice at an interval of two weeks by an examiner .
the method errors of double registration of all the measurements were calculated using the dahlberg 's formula.12 the results were as follows : 0.29 mm for the incisor to molar , 0.29 mm for the intermolar width , and 0.27 mm for the incisor height .
in addition , intraclass correlation coefficients ( icc ) were evaluated using a two - way mixed - effects model with absolute agreement to evaluate the reliability of intra - examiner measurements .
the icc values for the 3 linear measurements according to the time elapse were 85% to 95% .
the means and standard deviations of the actual measurements were calculated for each material and for each time period .
pair - wise comparisons were carried out using the t - test to identify differences between the control and each digital model according to elapsed time .
the means and standard deviations of changes in measurements according to the time elapse were calculated .
the changes within the measurement error ( 0.29 mm for the incisor to molar , 0.29 mm for the intermolar width , and 0.27 mm for the incisor height ) were regarded as clinically acceptable in this study .
the changes within the measurement error were assessed to evaluate the time point at which clinically relevant differences began to appear .
differences in the measurement change between the materials were also evaluated within the setting time .
all statistical analyses were carried out using the ibm spss statistics software ( version 20.0 ; ibm co. , armonk , ny , usa ) .
in order to assess the measurement errors , 20 images were selected randomly , and the measurements were obtained twice at an interval of two weeks by an examiner .
the method errors of double registration of all the measurements were calculated using the dahlberg 's formula.12 the results were as follows : 0.29 mm for the incisor to molar , 0.29 mm for the intermolar width , and 0.27 mm for the incisor height .
in addition , intraclass correlation coefficients ( icc ) were evaluated using a two - way mixed - effects model with absolute agreement to evaluate the reliability of intra - examiner measurements .
the icc values for the 3 linear measurements according to the time elapse were 85% to 95% .
the means and standard deviations of the actual measurements were calculated for each material and for each time period .
pair - wise comparisons were carried out using the t - test to identify differences between the control and each digital model according to elapsed time .
the means and standard deviations of changes in measurements according to the time elapse were calculated . the changes within the measurement error ( 0.29 mm for the incisor to molar , 0.29 mm for the intermolar width , and 0.27 mm for the incisor height ) were regarded as clinically acceptable in this study .
the changes within the measurement error were assessed to evaluate the time point at which clinically relevant differences began to appear .
differences in the measurement change between the materials were also evaluated within the setting time .
all statistical analyses were carried out using the ibm spss statistics software ( version 20.0 ; ibm co. , armonk , ny , usa ) .
the means and standard deviations of the measurements for each material and each elapsed time are presented in table 1 .
all measurements showed a decreasing tendency with an increase in the elapsed time after the impression .
the comparison of each image obtained at different elapsed times with the control showed no statistically significant differences at the time point of 1 hour .
statistically significant differences began to appear from the time point of 2 hours after the impression in all three materials ( table 1 ) .
cavex colorchange , which is an extended - pour alginate material , exhibited a less severe decreasing tendency than the other two traditional alginates .
however , there were no statistically significant differences between the materials within the setting time .
only descriptive statistics was used in table 2 . in the evaluation of the difference in measurements based on the measurement errors
( 0.29 mm for the incisor to molar and the intermolar width , and 0.27 mm for the incisor height ) , the changes were found to exceed the measurement error between the time points of 3 and 4 hours after the impression ( figure 3 , table 2 ) .
current clinical orthodontic practices are becoming more dependent on digital records including radiographs , clinical photographs and dental models .
the use of a digital dental model is particularly advantageous considering the storage space required for traditional plaster casts and the ease of retrieval.13 the most popular way to obtain a digital dental model is to have it created at a laboratory that provides commercial digitizing service .
diagnostic impressions of the patient 's dentition are mailed to the company , and the impressions are scanned using various technologies unique to the company .
some companies produce digital orthodontic dental models by laser scanning or cbct imaging of plaster models ( orthocad by cadent , carlstadt , nj , usa ; emodel by geodigm , chanhassen , mn , usa ) . to use these systems , practitioners are required to fabricate plaster dental models from alginate impressions and send them to the company . during transportation , plaster models are not only inaccessible but also subject to loss and fracture .
other companies use cbct scanning of dental impressions to produce digital dental models ( digimodel by orthoproofusa , albuquerque , nm , usa ) .
however , a drawback of this system is that additional 3d printing needs to be performed to produce a physical model from virtual images in cases where successive laboratory work is needed , such as in the fabrication of indirect bonding trays .
the dimensional stability of traditional alginate material is the main concern when shipping alginate impressions to a distant laboratory is required , since the duration between taking the impression and cbct scanning is 2 to 3 days.14 to overcome the dimensional instability of traditional alginates , manufacturers have invented new extended - pour alginate impression materials , and claim that these new alginates are dimensionally stable for up to several days . in addition , digital model providers recommend using either a vinylpolysiloxane material or at least an extended - pour alginate material while traditional alginates are generally used in orthodontic clinics .
the present study used a common cbct scanner which is becoming more widely available in clinics and enabled the use of traditional alginate materials , as shipment to a laboratory was not required .
the present study used 3 different alginate materials , including two commonly used traditional alginate materials and an extended - pour alginate material , cavex colorchange .
some previous studies have validated the dimensional stability of extended - pour alginate materials.1516 in this study , however , the alginate impressions were not stored under ideal conditions such as in 100% humidity , which is recommended by most manufacturers . in a clinical situation ,
plaster pouring or the scanning of impressions can be delayed under ambient conditions , and few studies investigating the effects of ambient storage conditions have been performed .
therefore , the present study aimed to evaluate dimensional changes in alginate impressions made using both traditional and extended - pour alginates under ambient conditions .
as expected , the results of the present study showed a gradual decrease in the measurement values in all dimensions within the setting time , indicating that the alginate materials underwent shrinkage over time .
a similar study was performed by todd et al.17 in which two extended - pour alginates ( kromopan ; lascod , florence , italy ; and triphasix ; parkell , edgewood , ny , usa ) , two traditional alginates ( jeltrate ; dentsply - caulk , york , pa , usa ; and kromatica ; matech , sylmar , ca , usa ) , and one vinylpolysiloxane ( vp mix ; henry schein , melville , ny , usa ) were studied to evaluate the dimensional accuracy of the impression materials . the distance between score lines on the impressions
the authors concluded that all alginate impression materials in their study exhibited significant changes at 24 and 100 hours .
our study focused more on identifying the precise time point at which actual dimensional changes began to occur , especially when placed under ambient conditions .
the results of the present study showed that a statistically significant difference was not observed for 1 hour and a difference was observed from 2 hours after the impression .
this confirmed that impressions should be scanned as soon as possible after being obtained to provide dimensional accuracy when the impressions are not stored under special conditions . on the other hand , it is interesting to note that there were no significant differences among the materials . the extended - pour alginate material did not show a statistically significant difference from the other two traditional alginates although decreasing tendency with increased elapsed time was less with the extended - pour alginate .
this indicates that the use of extended - pour alginate material is meaningless under ambient conditions although it might be effective under special conditions such as 100% humidity . in the present study , to identify the time point at which clinically relevant differences begin to appear , the changes within the measurement error were regarded as clinically acceptable .
the findings revealed that the changes exceeding the measurement error occurred between the time points of 3 and 4 hours after the impression .
the results suggest that if a cbct scan of alginate impressions is planned for the production of a digital dental model , the impressions should be scanned immediately after the impression or at least within 2 to 3 hours . on the other hand
, it should be noted that all experiments were performed under ambient conditions in this study .
this indicates that special storage conditions might not be critical if the impressions are scanned within 2 to 3 hours . in clinics equipped with cbct scanners ,
alginate impressions can be scanned first to create a digital model , followed by plaster pouring to obtain a physical model for successive laboratory work .
this workflow strategy will significantly reduce the time and cost previously required to send impressions or plaster models to a remote laboratory .
the present study evaluated the dimensional accuracy of digital dental models obtained from cbct scan of alginate impressions according to the time elapsed after impressions were taken .
each image obtained at a different elapsed time after impression taking was compared with an image scanned immediately after impression taking . the dimensional accuracy observed in this study
does not necessarily mean that the digital dental models obtained in this study are accurate or detailed enough because inaccuracy might also result from many other procedures , such as impression taking .
in addition , the scanned image obtained immediately after impression can not be a perfect gold standard because it was scanned after a lapse of 5 minutes .
on the other hand , the study evaluated dimensional changes in alginate impressions under ambient conditions .
further research is needed to evaluate time - related changes in alginate impressions stored under ideal conditions , such as in 100% humidity .
the results of this study indicate that digital dental models can be obtained simply from a cbct scan of alginate impressions without sending them to a remote laboratory .
however , the impressions should be scanned immediately or at least within 2 to 3 hours after impression taking to provide dimensional accuracy when the impressions are not stored under special conditions .
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### Summary:
: objectiveto investigate the dimensional accuracy of digital dental models obtained from the dental cone - beam computed tomography ( cbct ) scan of alginate impressions according to the time elapse when the impressions are stored under ambient conditions.methodsalginate impressions were obtained from 20 adults using 3 different alginate materials , 2 traditional alginate materials ( alginoplast and cavex impressional ) and 1 extended - pour alginate material ( cavex colorchange ) .
the impressions were stored under ambient conditions , and scanned by cbct immediately after the impressions were taken , and then at 1 hour intervals for 6 hours . after reconstructing three - dimensional digital dental models ,
the models were measured and the data were analyzed to determine dimensional changes according to the elapsed time .
the changes within the measurement error were regarded as clinically acceptable in this study.resultsall measurements showed a decreasing tendency with an increase in the elapsed time after the impressions .
although the extended - pour alginate exhibited a less decreasing tendency than the other 2 materials , there were no statistically significant differences between the materials .
changes above the measurement error occurred between the time points of 3 and 4 hours after the impressions.conclusionsthe results of this study indicate that digital dental models can be obtained simply from a cbct scan of alginate impressions without sending them to a remote laboratory .
however , when the impressions are not stored under special conditions , they should be scanned immediately , or at least within 2 to 3 hours after the impressions are taken .
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great majority of compounds synthesized by chemists exist at
room temperature as solids , often in crystal form .
crystallization
itself can be a challenging part of the synthetic process , further
complicated by polymorphs ( the existence of multiple crystal structures
of a given compound ) , impurities , or the desire for crystals with
particular structural properties .
the
physical properties of an organic molecular crystal must derive in
part not only from those of its constituent molecules but also by
the arrangement of molecules in a crystal and the intermolecular interactions
that either drive , or result from , a particular crystal packing .
many
of the molecules which the chemist is interested in synthesizing are
chosen due to their solid - state properties , such as in the fields
of organic semiconductors , pigments , and porous molecular materials .
the selection and control of solid form is also vitally important
in developing pharmaceutical molecules into tablets with satisfactory
stability and bioavailability ; the issues raised by polymorphism in
pharmaceutical chemistry have been characterized extensively .
a large proportion of organic molecules is known
to be polymorphic , although the relationship
between molecular characteristics and the existence of polymorphs
is unclear . for the above reasons ,
the importance of characterizing
the crystal
structure is key to rationalizing many properties .
many tools used
to probe the molecular structure , such as x - ray diffraction , solid
state nmr , or those of solid - state spectroscopy , are sensitive to the local and long - range structure of a molecule
within the crystal . from a theoretical perspective , the prediction
of crystal structures ab initio is a natural challenge
to theoretical and computational chemists and has valuable applications
in characterizing the landscape of possible crystal structures available
to a given molecule
. this challenge has drawn a community of researchers
who seek to solve these structures from limited initial data and preferably
from just the two - dimensional chemical diagram of the molecular structure .
the progress that has been made by this community is clear from
published studies on large and flexible molecules and can be tracked in a series of collaborative exercises in which
active members of the field have been challenged to predict the structures
of unpublished crystals .
these blind
tests of crystal structure prediction ( csp ) attempt to benchmark
the successes and limitations of the different contemporary approaches ,
the progress that has been made , and that which is still required . a fundamental concept in our approach to csp is to represent the
internal potential energy of a crystal structure as a function of
the intra- and intermolecular coordinates , where the intramolecular
structure , energy , and properties are calculated using quantum chemical
methods , and intermolecular interactions are calculated using anisotropic
atom atom potentials .
although
research in our group into methods for efficiently handling molecular
flexibility , and for the calculation of free - energies , is active , this paper is concerned with characterizing
the potential energy surface describing the crystal packing of rigid
molecules .
thus , our configurational space is the union of the coordinates
which describe the positions and orientations of the molecules in
the crystal s asymmetric unit and the degrees of freedom which
determine the unit cell .
our potential energy surface ( pes ) , which
is a function of these variables , is a force field which comprises
an exp-6 model of short - range and dispersion interactions combined
with an atomic multipole electrostatic model derived from single molecule
dft calculations .
we seek to characterize the resulting lattice energy
surface by reliably locating and ranking all local minima within a
certain energy of the global minimum .
each local minimum on the lattice
energy surface could represent an observable polymorph of the molecule
in question .
efforts toward improving our ability to predict
crystal structures
largely focus on either the evaluation of more accurate lattice energies
or the challenge of locating all possible structures through sampling
of the pes .
the problem of sampling phase space is the chief concern
of this paper , and we describe methods that have been implemented
in our global lattice energy explorer ( glee ) software which
is described herein .
each minimum on the pes will have an associated
basin within which any structure will , when relaxed using local lattice
energy minimization , be reached .
the structure generator outlined
here seeks to sample trial structures such that all local minima are
located during the minimization step .
we take an approach of ensuring
as diverse a sampling as possible , because we are not only interested
in the structure corresponding to the global lattice energy minimum
but rather the entire
, the landscape
should be sampled as completely as possible within the energy range
of expected polymorphism .
recent calculations on over 1000 crystal
structures of known polymorphs show that , while the majority of polymorphs
are separated by less than 2 kj mol , occasional
pairs of known polymorphs differ by 10 or more kj mol .
the number of distinct crystal packing
alternatives within such an energy window above the global minimum
usually amounts to many 10s and very frequently over 100 distinct
crystal structures for small organic molecules . in the class of crystals which can support inclusion compounds
,
it may be that the structures which are higher in energy , and less
perfectly packed from a purely energetic point of view , are the most
interesting . a focus on too small a set
of structures at , or around
, the global lattice energy minimimum would
be to risk losing the richness of the landscape and potential solid
form diversity of a molecule , which must be considered in developing
a molecule into a useful material .
alternative approaches to
crystal structure generation which have
been applied to molecular crystals include simulated annealing and more sophisticated variants of monte carlo searches and genetic algorithms , as well as the early pioneering csp studies using purely random
or grid searches .
in fact , these simplest methods have been remarkably
successful , consistently performing well in the structure searching
aspect of the blind tests of csp .
we follow
previous groups who favor low - discrepancy , quasi - random sampling , as we require an algorithm that samples the phase - space completely
and efficiently .
quasi - random sequences have attractive properties
for locating local minima ; in particular , at each step in the sequence
the configurational space is as uniformly sampled as possible . unlike
a deterministic method such as a grid - based search , the convergence
of the search can be continuously monitored and extended until one
is suitably confident that all relevant local energy minima have been
sampled .
the problems of structure generation and lattice energy minimization
can be programmed in this way to make full use of the computational
resources available to us , to require very few pieces of input information ,
and to be repeatable .
chemical diagrams of the three molecules studied here :
a ) artemisinin ,
b ) quinacridone , and c ) cc1 .
the purpose here is to describe our implementation of a quasi - random
search , whose use has already been demonstrated in studies of mechanochemical
reactions and cocrystal formation , as well as to investigate and optimize the performance
of our algorithm .
while quasi - random csp methods have been extensively
applied to csp , there have been few detailed studies of the performance
of such a search . for the purposes of this study
, we follow the convergence
of finding a complete set of possible low energy crystal structures
for three molecular systems .
we investigate the coverage of packing
space as a function of the number of trial structures that have been
generated and lattice energy minimized and the influence of modifying
the volume available to the molecule during the structure generation .
we also describe the use of the separating axis theorem to relieve
molecular clashes in generated structures , in place of rejection .
the three molecules studied , artemisinin , quinacridone , and an
organic cage ( figure 1 ) , were chosen for diversity in molecular characteristics , in terms
of shape and intermolecular interactions , and from three areas where
csp has found applications .
artemisinin , whose discovery was honored
by the 2015 nobel prize in medicine , is a drug used in the treatment
of malaria and , potentially , cancer .
quinacridone finds use in the pigment and semiconductor
industries and has known polymorphism .
the third molecule investigated , hereafter referred to as cc1 , is
one of a series of porous organic cages that we have studied previously
using simulated annealing ; these cages are of
interest as solution processable porous materials , and cc1 has the
interesting behavior of switching between porous and nonporous polymorphs .
these three molecules not only exemplify the
relevance of csp in various application areas but also test and demonstrate
the performance of the glee code in cases with a range of
known experimental polymorphs , molecular geometries , and intermolecular
interactions .
for rigid
molecules , the process of csp involves the following
general steps : ( i ) molecular geometry optimization ; ( ii ) trial crystal
structure generation ; and ( iii ) local lattice energy minimization
of trial structures .
clustering of structures is performed after their
lattice energy minimization to remove duplicates and assess the completeness
of the search .
all calculations presented here are performed
with rigid molecular
geometries after step ( i ) , taken from isolated molecule geometry optimization
using the b3lyp functional with a 6 - 311 g * * basis set within the gaussian09
software .
our sampling of the crystal packing configurational
space is based on quasi - random , low - discrepancy sequences generated
by the sobol method , in a similar manner
to della valle and co - workers and pantelides
and adjiman .
the present study is restricted
to rigid molecules , for which the molecular geometry is kept fixed
throughout the generation and optimization of crystal structures .
in this approximation ,
each independent molecule in the asymmetric
unit requires three parameters to determine its position and three
for its orientation .
the values of a further x ( x = 16 ) parameters must be generated in order to
specify the internal angles and lengths of the unit cell parallelepiped : x = 6 in the case of a triclinic cell , although fewer for
lattices with restrictions on cell lengths and angles .
each parameter , pi , is associated with a quasi - random
number , xi [ 0,1 ) ,
although , as is discussed below , not all parameters are determined
independently of each other .
the mapping
from three random numbers
to the three positions of a molecule s centroid is trivial .
each number , xi , is taken
as a position in fractional coordinates along a particular cell axis .
to keep the method general ,
we include translation along all three
lattice vectors in all space groups , regardless of whether the energy
is invariant to particular translations in certain space groups .
molecular
orientations relative to the global axis frame are sampled using the
quaternion based shoemake method , which
has previously , for example , been used in the generation of molecular
dimers .
the positions and orientations
of all molecules in the unit cell are then generated by applying space
group symmetry operators to the asymmetric unit .
each unit cell angle , j , that is not constrained by space group
symmetry is sampled to give an even distribution in cos(j ) according to1with n = 2 and , and xi is the relevant element of
the sobol vector .
this choice samples
the range from to with a probability density that is highest
at its center of .
the function
used to sample cell angles
was chosen to provide a balance between sampling a spread of angles
and avoiding problematic representations of structures .
it is not
generally the case that a particular crystal structure has a unique
choice of lattice vectors . in triclinic and monoclinic systems ,
many
options for the unit cell have very acute or obtuse angles , which
are computationally awkward and inefficient to lattice energy minimize .
the chosen range for cell angles will not exclude any structures but
attempts to only generate versions of structures without flat unit
cells .
it is only at the stage of selecting bounds for the cell
lengths that our algorithm includes specific information pertaining
to the individual system .
our sampling is influenced by the box
model of pidcock and motherwell , which established relationships between molecular dimensions and
unit cell lengths .
we establish a target volume for the unit cell
as the sum of the volumes of all molecules in the unit cell , multiplied
by a constant , henceforth referred to as the target volume parameter
( tvp ) .
tvp takes a default value of 1.0 but is varied in a later section
of this paper to investigate its influence on the performance of the
method .
the molecular volume is calculated as that of a box chosen
to enclose all of its atoms .
this box is defined by calculating the
axes of inertia of each molecule and finding the maximum and minimum
value of the projection of each of its atomic coordinates onto these
axes , including standard van der waals radii for each atom . in this section ,
the difference between the maximum
and minimum value of the projections of atomic coordinates , with an
appropriate consideration of each atom s van der waals radius ,
will be referred to as the molecule s shadow
onto that axis . as a measure of the volume of the molecule , the product
of these three shadows onto the molecule s axes of inertia
would be an overestimate when compared to a more usual measure of
volume based on atomic volumes or the molecular van der waals surface .
however , when generating crystal structures we expect to start with
a larger volume before allowing the cell to contract under intermolecular
forces at a later stage of the process . molecular projections
onto lattice vectors , used to define the
sampling range for unit cell lengths .
the directions of the three
lattice vectors , l1,2,3 , are shown , and
the molecular projections of two quinacridone molecules are shown
onto lattice vector l2 .
thin lines show
the projection of the edges of the van der waals radii of each atom
onto the lattice vector .
bold red and blue lines show the molecular
shadows onto l2 . in this example , s2min = 9.13 and s2max = 9.57 .
the bounds of the three
cell lengths can be calculated by considering
this target volume and also the projections of the atomic positions
onto the lattice vectors .
given that the unit cell angles have been
determined , we are able to fix the direction of each unit cell vector
in a global axis frame and can calculate the shadow of each lattice
vector onto each of our global axes .
we must consider separately all
molecules in the unit cell that differ by rotation and find the maximal
and minimal values of molecular projection on each cell vector , j , which we denote sjmax and sjmin , respectively
( figure 2 ) .
to sample
a physically realistic range of cell lengths , we choose the length
of the first unit cell vector in the range from c sjmin to c n sjmax , where n is the number of molecules
in the unit cell , and c is a constant used to scale
the entire range:2 the constant c is fixed at 0.75 in this study ,
reflecting the fact that molecular dimensions can extend past the
length of unit cell dimensions . the second
unit cell length is sampled in the same manner , using projections
of the molecular dimensions onto the direction of the second vector
and taking the next element of the sobol vector to sample the relevant
range .
the third ( final ) cell length is chosen to give a normal distribution
of cell volumes , whose mean is the target volume described above .
thus , the next element of the sobol vector samples a normal distribution
with a standard deviation of 0.15 sjmin , which we find yields a reasonable distribution of volumes .
the only cases where this sampling of unit cell lengths is altered
are ( i ) when n =
1 , where sjmax is increased
by 50% to ensure a spread of unit cell lengths is sampled and ( ii )
in crystal systems that place restrictions on cell lengths , where
fewer independent unit cell lengths must be determined .
we also cycle
through the permutations of possible orderings in which the cell lengths
could be assigned , so as to avoid any possible systematic bias . before
the crystal structure s parameters are optimized with
respect to the lattice energy , unphysical structures , particularly
those in which molecules overlap ,
, the convex hull of the molecule is calculated , and the separating axis theorem is employed to calculate the overlap it has with its neighbors .
the molecule s convex hull is a polytope whose vertices are
at atomic positions ; these are defined such that the object is convex ,
and all atomic positions that are not vertices of the hull lie within
its volume . a common analogy is to compare the convex hull of an object
to its shape if it were wrapped in wrapping paper . as the number of
vertices defining the convex hull grows more slowly than the total
number of atoms in the molecule , it is an efficient object to deal
with when molecules are large .
furthermore , in the case of rigid molecules ,
the convex hull needs only to be calculated once for each type of
molecule , which is performed before generating structures .
the convex
hulls can be manipulated with the usual symmetry operators , and all
neighboring molecular pairs are tested for overlap . from the
separating axis theorem
we determine whether a pair of convex hulls
overlap and the vector of minimum length which is required to separate
the two objects .
a set of vectors is taken , which are either normal
to the faces of a hull or to an edge from each . onto this set
, the shadow of each convex hull is projected
( as always , considering the finite size of the atoms by including
the appropriate van der waals radius ) , and the overlap of the two
shadows is measured .
the minimal length of overlap along any vector
in this set yields the smallest vector required to separate the objects .
if there is no overlap of the shadows on any axis in the set , the
convex hulls do not overlap , as is the case in the example in figure 3 . separating axis theorem
test for molecular overlap .
the separating
axis theorem prescribes the vectors upon which to project the vertices
of the convex hulls when testing polytopes for their overlap in space .
an example for the cage molecule cc1 is shown with convex hulls overlaid
on the molecular geometry . in the geometry shown there is a vector
upon which the shadows of their hulls , the blue and
red vectors , do not overlap . if they did overlap , the set of overlapping
blue and red vectors would determine the minimum displacement necessary
to separate them in the direction of that vector .
the result of the separating axis theorem test can be used
in one
of two ways , each of which are investigated in this study .
the simplest
procedure is to reject any trial crystal structure that contains overlapping
molecules .
the proportion of rejected structures decreases as the
target unit cell volume ( as determined by the parameter tvp ) is increased ,
which makes more efficient use of the sobol sequence , at the expense
of creating crystal structures that are farther from their final ( post
energy minimization ) density and thus more expensive to lattice energy
minimize . for this reason
, we test the influence of our choice of
tvp on the performance of the search . in this study
, we test the structure
generation procedure with rejection of trial structures using tvp
= 1.0 , 1.5 , 2.0 , and 2.5 .
the second option that we have implemented
is to adjust trial crystal
structures to remove the overlap between molecules .
we do this by
expanding lattice vector lengths according to3 the lattice vector indexed by i grows due
to the
relationship of the overlap vector , v , and the vector between the centroids of the
objects , v. when
both vectors are given in fractional coordinates , the increase in
cell length , lj , is given by the ratio of their components along that axis . for
numerical stability
, the cell is only expanded along axis j when vjcentroid > 0.05 ,
and we add a parameter , , to lj with the value 0.001 in this study .
this lattice vector expansion procedure is iterated until the structure
contains no overlapping molecules . in cases where molecules are positioned
close to a space group symmetry element
, the cell expansion required
to relieve molecular overlap can lead to very large unit cells .
we
therefore place a limit on unit cell volume after lattice vector expansion ,
above which the trial structure is rejected .
we define this limit
( maximum volume parameter , mvp ) in reference to the molecular volumes
used to calculate the target volume parameter , tvp , as 2.5 times the
sum of molecular volumes in the unit cell .
a typical use of
the crystal structure generation procedure is
to generate a set number of trial structures within a specified space
group , to allow them to reach a minimum on the pes through lattice
energy minimization , and then to monitor the results achieved to assess
whether the sampling of possible structures is sufficiently complete .
if more structures must be generated for a particular space group ,
then the search is continued , starting from the highest value of sobol
seed that has previously been used .
the crystal
structure generator described above creates trial structures that
could be lattice energy minimized by any method that can affordably
be applied to the number of structures required to sample the pes .
currently , the glee software is interfaced with the dmacrys crystal structure modeling software , to make use of anisotropic atom
all
lattice energy minimizations reported here were performed using dmacrys , which employs a quasi - newton raphson , rigid - molecule
optimization of molecular positions , orientations , and unit cell parameters
with space group symmetry constrained .
the intermolecular interaction
energy between molecules m and n was modeled with an anisotropic model potential of the form4where i , k are atoms of type and belonging
to molecules m and n , respectively ,
separated by the
distance rik .
the first
two terms model the repulsive and attractive nonelectrostatic intermolecular
interactions , whose parameters are taken from a revised version of the williams99 force field .
the
final term , describing electrostatic interactions , is calculated from
atom - centered multipoles up to rank 4 ( hexadecapole ) on all atoms ,
obtained from a distributed multipole analysis ( dma ) of the b3lyp/6 - 311 g * * charge density .
dipole , and dipole dipole interactions were calculated
using ewald summation , while repulsion dispersion interactions
and all higher multipole
the summation cutoff ( for exp-6 interactions
and higher - order multipole - multipole interactions ) was set to 30
for cc1 and quinacridone and 15 for the more compact artemisinin
molecule .
any method for structure
prediction requires a procedure for comparing pairs of generated structures
and determining whether they are , to within a set tolerance , identical .
this step is essential to both remove duplicates from a data set and
also to monitor the convergence of the completeness of the sampling .
various methods exist to perform this task in
csp , including the comparison of similarities of computed x - ray powder
diffraction patterns and the compack
algorithm , which tests interatomic separations ,
and performs an overlay of molecules in order to quantify the similarity
of the structures .
structure comparison and clustering in this
work has been processed with our in - house method , which is related
to the compack approach .
a cluster of molecules is constructed surrounding
each molecule in the asymmetric unit ( we use clusters of 25 molecules
in this work ) .
we then construct a list of the displacements between
atoms in the neighboring molecules and the centroid of the reference
molecule .
two such lists can be compared , by positioning the origins
of both clusters at the same position and testing whether , for every
molecule in one cluster , a set of points occurs in the second which
can be overlaid upon the first by the action of rotation only .
an
algorithm to calculate the optimal rmsd exists , and we use a tolerance for comparing pairs of structures ,
in , of 0.5 + 0.05 r(c1 ) , where r(c1 ) is the distance
of the centroid of the molecule in the first list , to that of the
reference molecule around which the cluster is built . if the centroid
to origin distance of the molecule in the second structure , r(c2 ) , is not within 20% of that of r(c1 ) , or if the molecules contain different
numbers of atoms ( in the case of multicomponent crystals ) , the test
fails automatically .
if , under this criterion , the lists of clusters
of atomic coordinates are determined to match for clusters around
all molecules in the asymmetric unit , then the crystals are judged
to have identical packings , corresponding to identical minima of the
pes . in order to build up the clusters in a robust and computationally
efficient manner
the
reduced cell vectors are calculated using an algorithm from the computational
crystallography toolbox .
furthermore ,
to improve the performance of the algorithm in comparing crystal structures
whose molecules are large , the set of atomic positions used in the
comparison is reduced to those atoms which comprise the convex hull
of the molecule , after the hydrogen atoms have been removed .
the algorithm which
calculates the optimal rmsd of the overlaid points is sensitive to
the order of the coordinates , and hence up to s overlays
may have to be performed , where s is the order of
symmetry of the molecule . without making assumptions about combinations
of crystal and molecular symmetry operations , when building up lists
of atomic positions , s such lists must be calculated :
one for each set of coordinates that are equivalent under the internal
symmetry of the molecule .
we calculate the matrices for each of these
operations , and by maintaining a consistent atomic labeling scheme
and limiting ourselves , in this paper , to rigid molecules , this calculation
is only required once .
the cc1 cage is a particularly symmetric molecule ,
with s = 12 , but even with this worst case
we start with the
results for a selection of molecule / space group
combinations , choosing the space groups of the observed polymorphs
of each molecule for detailed investigation of the convergence of
the search for crystal structures . since we must treat whole molecules
in the crystal structure generation procedure , we consider the space
groups of the observed structures after removing space group symmetry
elements that correspond to intramolecular symmetry .
searches were
performed with one molecule in the asymmetric unit ( z = 1 ) in p212121 for artemisinin ; p1 and p21/c for cc1 ; and p21/c and p1 for quinacridone .
quinacridone has a known polymorph with two independent molecules
in the asymmetric unit ( z = 2 ) , so searches
were also performed with z = 2 in space group p1 .
we generated trial structures with each
of the five variations
on the structure generation procedure for each system ( molecule / space
group combination ) with z = 1 .
four seaches
employed rejection of trial structures with overlapping molecules ,
using different target cell volumes in the assignment of lattice parameters
to the trial structures ( tvp = 1.0 ; 1.5 ; 2.0 ; 2.5 ) . a fifth search
was performed for each system using the cell expansion method in place
of rejection , with tvp = 1.0 and a maximum expansion of the unit cell
volume ( mvp ) to a volume parameter of 2.5 ( we refer to this method
hereafter as sat - expand ) .
the sat - expand method should be viewed as
a variation on the simpler tvp = 1.0 search , but where structures
with overlapping molecules are retained if this overlap can be relieved
through expansion of the unit cell volume by up to 250% .
10000
trial structures were generated ( after rejection ) with each
variation of the method for the searches with one molecule in the
asymmetric unit .
we expect this to be more structures than would generally
be required per space group in a csp study .
50000 structures were
generated for the quinacridone z = 2 search
with each method ; a larger number is expected to be required to cover
the higher dimensional space . a second , low symmetry ( p1 , z = 4 ) polymorph of artemisinin is known .
therefore , to test
if this structure could be located with our method ,
a 50000 structure search was performed for artemisinin in p1 with z = 4 with the sat - expand
method only .
we first examine the efficiency with which each
variation of the structure generation method uses the sobol sequence .
since the low - discrepancy sampling is designed to uniformly sample
phase space , we want a method that makes the best use of each point
in the sequence ; high rates of rejecting trial structures could undermine
the uniformity of the search .
as expected , we find that fewer
trial crystal structures are rejected when the target volume is increased
( table 1 ) .
.
between 1 in 3 and 1 in 50 trial structures contain overlapping molecules
when the target unit cell volume is chosen to just fit the molecules
( tvp = 1.0 ) and there are large variations in the rejection rate between
molecules .
quinacridone leads to the most rejected structures : this
long , thin molecule clashes with neighbors in most orientations generated
from a random sampling .
trial structures of the more isotropically
shaped cc1 and artemisinin less frequently contain molecular clashes .
p21/c generally leads to more rejected structures than
simpler space groups
with fewer symmetry elements ( p21/c vs p1 for cc1 , p21/c vs p1 for quinacridone ) ,
since more of the configurational space lies sufficiently close to
a symmetry element such that symmetry generated molecules overlap
with the original .
the z = 2 search is particularly
problematic : the generation of 50000 accepted structures required
almost 10 trial structures with tvp = 1.0 , an acceptance
rate of 0.05% .
the number in parentheses is the number
of accepted structures that lead to a successful lattice energy minimization . considering only z = 1
, the differences
in rejection rate between space groups and between molecules nearly
disappear at large target volumes , where the proportion of rejected
structures is decreased .
an increase of only 50% to the target volume
( tvp = 1.5 ) has the largest impact on systems where rejection rates
were very large ( cc1 p21/c and both space groups for quinacridone ) . at tvp = 2.5 ,
the acceptance
rates are quite high : almost all trial structures of artemisinin are
accepted , and acceptance rates are in the 4050% range for
cc1 and quinacridone . the acceptance rate for z
= 2 is also improved dramatically when a larger target volume is used ,
so that almost 1 in 10 structures is accepted for tvp = 2.5 .
increasing the volume of generated unit cells clearly makes more
efficient use of the sobol sequence . on the other hand ,
trial structures
with smaller volumes are closer in cell parameters to the final densely
packed , lattice energy minimized crystal structures . as a result ,
the proportion of accepted structures that results in successful lattice
energy minimization is highest ( 9699% ) when the target volume
is matched with the molecular volume ( tvp = 1.0 ) .
trial unit cells
with large volumes prove more challenging for the lattice energy minimizer ;
up to 23% of accepted z = 1 trial structures
fail to find a local minimum using tvp = 2.5 ( table 1 ) .
furthermore , it could be conjectured that
making initial guesses that are close to the final , energy minimized
structures are more likely to end up in narrow wells and thus more
reliably locate all low energy structures than when tvp is set artificially
high . in searches where structures with overlapping molecules
are rejected
,
there is a balance between efficient use of the sobol sequence , which
is best at high target volume , and ease of lattice energy minimization ,
which is best at smaller target volumes .
the sat - expand method compares
favorably to the rejection - based methods on both criteria ( final column , table 1 ) .
the rate of accepting
trial structures is as high as the tvp = 2.5 searches , since only
those that require excessively large unit cell expansion to relieve
molecular clashes are rejected .
however , since structures in the sat - expand
approach are initially generated with tvp = 1.0 and many of these
do not require significant expansion , many of the structures entering
energy minimization are close to the densities of the final lattice
energy minima .
this results in higher success rates of lattice energy
minimization than generating directly with large unit cells ( e.g. ,
tvp = 2.5 ) .
number of unique crystal structures , within 15 kj / mol of the global
minimum , for artemisinin in space group p212121 , displayed ( a ) as a function of the current
position in the sobol sequence and ( b ) as a function of the total
number of successfully energy minimized structures . as a first analysis of the convergence of the crystal
structure
searches , we monitored the number of unique , low energy lattice energy
minima that had been located as the search progressed .
for this analysis ,
we defined the low energy region as that within 15 kj / mol of the global
minimum .
figure 4 displays
the results for artemisinin in p212121 ( corresponding plots for the other systems can
be found in the supporting information ) .
the rate of finding new crystal structures is high at the beginning
of the search but levels off to the point where no new crystal structures
are being located .
we observed that all of the methods converge to
the same number of unique structures .
the tvp = 1.0 method converges
most slowly as a function of the number of sobol vectors attempted
but fastest as a function of the number of valid , lattice energy minimized
structures .
given that lattice energy minimization is the most costly
part of the process , this suggests a slight advantage of generating
trial structures with small unit cell volumes .
again , the sat - expand
approach compares favorably with simple rejection , making efficient
use of the sobol sequence and converging quickly with respect to the
number of lattice energy minimizations .
as well as monitoring
how the total number of unique low energy
crystal structures converges during a crystal structure search ( figure 4 ) , it is useful to
monitor the evolution of the energy of the lowest energy structure
found during a search , as a function of the number of structures that
have been energy minimized . figure 5 displays the rate at which the energy of both the
lowest individual structure , and the set of the lowest 10 structures ,
converges with respect to the number of successful energy minimizations
for artemisinin ( p212121 ) and cc1 ( p21/c ) .
average lattice energy of the ten lowest energy structures is shown ,
as a function of the number of minimized structures generated in the
experimentally observed space group for a ) artemisinin in p212121 and b ) cc1 in p21 .
the dashed lines indicate the energy of
the single lowest energy structure , where the color relates to the
same method in the legend .
the data had converged after 1000 and 6500
minimizations for a ) and b ) , respectively , so is not shown beyond
this point for clarity .
the lowest energy
structure
in the set is found rapidly , which we find to be true for all systems
studied here ( see the supporting information for results for the other systems ) .
once the lowest energy structure
remains stable with respect to the number of energy minimized structures ,
we assume that this corresponds to the true global minimum on the
lattice energy surface .
we also monitor the mean energy of the 10
lowest energy structures that have been located , to see by which point
in the search this larger set of low energy structures remains stable .
we find that convergence of the set of the 10 lowest energy structures
is about an order of magnitude slower than the rate of finding the
global minimum and that the convergence is quicker for artemisinin
than cc1 . for artemisinin
, the sampling in this space group appears
to be complete for all variations of the search ( different tvp and
sat - expand ) well before 1000 successful lattice energy minimizations .
we observe that searches using a large tvp generally appear to
converge more slowly than the smaller target volumes , with the sat - expand
method performing fairly well ; this is in line with our expectations
based on the convergence of the number of unique structures ( figure 4 ) .
the change in
performance of the search upon changing tvp is particularly stark
for cc1 in p21/c , where
the entire set of 10 lowest energy structures converges slowly for
tvp 1.5 . on the basis of these results ,
the most satisfactory
results are obtained when searching either with rejection - based sampling
and a small target volume , recognizing that many trial structures
will be rejected , or the sat - expand method .
there is evidence and intuition behind
the idea that the deeper wells on the pes may well also have a large
watershed around them , and a quasi - random search seeks to take advantage
of this .
the rapid convergence of the set of lowest energy structures
is a useful property when looking to make rapid searches in a wide
range of space groups , as it should be possible to estimate the limit
of the lowest energy structure in the set before completeness is achieved .
noting the number of structures needed to find the ten lowest energy
structures gives us a ball park figure of the absolute minimum number
of structures that we would wish to successfully lattice energy minimize
in these space groups . in some cases
, this can be as few as several
hundred lattice energy minimizations , although the small computational
expense of generating and minimizing structures means that we would
generally afford ourselves several thousand structures in space groups
whose lowest energy structure is within the lattice energy range of
interest to us .
the number of times that each low energy
predicted crystal structure
is located can be studied in detail , to investigate how our attempt
at uniform sampling of configurational space during trial structure
generation translates into uniformity of sampling of local energy
minima .
figure 6 displays
the number of times that each of the 10 lowest energy crystal structures
appear in each search for four of our systems .
the sampling of individual
low energy crystal structures is clearly uneven ; each system has some
structures that are more rarely located than others .
bar charts showing the
frequency with which each low energy structure
is located . for each of the lowest 10 unique structures , for the denoted
systems
, the energy above the minimum in the set is displayed on the
horizontal axis , and the number of times that it was found in the
search is read from the vertical axis .
the five methods appear alongside
each other , with the color of the bar signifying the method .
the case of cc1 in space group p1 ( figure 6 ) is very simple : the frequency
of finding each minimum decreases as the lattice energy increases ,
and for all methods , well over half of the initial structures relax
to the two lowest minima ( 40005000 hits to te global minimum ,
15002000 hits to the second lowest energy structure ) .
cc1
( p1 ) is also the system with the largest energy differences
between structures , since there are few ways to achieve a low energy
crystal packing when all molecules are related by translational symmetry
only ( space group p1 ) .
the five variations on the
sampling method show very similar performance for cc1 ( p1 ) , with the searches that sample smaller volume trial structures
leading to slightly more structures overall , as the rate of achieving
successful lattice energy mimimization is slightly larger from these
trial structures .
the tendency for the lowest energy structures
within a space group
to be frequently located is repeated for all other systems , with the
global minimum always one of the most sampled structures ; this finding
explains the rapid convergence of the global minimum energy shown
in figure 5 .
however ,
the lattice energy surfaces of most systems are more detailed than
that of cc1 ( p1 ) , with more low - lying energy minima ,
and a less clear relationship between the energy of a local minimum
and the frequency of finding it in a search . for example
, the structure
search for quinacridone in space group p1
leads to many energetically similar crystal structures , with similar
layered packings of the planar molecule .
the first two structures
are found frequently , but we observe that it is much harder to locate
all of the others ( figure 6 ) . the differing frequencies of obtaining each minimum are
difficult to explain , as only 6.68 kj / mol separate the set , and they
are structurally very similar ; as will be noted later , we also have
concerns with regard to our force - field for this system .
it
is those crystal structures that are located infrequently that
are most concerning , as they could easily be missed if sampling is
stopped too early , and most systems that we studied have such structures
on their landscapes .
the fourth lowest energy structure in cc1 ( p21/c ) , with a relative lattice
energy of 4.15 kj / mol is one such example ( figure 6b ) , as are structures 4 ( 1.81 kj / mol ) and
810 for quinacridone in p1 ( figure 6b ) and , to a lesser
extent , structures 2 ( 0.58 kj / mol ) , 5 ( 2.27 kj / mol ) , and 7 ( 2.72 kj / mol )
for artemisinin ( figure 6d ) . in most cases ,
the rate at which these challenging structures
are found decreases as tvp is increased , meaning that the rejection - based
methods with large unit cell volumes have a high risk of missing some
low energy structures .
an advantage of the sat - expand method is that
a range of initial volumes are covered during the search , and we find
this method performs well on the challenging , infrequently sampled
crystal structures .
hits to the 10 lowest ranked crystal structures of quinacridone p1 based on the combined complete search of the
five methods .
each point represents a lattice energy minimization
from a trial structure , showing the step in the sobol sequence where
the trial structure was generated and the lattice energy minimum to
which it optimizes .
another way of examing
the sampling of low energy structures is
to keep track of where each occurrence of each low energy crystal
structure was generated in the original sobol sequence ( figure 7 ) .
this representation reassures
us that the sobol sequence is evenly exploring the configurational
space , as the points leading to each low energy structure are evenly
distributed along the series .
this representation of how well the
low energy structures are sampled is useful for monitoring a calculation
as it proceeds , since it provides an immediate picture of the state
of completeness .
again , we clearly see that increasing tvp hinders
the sampling of some low energy structures ( figure 7b ) and that a more even sampling is achieved
with the sat - expand method ( figure 7c ) . convergence
and sampling of the quinacridone p1 z
= 2 search for crystal structures .
a ) the number
of unique structures within 15 kj / mol of the global minimum as a function
of the total number of successful lattice energy minimizations , using
each variation of the structure generation method .
b ) hits of the
10 lowest energy crystal structures througout the sobol sequence ,
using the sat - expand method .
our calculations on z= 2 crystal
structures
of quinacridone demonstrate the increased difficulty of predicting
crystal structures with multiple independent molecules in the asymmetric
unit .
the inclusion of a second independent molecule can greatly increase
the number of sobol seeds needed to generate the desired number of
crystal structures .
this can be seen in table 1 , where far higher values in the sobol sequence
must be used for quinacridone p1 z = 2 across all tvp values compared to the same
space group with z = 1 .
the larger sobol
sequences are needed as a large proportion of structures is rejected
due to overlap of molecules .
this is a particular problem with tvp
= 1.0 ; large numbers of rejected structures lead to much more time
spent on the structure generation as a whole .
the other challenging
aspect of z = 2 is the higher dimensionality
of the energy surface and , hence , the smaller relative volume of configurational
space that is expected to lattice energy minimize to any particular
crystal structure .
although the number of unique z = 2 crystal structures in the low energy region is small ,
some of our searches do not find the full set of structures until
well over 10000 lattice energy minimizations have been completed ( figure 8) ; the tvp = 2.0
search has not located one of the low energy structures , even as 50000
lattice energy minimizations are approached .
the sat - expand method
performs well in finding all low energy structures in a relatively
low number of lattice energy minimizations but still suffers from
very infrequent sampling of some structures ( figure 8b ) .
a second polymorph is known for
artemisinin , with four independent
molecules in the asymmetric unit .
ensuring complete searches of high z structures is known to be difficult due to the very high dimensionality of search
space , and we know of few previous studies which have successfully
located z = 3 and z = 4 polymorphs
in csp studies . as a test of our methods
, we generated 50000 structures
in the relevant space group , p1 with z = 4 , and found the known crystal structure to be the lowest
energy structure of all .
however , there were only 3 matches to the
experimentally observed structure from 38510 valid lattice energy
minimizations .
as with z = 2 quinacridone ,
the search required a large number of steps in the sobol sequence
( table 1 ) , due to a
high proportion of unphysical structures .
the sat - expand method ,
with a maximum volume parameter of 2.5 , showed some of the best characteristics
in the above tests and was used in an extended search across a range
of space groups .
currently , 95 space groups are available to be searched
in the glee program , but we restrict ourselves here to a
subset of the most commonly observed symmetries for organic molecular
crystals . for chiral , enantiomerically pure artemisinin ,
5000 structures
were generated in each of 8 space groups ( p1 , p21 , c2 , p21212 , p212121 , c2221 , p41212 , and r3 ) .
these space
groups were searched for cc1 and quinacridone , in addition to p1 , cc , p21/c , c2/c , pna21 , pbcn , pbca , and pnma ,
all with 5000 accepted structures .
all calculations were performed
with one molecule in the asymmetric unit , except for the case of a
search for the z = 4 polymorph of artemisinin
which has been included as a special example .
lattice energy minimization
and clustering were performed using the same procedures as have been
employed throughout .
each point corresponds to a distinct crystal structure ( a
unique minimum on the pes ) . for the case of quinacridone ,
two sets
of data have been calculated , and the basis set used in generating
the electrostatic model is included in parentheses in the subcaption .
the polymorph was located at too high a lattice energy to
appear on the graph in the case of the 6 - 311 g * * basis set . for artemisinin
the z = 4 structure is added
. predicted structures
that geometrically match the experimental structures ( see table 2 ) are circled and
labeled .
results are summarized in figure 9 , where each structure
is represented by its calculated
lattice energy and density .
a central assumption of crystal structure
prediction by global lattice energy minimization is that the most
likely structure to be observed experimentally is that with the lowest
free energy of formation .
although free energy contributions associated
with the dynamics of molecules about the equilibrium positions can
be significant , in this study we have focused
on the lattice energy , which is the largest contribution to the free
energy difference between crystal structures .
the existence of polymorphs
indicates that the process of crystallization is more subtle than
a simple drive toward the single lowest lattice energy structure ,
but our methodology is predicated upon the assumption that all solvent - free ,
stable crystal structures can be located in a set of low - lying , lattice
energy ordered structures determined from a quasi - random search . for artemisinin , we find that the second lowest energy structure
from the full search of z = 1 structures
corresponds to the known crystal form ( figure 9a ) , to within 1.6% in lattice dimensions
( table 2 ) .
the structure
is only 0.15 kj / mol above the global minimum within the constraint
of z = 1 . as described above , the second
known artemisinin polymorph , in p1 with z = 4 , was located in our search , as the global minimum in p1 with z = 4 and lower in energy
than any other crystal structure that was generated in our full search
( figure 9a ) .
these
results suggest that this low symmetry crystal structure results from
lowering the lattice energy , rather than being kinetically trapped
as an incomplete crystallization .
our results for quinacridone were surprisingly sensitive
to the
basis set used in generating the electrostatic model for intermolecular
interactions . among the quinacridone structures generated in the full
search using b3lyp/6 - 311 g * * electrostatics ,
the polymorph
( encircled figure 9c ) is the lowest energy experimentally known structure located , being
the fifth lowest structure in energy 3.4 kj / mol above the global minimum .
the ( encircled figure 9c ) and polymorphs sit
at 9.9 and 16.9 kj / mol above the global minimum , respectively .
these
energy rankings are surprisingly high , and there is no reason to believe
that these polymorphs are truly high energy crystal forms .
furthermore ,
the predicted structures are geometrically in fairly poor agreement
with the structures determined from x - ray diffraction ( table 2 ) .
to investigate the
sensitivity of these results to the electrostatic
model used in the force field model , all predicted crystal structures
were reoptimized using atomic multipoles derived from a smaller basis
set ( 6 - 31 g * * ) .
the ranking of observed structures within the predictions
changes significantly ; is now the global minimum ( encircled figure 9d ) with and
3.4 and 5.68 kj / mol above the
minimum .
while no full search was performed for z = 2 , the proposed structure of has been located in each of the preliminary csp searches that
have been used above to analyze the performance of tvp values and
the sat - expand method , with both 6 - 311 g * * and 6 - 31 g * * basis sets .
however , as reported by paulus et al .
, we observe that the z = 2 structure relaxes to the z
= 1 structure during lattice energy minimization .
these two
polymorphs seem to correspond to the same minimum on the lattice energy
surface .
rmsd30 is the deviation
in atomic positions of a cluster of 30 molecules taken from predicted
and experimental structures , not including hydrogen atoms .
cc1 ( r3 ) was generated in the p1 space group ,
which reduces to r3 on account of intramolecular
symmetry , hence the cell angles differ at the second decimal place .
the experimental structures of cc1 also contained residual solvent ,
which was removed for purposes of comparison .
we have maintained the same methodology for
generating a force field for all systems , but while the success has
been fairly strong for the cases of artemisinin and cc1 , it was not
so for quinacridone .
previous work by leusen located the known polymorphs of quinacridone among the lowest structures
generated and minimized with a simple , isotropic atom force field ,
but kraft has demonstrated the importance of anisotropic force fields
in modeling the pes of polyaromatic hydrocarbons .
we include an ab initio anisotropic electrostatic
model , but it is highly sensitive to the underlying dft calculations .
the results for quinacridone demonstrate important differences in
how the atomic multipoles model intermolecular electrostatics , which
may be due to the strong basis set dependence of the original distributed
multipole analysis algorithm that we employed here .
when we change the basis set used for the electrostatic
model , we use a empirically fitted exp-6 parameter set for all other
intermolecular interactions , although not one that is fitted to polyaromatic
hydrocarbons specifically .
even so , we would not expect such large
changes in lattice energy and polymorph ordering as have been observed
in this case .
we also note that , even at the level of hckel
theory , the electronic structure of a system will change as
multiple rings are fused together , and , of course , this molecule is
semiconducting in the solid state , indicating its unusual character .
from the literature on enhanced van der waals interactions
in aromatics
, grimme has suggested that stronger dispersion effects
arise in systems beyond three fused rings , which would include quinacridone , but few systems from which our
potential has been fitted .
this study has , at the least , highlighted
the need for more work to produce a transferable , accurate force field
for these systems , while also tested the search methodology in a difficult
case .
finally , the results for cc1 agree with our earlier study
of this
molecule , which used a monte carlo simulated
annealing approach to generating trial crystal structures . the two
polymorphs are found in the low energy region of the landscape and
are good geometrical matches to the structures determined by x - ray
diffraction .
the crystal structures of this organic cage are obtained
by desolvation of solvate structures in which guest solvent molecules
fill the voids within and between cage molecules .
the structure - directing
effect of the included solvent has been shown to be so strong that
polymorph transformation can be achieved through exposure to solvent
vapor .
in this situation of strong solvent
directing effects , it is unsurprising that the observed structures
do not correspond to the lowest energy possibilities on the solvent - free
energy landscape .
indeed , re - evaluation of the energies of the predicted
structures of cc1 using dispersion - corrected solid state dft shows
little energetic reranking , providing
further confidence in the force field based relative energies .
this paper outlines a method of generating
trial structures of
molecular crystals , which is an essential part of an ab initio crystal structure prediction methodology .
a core idea of our methodology
is to consider the shape of the molecules but to use as few other
restrictions as possible in our quasi - random search .
we have demonstrated
that this is an effective method of determining the full set of low
energy crystal packing possibilities of a molecule , which includes
the experimentally observed polymorphs in the cases that we have studied
here .
we find that the global lattice energy minimum is typically
located early in a search and sampled frequently throughout a quasi - random
search .
this is an important finding , as it suggests that short quasi - random
searches can be applied to rapidly evaluate a molecule s crystal
packing preferences , which can be extended to complete , converged
searches if desired .
however , we also find that some low energy crystal
structures are more infrequently sampled , making the frequency of
locating such difficult structures rate - limiting when a complete crystal
structure search is required .
we examined the influence of increasing
the target unit cell volume
in generating trial crystal structures , but large target volumes led
to less reliable sampling of structures .
our use of the separating
axis theorem allows us to quickly rule out unphysical trial structures ,
and by expanding the cell to relieve clashes , we can keep a larger
proportion of trial structures .
this is important , as the sobol sequence
is designed to cover the manifold of random numbers in an efficient
way and helps us to rapidly consider a wide range of potential structures
in the search .
this sat - expand approach has the best characterists ,
overall , of the variations on our method that we have investigated .
this tool not only provides us with a method to conduct a crystal
structure prediction study for rigid molecules but also provides a
platform upon which further functionality can be built .
we have a
robust method of exploring the pes that we show to be effective for
a set of different molecules and structures with multiple molecules
in the asymmetric unit ( z = 2 and 4 ) .
the search methodology
also finds polymorphs whose crystallization is determined by solvent
templating rather than the principle of close packing ( cc1 ) or even
in a case for which our energy model is not optimized for a particular
case ( quinacridone ) .
the principle of a pseudorandom number search ,
when coupled to our code base , provides us with a lot of flexibility .
we are currently extending this methodology to include further functionality ,
such as molecular flexibility , and are also incorporating these tools
into high - througput screening of molecules for discovering molecular
crystals with targeted properties .
|
### Summary:
: generating sets of trial structures
that sample the configurational
space of crystal packing possibilities is an essential step in the
process of ab initio crystal structure prediction
( csp ) .
one effective methodology for performing such a search relies
on low - discrepancy , quasi - random sampling , and our implementation
of such a search for molecular crystals is described in this paper .
herein we restrict ourselves to rigid organic molecules and , by considering
their geometric properties , build trial crystal packings as starting
points for local lattice energy minimization .
we also describe a method
to match instances of the same structure , which we use to measure
the convergence of our packing search toward completeness . the use
of these tools is demonstrated for a set of molecules with diverse
molecular characteristics and as representative of areas of application
where csp has been applied .
an important finding is that the lowest
energy crystal structures are typically located early and frequently
during a quasi - random search of phase space .
it is usually the complete
sampling of higher energy structures that requires extended sampling .
we show how the procedure can first be refined , through targetting
the volume of the generated crystal structures , and then extended
across a range of space groups to make a full csp search and locate
experimentally observed and lists of hypothetical polymorphs . as the
described method has also been created to lie at the base of more
involved approaches to csp , which are being developed within the global
lattice energy explorer ( glee ) software , a few of these extensions
are briefly discussed .
|
<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:
: colorectal cancer ( crc ) is the third most commonly diagnosed cancer and the second most common cause of cancer related deaths in canada and the united states ( us ) . in 2014 ,
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although the initial focus of crc screening activities was to identify the benefits and then the preferable test for crc screening , lately increasing efforts are focusing on reducing disparities in crc screening .
a reduction of disparities will be necessary to reach crc screening goals set by the united states center for disease control and prevention ( cdc ) ( > 80% screened ) and the canadian partnership against cancer ( > 60% with a fecal occult blood test [ fobt ] ) .
the most commonly used crc screening tests include guaiac - based fobts ( g - fobts ) , fecal immunochemical tests ( fit ) , flexible sigmoidoscopy ( fs ) , and colonoscopy .
additional most promising screening tests include computed tomographic ( ct ) colonography , and fecal dna testing .
crc screening using the g - fobt has been found to reduce mortality in several randomized controlled trials ( rct ) . in 2008 ,
a meta - analysis that included four rcts found that biennial g - fobt screening was associated with a 15% reduction in the relative risk of crc mortality .
long term follow - up of one of these rcts suggests that the effect of g - fobt screening on crc mortality persists even 30 years after initial screening .
since fit requires only 1 day sample and no diet restriction , the acceptance among the public is much higher for fit than for g - fobt .
although , several rcts have also reported that screening with fs can lead to a reduction in crc mortality , the use of fs in canada and the us continues to decline .
though there is strong indirect evidence for the effectiveness of colonoscopy for crc screening , rcts ( the gold standard study design to assess cancer screening tests ) of colonoscopy use ( including comparisons of colonoscopy and fit ) for screening have been initiated recently . despite the fact that colonoscopy has become the preferred test for crc screening in the us ,
it is not an ideal crc screening test as it is resource intensive , requires highly trained personnel , is somewhat invasive , and incurs an increased risk of rare , serious harms , such as bowel perforation , hemorrhage , and death .
fecal dna testing is a very promising test and may eventually replace both fit and colonoscopy . a recent , large
, multicenter study reported that the fecal dna test detected 92.3% of crcs detected on colonoscopy , which was much more than the 73.8% detected by fit .
based on this study result , fecal dna testing has been approved by the food and drug administration in the us and is now available for usual clinical use at the mayo clinic . however , there are no trial data to guide frequency of fecal dna testing which is also currently much more expensive than other stool tests .
ct colonography is more sensitive than barium enema for detecting crc and its precursor lesions and has almost replaced the use of barium enemas in the north america , becoming the preferred test for those with incomplete colonoscopy .
however , although ct colonography can detect 90% of polyps and cancers larger than 10 mm in diameter , its cost - effectiveness as the initial test for crc screening is highly dependent upon the threshold of lesion size used for referral for colonoscopy and it can lead to invasive tests to investigate incidental benign findings . moreover , there are no nonmodeling studies demonstrating effectiveness of ct colonography in reducing crc incidence or mortality .
several canadian and us guidelines recommend that most individuals between the ages of 50 and 74 should have crc screening .
for example , in 2001 , the national committee of health canada recommended screening for crc using a fecal test every 2 years for individuals 50 years of age and older ; a recommendation , which has led to the implementation population based crc screening programs in most canadian provinces .
the canadian association of gastroenterology currently recommends that average risk individuals over 50 years of age be screened with a fobt every 2 years , fs every 10 years , or colonoscopy every 10 years .
there are similar recommendations ( published in 2008 ) from the united states preventive services task force ( uspstf ) and the united states multi - society task force on crc , which recommend the use of a fit or a high - sensitive fobt annually or biennially , fs every 5 years , or colonoscopy every 10 years for screening for crc .
updated guidelines from uspstf and equivalent canadian task force on preventive health care are expected in 2015 .
despite these recommendations and clinical practice guidelines , which are based on high quality evidence of the benefits of crc screening , many individuals remain unscreened . estimates from 2011 suggest that the percentage of individuals in canada that were up - to - date with crc screening ( defined as those who had a fobt in the previous 2 years or a colonoscopy or a fs in the previous 5 years ) was 43% ( an increase from 38% in 2009 ) . in the us , crc screening rates are some of the highest in the world , but it is estimated that only 59.6% of individuals in 2010 in the us were up - to - date for crc screening . therefore , although crc screening rates are improving in north america , participation rates are still considerably lower than those for other types of cancer .
several studies have explored crc screening participation rates for different sub - groups of the population to better understand barriers to access and utilization of crc screening .
inequities in crc screening use arise from variety of individual , provider , and health care system - related barriers .
individual - level barriers to crc screening are often related to socioeconomic status ( ses ) ( i.e. income and education ) .
inequalities in cancer screening participation by income level have been shown in several studies in countries both with and without universal health care insurance .
information from the 2008 canadian community health survey showed that crc screening rates were lower for individuals from lower - income households ( 25.2% ) than in those from higher - income households ( 37.7% ) .
individuals with lower incomes may experience a higher frequency of stressful events , have fewer social or economic resources available to help cope with stress , or have less time available to practice preventive health behaviors such as screening .
screening rates also differ across cultural and ethnic groups . in a review of the literature on the equity of participation in crc screening among different ethnic populations , javanparast et al . found that socio - cultural factors and cultural expectations play an important role in the acceptability , accessibility , and utilization of screening .
common barriers cited include a lack of knowledge about crc and the importance of screening , the belief that screening is not required in the absence of symptoms , concerns about embarrassment , discomfort , or test preparation , fear about the results , and a distrust of doctors .
studies have also found that immigrants , particularly those with shorter residency in north america , are less likely to participate in preventive cancer screening .
up - to - date crc screening among recent immigrants to canada is 19.2% compared with 35% for longer term immigrants and
in addition , many recent immigrants do not speak english as their primary language and face an additional barrier in communicating with health care providers .
liss and baker used the data from the 2010 behavioral risk factor surveillance system data to examine crc screening by race and ethnicity in the us .
this study provides the most complete and updated analysis of racial / ethnic disparities in crc screening and the degree to which disparities are explained by ses and access to care .
overall , large racial and ethnic disparities in crc screening were found , including substantial differences between english - speaking and spanish - speaking hispanics .
these disparities were only partially explained by ses and access to care and suggest that even if financial barriers are removed , disparities for spanish - speaking hispanics and asians will persist unless interventions are tailored to these groups .
colorectal cancer screening among indigenous peoples ( american indians and alaska natives in the us and first nations [ fn ] , mtis , and inuit people in canada ) is particularly important since they now have a higher burden of crc and increasing crc mortality , strikingly in contrast to decreasing crc mortality among other groups in north america .
for example , the age - standardized crc incidence rate in manitoba , canada increased from 29.6/100,000 in 1984 - 1988 to 79.0/100,000 in 2004 - 2008 for fn individuals , but decreased from 68.4/100,000 in 1984 - 1988 to 66.8/100,000 in 2004 - 2008 for all other manitobans . unfortunately , crc screening rates have been consistently lower for indigenous peoples compared with other ethnic groups .
this has also been observed outside of north america : in australia , 17% of individuals who identified themselves as indigenous accepted an offer of fobt use compared with 38.6% of nonindigenous people .
some studies have found that individuals who live a rural area are less likely to be screened than individuals who live in an urban area while other studies have found no difference in crc screening participation by geography .
variation across studies may be due to diverse data sources and different definitions of rural and urban . since crc screening often requires a physician 's referral in the us , barriers to screening may be actually due to disparities in access to a primary health care provider . in canada , with universal health care and population - based crc screening programs ( which usually mail out the fecal test kits ) ,
crc screening rates are only slightly lower in very remote ( 29.2% ) and remote areas ( 27.7% ) compared to urban areas ( 33.0% ) . at the provider level , a doctor 's recommendation is the most consistent predictor of cancer screening behavior . having a regular health care provider , good continuity of care , and good communication with a health care provider all improve cancer screening participation .
a study by seeff et al . in the us found that frequent physician visits in the past year was the strongest predictor of crc screening and not receiving a physician recommendation was the most frequently stated barrier to screening .
older patient age and a shorter length of time as a resident in the us have been found to be inversely related to a physician 's recommendation for crc screening .
a canadian survey from 2012 found that only 32% of canadians reported that their physician initiated a conversation about crc screening .
weiss et al . found that individuals in wisconsin were more likely to be screened for crc if their health care provider was in practice for > 10 years , female , practiced internal medicine , or had a larger patient population that required crc screening .
research that has examined health care provider barriers to cervical cancer screening has found similar results .
health care system barriers include no health insurance or inadequate insurance coverage , no programs to recruit patients for screening , and inadequate monitoring for compliance with screening guidelines . a lack of health insurance is strongly associated with reduced crc screening in many studies .
however , a few studies have found that the provision of universal health insurance or insurance reimbursement alone did not reduce inequity in screening uptake .
a variety of interventions and strategies aimed at decreasing inequities in crc screening have been implemented and evaluated . at the individual level , these include client invitations and reminders , targeted and tailored interventions , small media , and mass media campaigns .
client reminders include letters or post cards that inform individuals about the need for screening .
they can be delivered by mail , telephone , e - mail , or text message .
baron et al . reviewed seven studies that examined effectiveness of client reminders for crc screening using the g - fobt .
they concluded that there is strong evidence for the use of client reminders for fobts although information was limited for fs and colonoscopy .
targeted or tailored reminders can be printed or verbal and address an individual 's risk profile or other relevant barriers to screening .
results are mixed ; some rcts that used socio - psychologically tailored crc screening interventions found an increase in participation while others did not .
most of these rcts used self - reported screening participation rates which may have biased the results . in 2014 , jerant et al .
undertook a rct that compared the crc participation rate after receiving a tailored , interactive multimedia computer program to a nontailored program among a multiethnic population .
the crc participation rate was confirmed using electronic and paper medical records . although the tailored message increased screening knowledge , self - efficacy , and readiness for screening , there was no difference in screening uptake between the groups .
small media include education materials that inform individuals about screening and motivate them to seek more information , talk to their health care provider , or make an appointment for screening .
the task force on community preventive services recommends the use of small media for crc screening using fobt based on the results of several studies that found a median increase in participation of 12.7% .
mass media , such as television , radio , newspapers , magazines , and billboards , are used to communicate educational and motivational information about screening to a community .
mass media is often used in conjunction with other strategies and has been shown to effectively promote child safety seat use , physical activity , and adolescent tobacco use . however , there is currently insufficient evidence to determine the utility of mass media for increasing fobt , fs , or colonoscopy use for crc screening participation as it is often combined with other strategies .
it has also been suggested that newer media forms such as mobile technology ( phones and tablets ) , internet interfaces , and social media can improve screening participation , but additional research is needed to demonstrate their effectiveness . at the provider level , strategies include office system interventions such as flags to remind physicians to recommend screening , in - depth patient education or navigation , and physician incentives . using a cluster randomized trial design in two canadian provinces , grunfeld et al . evaluated the effectiveness of a multifaceted , evidence - based , tailored practice - level intervention with a practice facilitator ( pf ) designed to improve chronic disease prevention and cancer screening .
each pf supported two primary care team practices ( eight physicians ) and conducted a 1-h visit with each patient .
crc screening increased by 10.1% in the pf group and was found to be cost effective .
this model supports the integration of an allied health professional specifically trained in chronic disease prevention and screening into the primary health care team .
navigators ( usually nurses or community health workers ) have been used in several rcts that use colonoscopy for crc screening with positive results .
matching the navigator 's linguistic capacities and cultural understanding with the population being served appears to be a key part of successful navigation .
since cost constraints in primary practice may influence the feasibility of implementing provider - level strategies , in 2006 , manitoba health ( the government agency responsible for health care in the province of manitoba , canada ) implemented a physician integrated network ( pin ) .
the pin uses quality based incentive funding as one of the key mechanisms for engaging physicians to meet primary care quality indicators which include crc screening . as of 2011
, there were 12 fee - for - service family practice clinics participating in pin representing a mix of urban and rural settings with practice sizes ranging from 5 to 25 physicians .
the percentage of patients in these practices who had a g - fobt in the past 2 years or a colonoscopy in the past 10 years increased from 25.5% in 2008 to 64.2% in 2011 .
however , this network has focused on a limited number of prevention activities in each practice setting and it remains unclear if the benefits seen will be maintained with multiple prevention and screening activities .
there is also evidence that increasing the supply of health care providers who can conduct fs and colonoscopy can also improve crc screening .
although many of these individual and provider - level interventions are successful , their impact remains small and often does not include those groups of individuals who experience the greatest barriers to screening .
therefore , to achieve large , sustainable effects , a system or multilevel approach has been suggested to be necessary to reach a wider population .
population - based , organized approaches to crc screening can increase crc screening rates and are expected to reduce ses disparities in screening participation .
although the us does not have a national crc screening program , several organized approaches to crc screening have been introduced in recent years .
the department of veterans affairs and kaiser permanente northern california ( kpnc ) have both found that an organized approach to crc screening can lead to participation rates of over 75% .
kpnc uses an electronic medical record to identify unscreened individuals and then sends them a fit kit by mail .
kpnc also uses chart reminders to prompt the offering of a screening test during primary care or specialist visits with orders to allow nonphysician clinical staff members to provide a fit when indicated .
the cdc created the colorectal cancer control program ( crccp ) in 2009 which funds 25 states and four tribal organizations to promote and increase population - wide crc screening with a focus on low income and under - served populations .
the crccp requires that its partners use the evidence - based strategies recommended by the task force on community preventive services . in 2002 , the state of delaware implemented a comprehensive population - based crc screening program that included coverage for screening ( using colonoscopy ) and treatment , patient navigation for screening and care coordination , and case management . from 2001 to 2009 , the percentage of black residents who had ever had a colonoscopy increased from 47.8% to 73.5% while the percentage of white residents increased from 58.9% to 74.7% effectively eliminating racial inequity in cancer screening .
importantly , during the same time period , the crc incidence rate decreased by 34% and 26% for black and white residents respectively . in response to low colonoscopy screening rates and significant ses disparities in screening in new york city ( nyc ) , the nyc department of health and mental hygiene ( dohmh ) implemented a similar program in 2003 .
the dohmh established a coalition of stakeholders , promoted colonoscopy through several health marketing campaigns for the public and the medical community , expanded the public hospital system 's endoscopy capacity , and encouraged provider referral using a one - on - one pharmaceutical detail model .
the media campaign focused on poor neighborhoods and populations with low screening rates . a direct endoscopy referral system and an in - hospital patient navigation program were developed to ensure that referred individuals were successfully screened . from 2003 to 2007 , the percentage of individuals who had a colonoscopy increased from 41.7% to 61.7% .
the racial / ethnic and sex disparities in screening observed in 2003 were eliminated although asians , the uninsured , and individuals with lower levels of education and income were still less likely to be screened .
most recently in the us , the affordable care act ( aca ) mandates that medicaid and insurance plans cover all preventive services recommended by the uspstf in full with no patient costs .
unfortunately , the aca does not include follow - up colonoscopies after a positive fobt or fs despite the fact that the provision of follow - up testing is one of the criteria necessary for effective screening as identified by wilson and junger for the world health organization in 1968 .
therefore , there is concern that aca may increase disparities in crc screening by deterring individuals from performing a fobt or fs if they can not pay for the follow - up tests or necessary treatment . as of 2010 ,
all canadian provinces had announced or had started to implement organized crc screening programs using an fobt or fit for individuals 5074 years of age with colonoscopy follow - up for positive screening results .
eleven quality indicators that range from participation rate to crc cancer detection rate were developed nationally to measure the on - going performance of the provincial screening programs . from 2009 to 2011 , between 5% and 37.4% of individuals to whom a program was available had completed a fobt or fit .
information is not yet available about whether or not the canadian provincial programs have reduced inequities in screening participation .
screening for crc and its precursors is highly effective in reducing deaths due to crc .
however , it is clear that there is inequitable crc screening between different groups in both canada and the us .
there is an urgent need for health care system interventions and health policies to help reduce disparities in crc screening .
although evidence suggests that client - directed interventions are effective , population - wide screening is also required to minimize the barriers experienced by individuals that have lower levels of screening ethnic minorities and indigenous individuals , new immigrants , low - income populations , individuals with lower levels of education , and some rural or remote populations .
most of the system - wide strategies recognize the importance of developing partnerships with community organizations to ensure that screening information and strategies are culturally appropriate and relevant .
partnerships are necessary to help screen individuals who are considered hard - to - reach and have never been screened ; this is particularly important since largest impact from crc screening is accrued from the first screen .
overall , to address disparities , achieve high crc participation rates , and reduce the burden of crc in the population , strategies at all levels ( patient , provider , and health care system ) are required .
kathleen m. decker : department of community health sciences , university of manitoba ; screening programs , cancercare manitoba , canada .
harminder singh : departments of community health sciences and internal medicine , university of manitoba ; department of haematology and medical oncology , cancercare manitoba , canada .
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### Summary:
: colorectal cancer ( crc ) is an important cause of mortality and morbidity in north america .
screening using a fecal occult blood test , flexible sigmoidoscopy , or colonoscopy reduces crc mortality through the detection and treatment of precancerous polyps and early stage crc .
although crc screening participation has increased in recent years , large inequities still exist .
minorities , new immigrants , and those with lower levels of education or income are much less likely to be screened .
this review provides an overview of the commonly used tests for crc screening , disparities in crc screening , and promising methods at the individual , provider , and system levels to reduce these disparities .
overall , to achieve high crc participation rates and reduce the burden of crc in the population , a multi - faceted approach that uses strategies at all levels to reduce crc screening disparities is urgently required .
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: the results of sequence - based , molecular phylogenetic analyses have reshaped current thinking about ancient evolutionary relationships , and have begun to establish a new framework for systematizing broad - scale eukaryotic diversity . among the most widely accepted of the new evolutionary hypotheses is a proposed sister relationship between animals ( + choanoflagellates ) and fungi ( see ref . 1 . , 2 . for thorough reviews ) and their combination into a new taxonomic kingdom , the opisthokonta ( 3 ) .
phylogenetic support for the opisthokonta comes from analyses of several well - sampled individual genes 4 .
, 5 . , 6 . as well as combined analyses of these and other sequences in concatenated data sets ( 7 ) .
in addition , alignments of elongation factor 1 ( ef-1 ) sequences show that animal and fungal genes contain a unique and apparently conserved insertion that is not present in other eukaryotes ( 5 ) .
the cumulative evidence from these investigations is impressive and has convinced many evolutionary biologists of the validity of the opisthokonta .
support for a sister relationship between animals and fungi began to gain steam in the mid-1990s as molecular sequence data became available from a diverse array of eukaryotes .
6 . was the appearance of two different and conflicting phylogenetic signals ; most available sequences supported an animals + fungi relationship , but a smaller subset of genes indicated a closer relationship between animals and plants .
curiously , there was little or no support for the third possible relationship ( plants + fungi ) .
this suggested that a persistent phylogenetic artifact , rather than noise , might be responsible for conflicts among gene phylogenies ( 5 ) .
most of the genes examined in these early studies were too short in length and/or too poorly sampled to permit a more thorough investigation , and those that specifically supported an animal - plant relationship have not been the focus of subsequent phylogenetic investigations .
nevertheless , preliminary combined phylogenetic analyses of a number of these sequences , from nine completed genomes , confirm the presence of an additive tree - building signal that clusters animal and plant sequences ( figure 1 ) , as do more widely sampled analyses of at least four of the genes individually ( figure 2 ) .
the alternative tree - building signal present in these genes reinforces early cautions ( 5 ) that a pervasive and directional artifact is present in sequences used to resolve the animal - plant - fungus trichotomy .
what phylogenetic analyses do not show , and what has not been investigated rigorously , is which of the signals is the artifact ; that is , whether the pervasive artifact favors the opisthokonta or whether it groups animals with plants ?
although further investigations certainly are needed to try to understand the underlying nature of this phylogenetic conflict , an ultimate determination of which tree - building signal is artifactual can not be made directly from the phylogenetic analyses themselves .
as more sequences become available for global eukaryotic comparisons , a cumulative tree - building signal undoubtedly will emerge that favors one or the other hypothesis .
there is no a priori basis , however , for assuming that historical signal will overwhelm a pervasive artifact as data sets grow larger . at deeper phylogenetic levels
, artifacts can entirely dominate the tree topologies recovered ( 8) . in analyzing the early evolution of metazoans , rokas and colleagues ( 9 ) concluded that tree - building artifacts so pervade ancient phylogenetic reconstructions as to make them inherently unreliable .
it seems increasingly clear that such alternative data are needed to test new hypotheses of ancient evolutionary relationships inferred from sequence - based phylogenies ; such characters may be particularly useful in resolving the animal - plant - fungus trichotomy .
in addition to sequence - based phylogenetic analyses , one molecular character has been extremely influential in building a case for the opisthokonta ; that is , a unique shared insertion in the ef-1 genes of animals and fungi , which is absent from all other eukaryotes sampled 1 .
, 5 .. in its apparently ancestral state , this insertion encodes 12 residues with sequence similarity across animal and fungal genes .
because of its reasonable length ( not easily explained by convergence ) , this insertion is interpreted most simply as a shared - derived character that was acquired in the common ancestor of the gene present in animals and fungi ; its absence from plants and other eukaryotes suggests that no other major group shares a gene derived from that ancestor ( 5 ) .
thus , the ef-1 insertion appears to offer compelling support for the opisthokont hypothesis ; it is an independent line of evidence that suggests sequence - based trees supporting an animal - plant relationship are due to phylogenetic artifacts .
genomic - proteomic comparisons of molecular and cellular processes have begun to yield additional lines of evidence that are equally or perhaps more compelling . in a number of cases ,
however , these new data strongly support a sister relationship between plants and animals . among of the most broadly investigated
in eukaryotic mrna processing , a 7-methylguanosine cap is linked to the 5 end of pre - mrna through a three - step pathway involving triphosphatase , guanylyltransferase and methyltransferase enzymes ( 10 ) . in most eukaryotes , including fungi , the three enzymes are encoded by separate genes , and their structures and biochemical properties are conserved strongly ( 11 ) .
animals and plants are exceptional ; in both groups the triphosphatase and guanyltransferase genes are fused and encode a single , bi - functional polypeptide ( 11 ) .
this fusion event , by itself , is not compelling evidence for an animal - plant relationship .
additional fusion events , some clearly convergent , have occurred among the three capping enzymes over the broad course of their evolution ( 11 ) . moreover ,
other gene fusions have been shown to support contradictory sets of relationships ( 12 ) .
it is reasonable that , although undoubtedly rare , fusions between proteins of related function would be favored by natural selection ; thus , convergent events may turn out to be relatively common on the evolutionary time scale in question .
what is highly significant about the capping enzyme , however , is the biochemical nature of the triphosphatase domain of the plant
animal and plant triphosphatases are members of the cysteine phosphatase super family and contain a conserved cys residue at the active site . this cys attacks the terminal phosphate of pre - mrna to produce a covalently bonded intermediate and release the diphosphate mrna product .
this reaction does not require a metal ion co - factor ; rather , it is inhibited in the presence of divalent cations ( 11 ) .
this contrasts sharply with the triphosphatase in fungi , which belongs to a different family of metal - dependent phosphohydrolases that specifically require divalent cations .
both the overall structure and catalytic properties of this enzyme clearly are distinct from the animal and plant triphosphatase ( 11 ) .
all other eukaryotes examined to date , including kinetoplastids , alveolates , microsporidians , dictytostelium , entamoeba , giardia , the oomycete ( stramenopile ) phytophthora , and the red alga cyanidioschyzon , contain the type of metal - dependent triphosphatase that is present in fungi ( 13 ) .
thus the switch to a new kind of triphosphatase and its fusion to the guanylyltransferase enzyme are best interpreted as shared - derived events that occurred in the common ancestor of plants and animals , after it diverged from other eukaryotes 11 .
, 13 .. although the ef-1 insertion can not be dismissed lightly , it is not apparent that a shared 12-amino - acid insertion should be given greater phylogenetic weight than the shared origin of a new triphosphatase enzyme and its subsequent fusion to gualylyltransferase .
additional evidence from proteomic and genomic features will help to determine which of these characters reflects the evolutionary history of the organisms involved .
orthologous gene families that are common to only a subset of eukaryotic taxa can represent shared - derived functions that evolved in the unique common ancestor of those taxa .
likewise , complex molecular or biochemical processes that are unlikely to be products of convergent evolution can offer compelling evidence for polarizing ancient relationships .
initial genome - wide comparisons have uncovered some remarkable similarities between plants and animals that are not shared by fungi or , at least thus far , by other eukaryotic groups .
nevertheless , major innovations and the origins of new processes have marked key evolutionary transitions , both from prokaryotic to eukaryotic cells and from simple to complex eukaryotes .
an overall inventory of orthologous protein families from 31 completed genomes , including six from plants , animals and fungi , does not agree with the evolutionary concept of opisthokonts ( 14 ) .
animals and plants share 41 orthologous groups , exclusive of fungi , whereas fungi and animals share only 15 groups exclusive of plants .
the raw proportion of shared groups among the three lineages is complicated by the possibility of more extensive gene loss in the few complete fungal genomes examined thus far . however , in several cases animal and plant orthologs share unique domain architectures that are not present in fungi or more distant outgroups .
no such unique - shared architectures were reported that link animals with fungi to the exclusion of plants ( see ref . 14 for full discussion ) .
there are additional intriguing examples of gene families and domain structures shared exclusively by animals and plants 15 . ,
, 17 . , but more comprehensive genome - scale comparisons , in particular sampling of more diverse fungal genomes , are required to determine whether overall inventories of other complicated metabolic machinery also favor an animal - plant relationship .
such inventories will provide powerful alternative sources of data for testing sequence - based phylogenetic hypotheses .
both animals and plants have the capacity to differentiate cell types into complex tissues that partition physiological functions .
a key master control over animal development is exerted by retinoblastoma protein ( rb ) , which is important for integrating both cell division and differentiation ( 18 ) .
an rb homologue in plants 19 . , 20 . has been shown to play comparable roles in regulation of the cell cycle ( 21 ) .
even more remarkable has been the discovery that the rb protein in plants is at the center of a complex array of interactions that occur during the g1 phase of cell division and involve e2f transcription regulators ( 22 ) and d - type cyclin kinases ( 21 ) . animals and plants also have the same master controls that prevent cellular differentiation , thereby permitting the maintenance of totipotent stem / meristematic cell lines 23 . , 24 .. all of these proteins and pathways appear to be homologous in plants and animals , performing the same roles in controlling cell division , coordinating growth and in the differentiation of tissue - specific cell type 24 .
, 25 .. previous genetic analyses , and a comprehensive search of available sequence databases ( author s unpublished results ) , reveal that rb protein is present across the broad diversity of green plants and animals , from nematodes to human and chlorophycean algae to angiosperms 26 .
, 27 .. in contrast , when queried with rb genes from both human and arabidopisis , tblastn ( 28 ) searches of all completed and partial fungal genomes , and of all other eukaryotic groups available through ncbi - linked blast resources ( http://www.ncbi.nlm.nih.gov:80/blast/ ) , return no significant hits from organisms outside the green plant and animal lineages ( author s unpublished results ) . a protein similar to rb
was reported in the cellular slime mold physarum polycephalum
( 29 ) , although this sequence is not recovered in database searches and its subsequent functional characterization has not been reported .
it remains possible that rb protein plays a role in cell division in eukaryotes other than plants and metazoans ; however , given evidence that slime molds branch within the animal - plant - fungus trichotomy ( 30 ) , even a true rb orthologue in physarum could be interpreted as a synapomorphy linking slime molds with an animal - plant grouping . in any case , clear rb homologues and , most significantly , the suite of g1 interactions that are central to controlling developmental and tissue specific cell differentiation , have been found only in green plants and animals ( 21 ) .
it has been hypothesized that the invention of the g1 pathway was a defining moment in the evolution of eukaryotes , one that permitted the elaboration of complex organisms with multicellular tissues ( 25 ) .
it remains possible that the g1 pathway is more ancient and has been retained only in animals and plants , the two major groups that went on to develop true tissue differentiation . under this scenario ,
the pathway would have been lost in all more developmentally simple eukaryotic lineages , including fungi ; however , cell cycle regulation by rb protein is conserved in the unicellular green alga chlamydomonas
( 27 ) .
this suggests that , once fully integrated into the cell cycle , the g1 pathway was not easily lost in groups that failed to attain multicellularity or more complex patterns of ontological development .
thus , the fact that fungi do not differentiate cells into true tissues may reflect their more ancient divergence from the ancestral lineage that led to plants and animals .
should additional sampling continue to support the current phylogenetic distribution of rb protein and the g1 pathway , it will offer strong support for the hypothesis that plants and animals share mechanisms for cell cycle control that originated and were canalized in their unique , common ancestor .
in addition to sequence - based phylogenetic analyses , one molecular character has been extremely influential in building a case for the opisthokonta ; that is , a unique shared insertion in the ef-1 genes of animals and fungi , which is absent from all other eukaryotes sampled 1 .
, 5 .. in its apparently ancestral state , this insertion encodes 12 residues with sequence similarity across animal and fungal genes .
because of its reasonable length ( not easily explained by convergence ) , this insertion is interpreted most simply as a shared - derived character that was acquired in the common ancestor of the gene present in animals and fungi ; its absence from plants and other eukaryotes suggests that no other major group shares a gene derived from that ancestor ( 5 ) .
thus , the ef-1 insertion appears to offer compelling support for the opisthokont hypothesis ; it is an independent line of evidence that suggests sequence - based trees supporting an animal - plant relationship are due to phylogenetic artifacts .
genomic - proteomic comparisons of molecular and cellular processes have begun to yield additional lines of evidence that are equally or perhaps more compelling . in a number of cases ,
however , these new data strongly support a sister relationship between plants and animals . among of the most broadly investigated
in eukaryotic mrna processing , a 7-methylguanosine cap is linked to the 5 end of pre - mrna through a three - step pathway involving triphosphatase , guanylyltransferase and methyltransferase enzymes ( 10 ) . in most eukaryotes , including fungi , the three enzymes are encoded by separate genes , and their structures and biochemical properties are conserved strongly ( 11 ) .
animals and plants are exceptional ; in both groups the triphosphatase and guanyltransferase genes are fused and encode a single , bi - functional polypeptide ( 11 ) .
this fusion event , by itself , is not compelling evidence for an animal - plant relationship .
additional fusion events , some clearly convergent , have occurred among the three capping enzymes over the broad course of their evolution ( 11 ) . moreover ,
other gene fusions have been shown to support contradictory sets of relationships ( 12 ) .
it is reasonable that , although undoubtedly rare , fusions between proteins of related function would be favored by natural selection ; thus , convergent events may turn out to be relatively common on the evolutionary time scale in question .
what is highly significant about the capping enzyme , however , is the biochemical nature of the triphosphatase domain of the plant animal fusion protein .
animal and plant triphosphatases are members of the cysteine phosphatase super family and contain a conserved cys residue at the active site . this cys attacks the terminal phosphate of pre - mrna to produce a covalently bonded intermediate and release the diphosphate mrna product .
this reaction does not require a metal ion co - factor ; rather , it is inhibited in the presence of divalent cations ( 11 ) .
this contrasts sharply with the triphosphatase in fungi , which belongs to a different family of metal - dependent phosphohydrolases that specifically require divalent cations .
both the overall structure and catalytic properties of this enzyme clearly are distinct from the animal and plant triphosphatase ( 11 ) .
all other eukaryotes examined to date , including kinetoplastids , alveolates , microsporidians , dictytostelium , entamoeba , giardia , the oomycete ( stramenopile ) phytophthora , and the red alga cyanidioschyzon , contain the type of metal - dependent triphosphatase that is present in fungi ( 13 ) .
thus the switch to a new kind of triphosphatase and its fusion to the guanylyltransferase enzyme are best interpreted as shared - derived events that occurred in the common ancestor of plants and animals , after it diverged from other eukaryotes 11 .
, 13 .. although the ef-1 insertion can not be dismissed lightly , it is not apparent that a shared 12-amino - acid insertion should be given greater phylogenetic weight than the shared origin of a new triphosphatase enzyme and its subsequent fusion to gualylyltransferase .
additional evidence from proteomic and genomic features will help to determine which of these characters reflects the evolutionary history of the organisms involved .
orthologous gene families that are common to only a subset of eukaryotic taxa can represent shared - derived functions that evolved in the unique common ancestor of those taxa .
likewise , complex molecular or biochemical processes that are unlikely to be products of convergent evolution can offer compelling evidence for polarizing ancient relationships .
initial genome - wide comparisons have uncovered some remarkable similarities between plants and animals that are not shared by fungi or , at least thus far , by other eukaryotic groups .
nevertheless , major innovations and the origins of new processes have marked key evolutionary transitions , both from prokaryotic to eukaryotic cells and from simple to complex eukaryotes .
an overall inventory of orthologous protein families from 31 completed genomes , including six from plants , animals and fungi , does not agree with the evolutionary concept of opisthokonts ( 14 ) .
animals and plants share 41 orthologous groups , exclusive of fungi , whereas fungi and animals share only 15 groups exclusive of plants .
the raw proportion of shared groups among the three lineages is complicated by the possibility of more extensive gene loss in the few complete fungal genomes examined thus far . however , in several cases animal and plant orthologs share unique domain architectures that are not present in fungi or more distant outgroups .
no such unique - shared architectures were reported that link animals with fungi to the exclusion of plants ( see ref .
. there are additional intriguing examples of gene families and domain structures shared exclusively by animals and plants 15 . , 16 . , 17 . ,
but more comprehensive genome - scale comparisons , in particular sampling of more diverse fungal genomes , are required to determine whether overall inventories of other complicated metabolic machinery also favor an animal - plant relationship .
such inventories will provide powerful alternative sources of data for testing sequence - based phylogenetic hypotheses .
both animals and plants have the capacity to differentiate cell types into complex tissues that partition physiological functions .
a key master control over animal development is exerted by retinoblastoma protein ( rb ) , which is important for integrating both cell division and differentiation ( 18 ) .
an rb homologue in plants 19 . , 20 . has been shown to play comparable roles in regulation of the cell cycle ( 21 ) .
even more remarkable has been the discovery that the rb protein in plants is at the center of a complex array of interactions that occur during the g1 phase of cell division and involve e2f transcription regulators ( 22 ) and d - type cyclin kinases ( 21 ) . animals and plants also have the same master controls that prevent cellular differentiation , thereby permitting the maintenance of totipotent stem / meristematic cell lines 23 .
, 24 .. all of these proteins and pathways appear to be homologous in plants and animals , performing the same roles in controlling cell division , coordinating growth and in the differentiation of tissue - specific cell type 24 .
, 25 .. previous genetic analyses , and a comprehensive search of available sequence databases ( author s unpublished results ) , reveal that rb protein is present across the broad diversity of green plants and animals , from nematodes to human and chlorophycean algae to angiosperms 26 .
, 27 .. in contrast , when queried with rb genes from both human and arabidopisis , tblastn ( 28 ) searches of all completed and partial fungal genomes , and of all other eukaryotic groups available through ncbi - linked blast resources ( http://www.ncbi.nlm.nih.gov:80/blast/ ) , return no significant hits from organisms outside the green plant and animal lineages ( author s unpublished results ) . a protein similar to rb
was reported in the cellular slime mold physarum polycephalum
( 29 ) , although this sequence is not recovered in database searches and its subsequent functional characterization has not been reported .
it remains possible that rb protein plays a role in cell division in eukaryotes other than plants and metazoans ; however , given evidence that slime molds branch within the animal - plant - fungus trichotomy ( 30 ) , even a true rb orthologue in physarum could be interpreted as a synapomorphy linking slime molds with an animal - plant grouping . in any case , clear rb homologues and , most significantly , the suite of g1 interactions that are central to controlling developmental and tissue specific cell differentiation , have been found only in green plants and animals ( 21 ) .
it has been hypothesized that the invention of the g1 pathway was a defining moment in the evolution of eukaryotes , one that permitted the elaboration of complex organisms with multicellular tissues ( 25 ) .
it remains possible that the g1 pathway is more ancient and has been retained only in animals and plants , the two major groups that went on to develop true tissue differentiation . under this scenario ,
the pathway would have been lost in all more developmentally simple eukaryotic lineages , including fungi ; however , cell cycle regulation by rb protein is conserved in the unicellular green alga chlamydomonas
( 27 ) .
this suggests that , once fully integrated into the cell cycle , the g1 pathway was not easily lost in groups that failed to attain multicellularity or more complex patterns of ontological development .
thus , the fact that fungi do not differentiate cells into true tissues may reflect their more ancient divergence from the ancestral lineage that led to plants and animals .
should additional sampling continue to support the current phylogenetic distribution of rb protein and the g1 pathway , it will offer strong support for the hypothesis that plants and animals share mechanisms for cell cycle control that originated and were canalized in their unique , common ancestor .
analyses of multi - gene concatenated alignments generally introduce an implicit assumption : that is , as sequences are combined into ever larger data sets , the dominant tree - building signal that will emerge from any given set of genomes comes from their historical pattern of relationships .
conflicting signals found among individual genes are then assumed to result from random noise or directional artifacts associated with smaller data sets .
the actual source of the dominant signal , however , could be consistent biases that can come to dominate tree - building algorithms as data sets increase in size 31 . , 32 .. under these circumstances , only a minority of genes might retain enough historical signal to out - compete the pervasive artifact and recover the true evolutionary history .
whatever relationship among plants , animals and fungi ends up favored by the global tree - building signal in eukaryotic molecular sequence data , it will be essential to determine whether that dominant signal is phylogenetic or artifactual in nature . that , in turn , requires alternative approaches for analyzing genome - level data
. initial investigations of proteomic networks and complex cellular processes have yielded intriguing insights into the workings of model plant , animal and fungal systems .
specifically a number of studies have suggested a greater similarity between animals and plants than between animals and fungi .
it is too soon to know whether the totality of these data will support such a relationship .
certainly some shared molecular features , even those representing large and co - adapted processes , could have evolutionary histories complicated by parallel gains and/or losses .
caution is in order , especially when evolutionary hypotheses are based on features known from relatively few eukaryotic taxa ; however , when broader taxonomic sampling continues to support the observed pattern of distribution , as has been true for the novel capping enzyme shared by animals and plants , the hypothesis of a unique , shared - derived character is strengthened . as has been true for both morphological and primary sequence data
, conflicts undoubtedly will arise in genomic and proteomic characters that need to be reconciled with any given phylogenetic hypothesis .
nevertheless , in building a strong consensus view on ancient eukaryotic relationships , evolutionary researchers must begin to take these alternative lines of evidence into account .
as of submission of this review , the functional and genome - level data highlighted here have yet to be cited in any phylogenetic investigation of broad scale eukaryotic relationships .
the goal of this contribution is to promote a broader appreciation of emerging bioinformatic , proteomic , and genomic data and their great potential for helping to resolve ancient evolutionary relationships .
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### Summary:
: sequence - based molecular phylogenies have provided new models of early eukaryotic evolution .
this includes the widely accepted hypothesis that animals are related most closely to fungi , and that the two should be grouped together as the opisthokonta .
although most published phylogenies have supported an opisthokont relationship , a number of genes contain a tree - building signal that clusters animal and green plant sequences , to the exclusion of fungi .
the alternative tree - building signal is especially intriguing in light of emerging data from genomic and proteomic studies that indicate striking and potentially synapomorphic similarities between plants and animals .
this paper reviews these new lines of evidence , which have yet to be incorporated into models of broad scale eukaryotic evolution .
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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 recent aging of society and , importantly , the spread of antibiotic - resistant strains , makes it worthwhile to consider the different aspects of epididymitis ( ep ) in older and younger patients , even though the etiology and therapeutic strategies of this disease are considered to be established .
thus , we investigated how age ( older or younger ) affects ep - related symptoms .
ep may have different characteristics in older and younger patients , especially in terms of causative microorganisms and severity ; however , research has focused mostly on younger men in the united states .
it has been debated whether ep is related to urinary tract infections ( utis ) , and the theory suggests that the cause of ep in younger men tends to be sexually transmitted infections ( stis ) and that the cause in older men tends to be utis .
this may be partly because the causative routes of infection are varied , and some routes involve the urinary tract and others involve urogenital organs such as the prostate or seminal vesicle .
ep presents with a variety of clinical features or symptoms ; for instance , the infection occurrence pattern can be acute or chronic , and the patients may or may not have fever .
considering that older patients have lower urinary tract symptoms ( luts ) from benign prostatic hyperplasia ( bph ) , urinary tract factors may affect this infectious disease ; for instance , pyuria , bacteriuria , or large volumes of residual urine might be risk factors for ep from uti . in this study
, we retrospectively examined 308 cases from seven hospitals in hyogo , japan , to explore the clinical risk factors for ep - related symptoms , with a particular focus on the patients ' age or urine findings of pyuria or bacteriuria .
these findings could provide the basis for prospective or randomized studies to establish the clinical risk factors for ep - related symptoms or algorithms for treatments in the future .
the ep data were gathered from seven hospitals ( kobe university hospital , yodogawa catholic hospital , steel memorial hirohata hospital , shinko hospital , kobe city medical center west hospital , kobe red cross hospital , and hara genitourinary hospital ) in hyogo , japan .
this study was admitted by the kobe university institutional review board and followed the basis of the declaration of helsinki ( approval number : 160148 ) .
ep was diagnosed by the physicians taking care of the patients as induration and tenderness of the epididymis .
all data included the following factors : age , febrile or afebrile , duration to improvement of fever , site , tenderness , pyuria , bacteriuria , and antibiotic treatments .
in addition , pyuria and bacteriuria were also investigated if they might have caused ep - related symptoms .
pyuria was defined as 5 or more white blood cells per high power field in urine and bacteriuria as a bacterial isolation of 10 or more colony forming units / ml in urine .
statistical analysis was conducted by using chi - square tests with jstat ( java virtual machine statistics monitoring tool ) . to examine
whether older age ( 65 years ) correlated with urine findings or ep - related symptoms in ep patients , we divided the patients into 2 groups by age , 65 years or older and 64 years or younger , and performed statistical analyses on the categories mentioned above .
in addition , statistical analyses were conducted to examine whether pyuria or bacteriuria correlated to ep - related symptoms with p<0.05 considered to indicate statistical significance .
these analyses were performed by use of univariate and multivariate analyses , and multiple regression analysis was performed by use of the pasw statistics 17.0 ( spss inc . , chicago , il , usa ) .
the ep data were gathered from seven hospitals ( kobe university hospital , yodogawa catholic hospital , steel memorial hirohata hospital , shinko hospital , kobe city medical center west hospital , kobe red cross hospital , and hara genitourinary hospital ) in hyogo , japan .
this study was admitted by the kobe university institutional review board and followed the basis of the declaration of helsinki ( approval number : 160148 ) .
ep was diagnosed by the physicians taking care of the patients as induration and tenderness of the epididymis .
all data included the following factors : age , febrile or afebrile , duration to improvement of fever , site , tenderness , pyuria , bacteriuria , and antibiotic treatments .
in addition , pyuria and bacteriuria were also investigated if they might have caused ep - related symptoms .
pyuria was defined as 5 or more white blood cells per high power field in urine and bacteriuria as a bacterial isolation of 10 or more colony forming units / ml in urine .
statistical analysis was conducted by using chi - square tests with jstat ( java virtual machine statistics monitoring tool ) . to examine whether older age ( 65 years ) correlated with urine findings or ep - related symptoms in ep patients , we divided the patients into 2 groups by age , 65 years or older and 64 years or younger , and performed statistical analyses on the categories mentioned above .
in addition , statistical analyses were conducted to examine whether pyuria or bacteriuria correlated to ep - related symptoms with p<0.05 considered to indicate statistical significance .
these analyses were performed by use of univariate and multivariate analyses , and multiple regression analysis was performed by use of the pasw statistics 17.0 ( spss inc . ,
in all cases in which data were available for analysis , age ranged from 5 to 98 years .
the site of ep included 150 right cases , 152 left cases , and 4 bilateral cases ( 2 unknown cases ) .
sixty - six cases ( 21.4% ) had high fever ( 38 ) and the mean duration to fever suppression was 3.351.83 days .
pyuria was seen in 147 of 308 cases ( 47.7% ) and bacteriuria was seen in 152 of 308 cases ( 49.4% ) .
causative microorganisms were escherichia coli and chlamydia in 8 cases each ( 2.6% ) , respectively .
as to other antibiotic - resistant strains , there were 2 cases each of extended spectrum beta - lactamase - producing e. coli and methicillin - resistant staphylococcus aureus ( 0.65% ) , respectively ( tables 1 , 2 ) .
all cases improved after treatment but 2 cases underwent orchiectomy for abscess formation . as therapeutic antibiotics , levofloxacin ( 133 patients [ 43.2% ] ) , cefozopran ( 73 patients [ 23.7% ] ) , and ceftriaxone ( 43 patients [ 14.0% ] ) were used frequently .
one hundred fifty - one patients ( 49.0% ) were treated with 1 kind of antibiotic and 139 ( 45.1% ) were treated with 2 kinds , but mostly they were used as a switching therapy . to determine if age correlated with urine findings such as pyuria or bacteriuria or ep - related symptoms such as scrotum swelling or fever , we set 65 years as the cutoff as mentioned above and then compared symptoms between the older age group ( 65 years ) and the younger age group ( 64 years ) .
we found that pyuria ( p=0.0027 ) and bacteriuria ( p=0.033 ) were observed at a significantly higher ratio in the older age group than in the younger age group .
however , there was no significant correlation between age and duration of fever ( p=0.057 ) . in the multivariate analysis ,
pyuria was significantly related to fever ( p<0.0001 for 37 or higher and p=0.0008 for 38 or higher ) , and this was observed as significant in the multivariate analyses as well ( p=0.0159 for 37 or higher ) ( table 4 ) .
in all cases in which data were available for analysis , age ranged from 5 to 98 years .
the site of ep included 150 right cases , 152 left cases , and 4 bilateral cases ( 2 unknown cases ) .
sixty - six cases ( 21.4% ) had high fever ( 38 ) and the mean duration to fever suppression was 3.351.83 days .
pyuria was seen in 147 of 308 cases ( 47.7% ) and bacteriuria was seen in 152 of 308 cases ( 49.4% ) .
causative microorganisms were escherichia coli and chlamydia in 8 cases each ( 2.6% ) , respectively .
as to other antibiotic - resistant strains , there were 2 cases each of extended spectrum beta - lactamase - producing e. coli and methicillin - resistant staphylococcus aureus ( 0.65% ) , respectively ( tables 1 , 2 ) .
all cases improved after treatment but 2 cases underwent orchiectomy for abscess formation . as therapeutic antibiotics , levofloxacin ( 133 patients [ 43.2% ] ) , cefozopran ( 73 patients [ 23.7% ] ) , and ceftriaxone ( 43 patients [ 14.0% ] ) were used frequently .
one hundred fifty - one patients ( 49.0% ) were treated with 1 kind of antibiotic and 139 ( 45.1% ) were treated with 2 kinds , but mostly they were used as a switching therapy .
to determine if age correlated with urine findings such as pyuria or bacteriuria or ep - related symptoms such as scrotum swelling or fever , we set 65 years as the cutoff as mentioned above and then compared symptoms between the older age group ( 65 years ) and the younger age group ( 64 years ) .
we found that pyuria ( p=0.0027 ) and bacteriuria ( p=0.033 ) were observed at a significantly higher ratio in the older age group than in the younger age group .
however , there was no significant correlation between age and duration of fever ( p=0.057 ) . in the multivariate analysis , older age groups correlated with pyuria ( p=0.0156 ) ( table 3 ) .
pyuria was significantly related to fever ( p<0.0001 for 37 or higher and p=0.0008 for 38 or higher ) , and this was observed as significant in the multivariate analyses as well ( p=0.0159 for 37 or higher ) ( table 4 ) .
the notable features of ep are as follows : ( 1 ) identification of the route of infection is sometimes unclear .
( 2 ) the causative microorganisms are often undetectable . ( 3 ) ep is comparatively easy to diagnose .
( 4 ) as mentioned below in the study limitations , it may be hard to test urine or pus cultures because patients with ep , like patients with male urethritis , tend to be cured in clinics and not in research institutions such as a university hospital .
therefore , there are fewer cases with treatment difficulties compared with other urological infections and thus research is lacking .
accordingly , we focused on the correlation between the patient 's age and urine findings related to inflammation or infection , and ep - related symptoms such as fever in order to further knowledge of ep and its etiology .
. stated that in their management of epididymo - orchitis they consider mumps and , especially in the immune - compromised host , tuberculosis as possible causative microorganisms and that consideration of gonorrhea is essential for decisions about antibiotics .
as to the antibiotic treatments , our cases included a high frequency of fluoroquinolone use according to the literature , followed by the third- or fourth - generation cephalosporins .
these differences in antibiotic use suggest that ( 1 ) our cases included older patients at higher ratios than in other studies and that enterobacteriaceae , which is not an sti - causing microorganism in general , should have been a target for treatment , and ( 2 ) regional guidelines may be necessary because not all regions will have the same trends in patients ' age and causative microorganisms . in terms of causative microorganisms , bbar et al .
stated in their review that asymptomatic chlamydia infection can cause symptomatic ep and that single - dose antibiotic treatments should be effective in uncomplicated cases . on the other hand ,
e. coli was most often isolated as the causative microorganism in our limited data ( because only 41 cases had positive urine or pus culture tests as mentioned below in the study limitations ) , which differs from other reports in which neisseria gonorrhoeae or chlamydia spp . were the most prevalent .
ep may be caused by symptomatic or asymptomatic utis , at least based on our data and especially in the older generation .
a report from korea showed that epididymo - orchitis was more common in patients not only with a history of urethral stricture but on clean intermittent catheterization ( cic ) rather than indwelling urethral catheterization .
those authors also added that cic , not urethral stricture , is a significant independent risk factor for epididymo - orchitis .
our data showed that pyuria correlated with fever ( p=0.0159 ) . in contrast to younger men , in whom sexually transmitted pathogens are predominant , in older patients with a history of subvesical obstruction , e. coli is the most frequent pathogen responsible .
these data support our data mentioned above and overcome the limited evidence for not only etiology but also treatments , especially in older patients .
first , the data were retrospectively gathered from seven hospitals over 5 years and lack some elements necessary for definitive statistical analyses .
however , we designed the study to include and reflect real clinical ep and its treatments .
in particular , bacterial studies were not always available , suggesting that physicians need to be educated on the need for culture tests when treating with antibiotics .
discussed the lower implementation rate of the european urological association guideline in the management of acute epididymo - architis . however ,
the references cited in that paper are older and considering the dramatic changes in society , especially in aging and antibiotic - resistant microorganisms , information on this disease needs to be updated by this kind of research .
these limitations should be overcome by the establishment of therapeutic strategies not only for antibiotic therapies but also for treatment goals and the management of risk factors such as uncontrolled luts from bph including pyuria or bacteriuria .
our retrospective data showed that older patients ( 65 years ) had a higher ratio of pyuria , and in the multivariate analysis , pyuria may have been significantly correlated with ep - related symptoms ( fever ) in this study of over 300 cases of ep .
these data suggest that age - specific guidelines may be necessary , and for this , additional clinical trials should be considered .
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### Summary:
: purposeaccording to the aging of society and the spread of antibiotic - resistant strains , it is worth considering the different aspects of epididymitis ( ep ) in older and younger patients , even though the etiology and therapeutic strategies of this disease are considered to be established .
thus , we investigated how age affects ep - related symptoms.materials and methodsdata were gathered from 7 hospitals in hyogo , japan , and the correlations of age ( older or younger ) with urine findings such as pyuria or bacteriuria and ep - related symptoms such as fever were investigated.resultsin all 308 cases with full data for evaluation , there were 66 febrile ( 38 or higher ) cases ( 21.4% ) and bacteriuria was seen in 158 cases ( 51.3% ) . in the multivariate analysis , older age (
65 years or older ) was significantly correlated with the presence of pyuria ( p=0.0156 ) .
regarding the relationship between urine findings and ep - related symptoms , pyuria was significantly related to fever ( 37 or higher ; p=0.0159).conclusionsour data showed that older patients with ep had pyuria significantly more often than did younger patients , which correlated with ep - related symptoms ( fever ) .
these data suggest that age - specific guidelines may be necessary .
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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:
: between july 1999 and may 2001 , 21 patients [ m : f=17:4 ; mean age , 57 ( range , 42 - 80 ) years ] were referred to our hospital for radiological intervention because of active gastric variceal bleeding due to liver cirrhosis .
the cirrhosis was caused by hbv in eleven patients , hcv in six , and chronic alcohol ingestion in four . in seven patients ,
hepatocellular carcinoma was also present . in order to determine an appropriate interventional procedure , all patients underwent ct scanning , and endoscopy was also performed in all patients except number 1 , in whom it was impossible because of massive hematemesis .
gastric varices located in gastric cardia and the gastric fundus were detected in all patients , and active bleeding from varices was observed . at ct ,
one of the 15 with gastrorenal shunt , patient 21 , had diffuse hepatocellular carcinoma of the liver and underwent brto .
the 14 remaining patients were randomly assigned to one of two groups , ' tips ' or ' brto ' .
thus , among patients with gastrorenal shunt , seven underwent tips ( group 2 ) and eight underwent brto ( group 3 ) .
the patients ' demographic data are summarized in table 1 , which shows that three patients had a history of hepatic encephalopathy prior to active gastric bleeding .
differences between the three groups in terms of child - pugh liver function score were not significant . in all cases , written informed consent to the procedures was obtained from patients or their families .
first , the patency of hepatic and portal veins was assessed by ct scanning . by means of the transjugular venous approach , venography of the right and , if necessary , middle hepatic vein was performed . to visualize portal veins , co2-wedged hepatic venography
tract creation , a ring transjugular intrahepatic access set ( cook , bloomington , ind .
was used ; in twelve of the thirteen patients , a shunt tract was created between the right hepatic and right portal vein , and in the other , between the middle hepatic and left portal vein because of bland thrombosis of the right portal vein . after puncturing the portal veins , portal venography was performed and the pressure gradient between the portal vein and right atrium was measured . before stent insertion , the tract was dilated with a 10-mm balloon catheter ( ultra - thin diamond ; boston scientific , watertown , mass . , u.s.a . ) .
self - expandable stents , wallstent ( boston scientific ) ( n=8 ) or niti - s ( taewoong , seoul , korea ) ( n=5 ) , were deployed in the shunt tract prior to further dilatation with a 10-mm balloon catheter .
the right internal jugular vein was punctured in all patients . a 7-fr occlusion balloon catheter with maximum 12 mm ballooning ( clinical supply , gifu , japan )
was inserted into the left adrenal vein through the left renal vein . for confirmation of feeding veins , draining veins , and gastric varix collaterals ,
if collateral gastric variceal drainage veins were identified , they were embolized with microcoils , glue , or gelatin sponge particles to prevent leakage of the sclerosing agent into systemic circulation .
the sclerosing agent used was a mixture of 5% ethanolamine oleate ( keuk dong pharmaceuticals , inchon , korea ) and iodized oil ( lipiodol(r ) ; laboratoire guerbet , riossy , france ) , mixed in a ratio of 3:1 - 6:1 .
the volume of sclerosing agent prepared depended on the volume of contrast media necessary to visualize the gastric varix by manual injection . using an occlusion balloon catheter
with the balloon inflated , the agent was slowly infused into the gastrorenal shunt in a retrograde fashion until the vascular space in the gastric varices was completely opacified and feeding veins from the portal or splenic veins began to be visualized .
the total of injected volume of sclerosing agent ranged from 13 to 36 ( mean , 25 ) ml ; to facilitate its complete infusion , the sengstaken - blakemore tube inserted for hemostasis was deflated .
the injected sclerosing agent remained in the varix for three hours with the balloon inflated , and as much of it as possible was then aspirated under fluoroscopy . to confirm the cessation of blood flow within the shunt ,
patient 1 died three days after tips , but the remaining twenty patients were followed up for 6 to 21 ( mean , 14.4 ) months .
immediate hemostasis , hepatic encephalopathy , rebleeding and survival were monitored , and changes in the amount of ascites and the child- pugh score before and after the procedures determined .
other than patient 10 , those in whom tips was performed underwent doppler ultrasonography during follow - up , and the patency of the tips tract and portal flow were thus assessed . in patients who underwent brto ,
ct was performed during the follow - up period , permitting evaluation of the obliteration of gastric varices and the gastrorenal shunt .
post - procedural endoscopic evaluation of gastric varices was performed in three group-1 patients , three in group 2 , and six in group 3 . immediately occurring procedure - related complications
hemostasis , rebleeding and encephalopathy , fisher 's exact test was used , and changes in the child - pugh score before and after the procedure in each group were statistically analyzed by means of wilcoxon 's signed rank test .
between july 1999 and may 2001 , 21 patients [ m : f=17:4 ; mean age , 57 ( range , 42 - 80 ) years ] were referred to our hospital for radiological intervention because of active gastric variceal bleeding due to liver cirrhosis .
the cirrhosis was caused by hbv in eleven patients , hcv in six , and chronic alcohol ingestion in four . in seven patients ,
hepatocellular carcinoma was also present . in order to determine an appropriate interventional procedure , all patients underwent ct scanning , and endoscopy was also performed in all patients except number 1 , in whom it was impossible because of massive hematemesis .
gastric varices located in gastric cardia and the gastric fundus were detected in all patients , and active bleeding from varices was observed . at ct ,
one of the 15 with gastrorenal shunt , patient 21 , had diffuse hepatocellular carcinoma of the liver and underwent brto .
the 14 remaining patients were randomly assigned to one of two groups , ' tips ' or ' brto ' .
thus , among patients with gastrorenal shunt , seven underwent tips ( group 2 ) and eight underwent brto ( group 3 ) .
the patients ' demographic data are summarized in table 1 , which shows that three patients had a history of hepatic encephalopathy prior to active gastric bleeding .
differences between the three groups in terms of child - pugh liver function score were not significant . in all cases , written informed consent to the procedures was obtained from patients or their families .
first , the patency of hepatic and portal veins was assessed by ct scanning . by means of the transjugular venous approach , venography of the right and , if necessary , middle hepatic vein was performed . to visualize portal veins , co2-wedged hepatic venography was routinely performed . for tips
tract creation , a ring transjugular intrahepatic access set ( cook , bloomington , ind . , u.s.a . ) was used ; in twelve of the thirteen patients , a shunt tract was created between the right hepatic and right portal vein , and in the other , between the middle hepatic and left portal vein because of bland thrombosis of the right portal vein .
after puncturing the portal veins , portal venography was performed and the pressure gradient between the portal vein and right atrium was measured . before stent insertion ,
the tract was dilated with a 10-mm balloon catheter ( ultra - thin diamond ; boston scientific , watertown , mass . , u.s.a . ) .
self - expandable stents , wallstent ( boston scientific ) ( n=8 ) or niti - s ( taewoong , seoul , korea ) ( n=5 ) , were deployed in the shunt tract prior to further dilatation with a 10-mm balloon catheter .
the right internal jugular vein was punctured in all patients . a 7-fr occlusion balloon catheter with maximum 12 mm ballooning ( clinical supply , gifu , japan )
was inserted into the left adrenal vein through the left renal vein . for confirmation of feeding veins , draining veins , and gastric varix collaterals ,
if collateral gastric variceal drainage veins were identified , they were embolized with microcoils , glue , or gelatin sponge particles to prevent leakage of the sclerosing agent into systemic circulation .
the sclerosing agent used was a mixture of 5% ethanolamine oleate ( keuk dong pharmaceuticals , inchon , korea ) and iodized oil ( lipiodol(r ) ; laboratoire guerbet , riossy , france ) , mixed in a ratio of 3:1 - 6:1 .
the volume of sclerosing agent prepared depended on the volume of contrast media necessary to visualize the gastric varix by manual injection .
using an occlusion balloon catheter with the balloon inflated , the agent was slowly infused into the gastrorenal shunt in a retrograde fashion until the vascular space in the gastric varices was completely opacified and feeding veins from the portal or splenic veins began to be visualized .
the total of injected volume of sclerosing agent ranged from 13 to 36 ( mean , 25 ) ml ; to facilitate its complete infusion , the sengstaken - blakemore tube inserted for hemostasis was deflated .
the injected sclerosing agent remained in the varix for three hours with the balloon inflated , and as much of it as possible was then aspirated under fluoroscopy . to confirm the cessation of blood flow within the shunt
patient 1 died three days after tips , but the remaining twenty patients were followed up for 6 to 21 ( mean , 14.4 ) months .
immediate hemostasis , hepatic encephalopathy , rebleeding and survival were monitored , and changes in the amount of ascites and the child- pugh score before and after the procedures determined .
other than patient 10 , those in whom tips was performed underwent doppler ultrasonography during follow - up , and the patency of the tips tract and portal flow were thus assessed . in patients who underwent brto ,
ct was performed during the follow - up period , permitting evaluation of the obliteration of gastric varices and the gastrorenal shunt .
post - procedural endoscopic evaluation of gastric varices was performed in three group-1 patients , three in group 2 , and six in group 3 . immediately occurring procedure - related complications
were also investigated . for statistical inter - group analysis in terms of immediate hemostasis , rebleeding and encephalopathy ,
fisher 's exact test was used , and changes in the child - pugh score before and after the procedure in each group were statistically analyzed by means of wilcoxon 's signed rank test .
the portosystemic pressure gradient fell to below 12 mmhg , and completion portography showed that in all patients except number 4 , whose pressure gradient was 19 mmhg , gastric varices had disappeared .
patient 1 died of sepsis , acute respiratory distress syndrome and persistent bleeding three days after the procedure , but in the remaining five patients , immediate hemostasis was achieved . during the follow - up period ,
post - tips hepatic encephalopathy occurred in one patient , number 3 , who underwent liver transplantation two months after tips .
the post - tips child - pugh score showed a decrease in three patients and an increase in the other three .
follow - up duplex sonography indicated that the patency of the tips tract was well maintained and there was no disturbance of portal flow .
follow - up endoscopy , performed in patients 3 , 4 and 6 , indicated that the varices had disappeared or become smaller .
the post - tips portosystemic pressure gradient fell to below 12 mmhg , except in patient 12 , whose gastric varix was not opacified at post - tips portography despite an unsatisfactory gradient decrease ( 17 mmhg ) . in patient 8 ,
because of persistent filling of the gastric varix at completion portography , post - tips coil embolization of the gastric varix was performed .
two patients , numbers 7 and 9 , underwent post - tips balloon angioplasty for splenic vein stenosis .
immediate hemostasis was achieved in all patients , and no immediate procedure - related complication occurred . during the follow - up period , rebleeding occurred in one patient ( number 13 ) five months after tips because of an occluded tips tract .
tips revision failed to reopen this tract sufficiently , and a satisfactory reduction in the portosystemic pressure gradient was thus not achieved .
to control the varix , brto was thus performed , and there was no further rebleeding . in patients 9 , 10 and 12 , hepatic encephalopathy developed ; hepatic failure 18 months after tips led to the death of patient 10 .
the post - tips child - pugh score decreased in two patients , increased in three , and showed no change in the other two .
follow - up endoscopy in patients 9 and 10 showed that the varices had become smaller or disappeared entirely .
one patient , number 18 , removed the occlusion balloon catheter herself after thirty minutes , but the injected sclerosing agent remained in situ without pulmonary embolism .
fever developed in two , numbers 14 and 15 , but subsided after conservative therapy . otherwise , no immediate procedure - related complications occurred .
the post - brto child - pugh score decreased in seven patients and showed no change in the other . during the follow - up period , neither rebleeding nor hepatic encephalopathy were encountered .
follow - up ct showed that in all patients , gastric varices were filled with sclerosing agents or obliterated .
follow - up endoscopy performed in six patients ( numbers 14 - 17 , 19 , and 21 ) revealed that varices had either disappeared or were smaller , though in patient 16 a newly developed esophageal varix was discovered two months after brto . with respect to immediate hemostasis ( p > 0.05 ) , rebleeding ( p > 0.05 ) and encephalopathy ( p > 0.05 )
a significantly decreased post - procedural child - pugh score was found in group 3 ( p = 0.02 ) , but not in groups 1 ( p = 0.91 ) or 2 ( p = 0.89 ) .
after tips , the portosystemic pressure gradient fell to below 12 mmhg , and completion portography showed that in all patients except number 4 , whose pressure gradient was 19 mmhg , gastric varices had disappeared .
patient 1 died of sepsis , acute respiratory distress syndrome and persistent bleeding three days after the procedure , but in the remaining five patients , immediate hemostasis was achieved . during the follow - up period ,
post - tips hepatic encephalopathy occurred in one patient , number 3 , who underwent liver transplantation two months after tips .
the post - tips child - pugh score showed a decrease in three patients and an increase in the other three .
follow - up duplex sonography indicated that the patency of the tips tract was well maintained and there was no disturbance of portal flow .
follow - up endoscopy , performed in patients 3 , 4 and 6 , indicated that the varices had disappeared or become smaller .
the post - tips portosystemic pressure gradient fell to below 12 mmhg , except in patient 12 , whose gastric varix was not opacified at post - tips portography despite an unsatisfactory gradient decrease ( 17 mmhg ) . in patient 8 ,
because of persistent filling of the gastric varix at completion portography , post - tips coil embolization of the gastric varix was performed .
two patients , numbers 7 and 9 , underwent post - tips balloon angioplasty for splenic vein stenosis .
immediate hemostasis was achieved in all patients , and no immediate procedure - related complication occurred . during the follow - up period , rebleeding occurred in one patient ( number 13 ) five months after tips because of an occluded tips tract .
tips revision failed to reopen this tract sufficiently , and a satisfactory reduction in the portosystemic pressure gradient was thus not achieved .
to control the varix , brto was thus performed , and there was no further rebleeding . in patients 9 , 10 and 12 , hepatic encephalopathy developed ; hepatic failure 18 months after tips led to the death of patient 10 .
the post - tips child - pugh score decreased in two patients , increased in three , and showed no change in the other two .
follow - up endoscopy in patients 9 and 10 showed that the varices had become smaller or disappeared entirely .
one patient , number 18 , removed the occlusion balloon catheter herself after thirty minutes , but the injected sclerosing agent remained in situ without pulmonary embolism .
fever developed in two , numbers 14 and 15 , but subsided after conservative therapy . otherwise , no immediate procedure - related complications occurred .
the post - brto child - pugh score decreased in seven patients and showed no change in the other . during the follow - up period , neither rebleeding nor hepatic encephalopathy were encountered .
follow - up ct showed that in all patients , gastric varices were filled with sclerosing agents or obliterated .
follow - up endoscopy performed in six patients ( numbers 14 - 17 , 19 , and 21 ) revealed that varices had either disappeared or were smaller , though in patient 16 a newly developed esophageal varix was discovered two months after brto . with respect to immediate hemostasis ( p > 0.05 ) , rebleeding ( p > 0.05 ) and encephalopathy ( p > 0.05 )
a significantly decreased post - procedural child - pugh score was found in group 3 ( p = 0.02 ) , but not in groups 1 ( p = 0.91 ) or 2 ( p = 0.89 ) .
tips has been considered the standard therapy for gastric varices unresponsive to pharmacological and endoscopic treatment , but recent reports have claimed that for their management , transvenous obliteration ( brto ) is less invasive and more effective than shunt surgery or tips ( 10 - 25 ) .
tips does not always induce their disappearance , and according to one report ( 17 ) , the improvement rate after tips is only 50% .
brto , on the other hand , can in most cases completely obliterate these varices .
( 27 ) reported the complete obliteration of gastric varices , demonstrated at ct , in all their 52 patients treated with brto .
our study also demonstrated complete obliteration in all our eight patients who underwent the procedure , a finding confirmed at follow - up ct .
to date , brto has been applied electively , as a prophylactic measure , in the treatment of gastric varices , but in this study it was used for the emergent or urgent treatment of active gastric variceal bleeding .
immediate hemostasis was achieved and no rebleeding was noted during follow - up , and brto was thus as effective as tips in the control of bleeding .
the spontaneous portosystemic ( splenorenal or gastrorenal ) shunt reported to occur in 28% of patients with portal hypertension ( 28 ) can increase the risk of chronic hepatic encephalopathy ( 29 ) . in such patients , tips can cause intractable hepatic encephalopathy due to the increased shunt volume ( 30 ) .
laberge reported an 18% incidence of hepatic encephalopathy after tips ( 31 ) , and in our study , its incidence among group 1 patients ( gastric varix without gastrorenal shunt and tips ) was similar .
group 2 ( gastric varix with gastrorenal shunt and tips ) showed a higher incidence , however : hepatic encephalopathy occurred in three of the seven patients . in brto , however , a spontaneous portosystemic shunt is occluded , and hepatic encephalopathy is thus not an obstacle .
( 3 ) recommended brto rather than tips for patients with gastric varices in association with a gastrorenal shunt or hepatic encephalopathy , and in our series of gastric variceal bleeding , no case of hepatic encephalopathy arose through the use of brto .
the augmentation of portal blood flow in brto ( shunt occlusion therapy ) can improve liver function in cirrhotic liver ( 23 , 32 ) , but tips ( shunt creation therapy ) , on the other hand , may decrease portal flow , leading to deterioration in liver function ( 33 ) . in our study , the child - pugh score showed a statistically significant improvement in patients who underwent brto , though in three tips patients in group 1 and three in group 2 , the child - pugh score worsened .
the occlusion of a gastrorenal shunt , the main way of reducing portal venous pressure , may - if there are no other collateral vessels outside the esophageal wall or elsewhere - aggravate existing esophageal varices or lead to the development of new ones , and this is one of the most significant complications of brto ( 21 , 27 ) . in our series , for example
, a new esophageal varix was detected at follow - up endoscopy two months after brto in one patient .
these varices can , however , largely controlled by endoscopic injection sclerotherapy or variceal ligation ( 21 )
. tips can give rise to various procedure - related complications such as hepatic arterial injury and hemoperitoneum due to extrahepatic puncture , and stenosis or occlusion of a tips tract is frequently observed during follow - up . in our study , however , there were no notable tips - related complications . since brto requires balloon occlusion to block the outflow of the gastric varix , as well as retrograde injection of the sclerosing agent , the existence of a dilated suprarenal vein for use as the usual draining vein should be confirmed before the procedure . also , since tips requires an appropriate portosystemic shunt tract between the hepatic and portal vein , the exact relation between these two vessels should also be pre - procedurally determined .
thin - section helical ct may play an important role in the evaluation of a gastric varix , gastrorenal shunt , and the hepatic vascular anatomy , and careful interpretation of the ct scans should help lay the groundwork for the proper interventional procedure .
the occlusion of collateral veins connected to a gastrorenal shunt is essential for successful brto .
( 3 ) devised a five - point scale to classify the degree of progression of gastric varices and collateral veins , basing their system on the results of adrenal venography performed during balloon occlusion .
except for grade 5 , in which the left adrenal vein could not be occluded by the balloon catheter because of a very large gastrorenal shunt with rapid blood flow , the appropriate embolization of collateral veins lead to successful brto . in our study , collateral veins were embolized in four patients , and the embolic materials used were glue , coils , and gelfoam .
when multiple fine collaterals existed , we retrogradely injected 222-mm gelatin sponge particles into the gastrorenal shunt tract while the proximal adrenal vein was occluded with an occlusion balloon catheter ( fig .
1 ) . conner et al . ( 34 ) and hoak et al . ( 35 ) reported that ethanolamine oleate promptly binds with albumin in the blood , thus becoming inactive , and decomposes to form oleic acid and ethanolamine .
if only a small amount is used , it is therefore safe for local treatment .
its possible side effects include , however , pulmonary embolism , renal dysfunction , pleural effusion , pulmonary edema , hypersensitivity reaction , pyrexia , and disseminated intravascular coagulation syndrome , and it also causes hemolysis of the blood vessels , leading to free hemoglobin , which may give rise to renal tubular disturbance and renal insufficiency . in brto , a relatively large amount of ethanolamine oleate is used , and to prevent or minimize systemic complications it is therefore important to prevent its abrupt systemic inflow .
the various preventative measures which can be used include allowing sufficient ballooning time for clotting , the aspiration of any ethanolamine oleate remaining in a gastrorenal shunt and gastric varix , and the embolization of collateral veins connected to a gastrorenal shunt .
some reports ( 3 , 7 , 14 , 21 - 23 ) have described the intravenous injection of haptoglobin , which combines with free hemoglobin , to prevent renal insufficiency associated with hemolysis ; in this study , we kept a balloon catheter inflated for three hours and aspirated as much of the infused sclerosing agent as possible .
because of the small number of patients in this study and the different follow - up periods involved , there may be certain problems asscociated with statistical analysis .
even though there was no statistical difference with respect to encephalopathy between group 1 and group 3 ( p = 0.38 ) or between group 2 and group 3 ( p = 0.08 ) , we are left with the impression that in a study involving more patients there would be significant differences between groups , especially between group 2 and group 3 , and that the results would be more exact . to overcome these limitations , further studies involving a larger series and longer follow - up period are needed . in conclusion , brto can effectively control active gastric variceal bleeding , and because of immediate hemostasis , the absence of rebleeding , and improved liver function , is a good alternative to tips in patients in whom such bleeding , accompanied by gastrorenal shunt , occurs .
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### Summary:
: objectiveto assess the feasibility of balloon - occluded retrograde transvenous obliteration ( brto ) in active gastric variceal bleeding , and to compare the findings with those of transjugular intrahepatic portosystemic shunt ( tips).materials and methodstwenty - one patients with active gastric variceal bleeding due to liver cirrhosis were referred for radiological intervention . in 15 patients , contrast - enhanced ct scans demonstrated gastrorenal shunt , and the remaining six ( group 1 ) underwent tips .
seven of the 15 with gastrorenal shunt ( group 2 ) were also treated with tips , and the other eight ( group 3 ) underwent brto .
all patients were followed up for 6 to 21 ( mean , 14.4 ) months . for statistical inter - group comparison of immediate hemostasis , rebleeding and encephalopathy ,
fisher 's exact test was used .
changes in the child - pugh score before and after each procedure in each group were statistically analyzed by means of wilcoxon 's signed rank test.resultsone patient in group 1 died of sepsis , acute respiratory distress syndrome , and persistent bleeding three days after tips , while the remaining 20 survived the procedure with immediate hemostasis .
hepatic encephalopathy developed in four patients ( one in group 1 , three in group 2 , and none in group 3 ) ; one , in group 2 , died while in an hepatic coma 19 months after tips .
rebleeding occurred in one patient , also in group 2 . except for transient fever in two group-3 patients , no procedure - related complication occurred . in terms of immediate hemostasis , rebleeding and encephalopathy , there were no statistically significant differences between the groups ( p > 0.05 ) . in group 3 ,
the child - pugh score showed a significant decrease after the procedure ( p = 0.02).conclusionbrto can effectively control active gastric variceal bleeding , and because of immediate hemostasis , the absence of rebleeding , and improved liver function , is a good alternative to tips in patients in whom such bleeding , accompanied by gastrorenal shunt , occurs .
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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:
: adhesion of sealers to dentin is a required property for root canal sealers . although
standard organization does not provide any data concerning the minimal required bond
strength for endodontic sealers , it has been subject of several studies .
it has been suggested that the ability of root canal sealers to adhere to core material
and to dentin may result in superior sealing ability , which could reduce coronal and
apical leakage .
differences in the adhesive properties of sealers to dentin may be expected for several
reasons , including differences of root dentin between specimens , or even in different
sites of the same root .
the presence or absence of smear layer
after root preparation has also been related as an important factor to be
evaluated as well , the sealer 's
chemical composition and its interaction with the dentin .
several root canal sealers have been used in endodontics , from zoe - based sealers to the
epoxy - resin based sealers , all of them proposed to be used in association with
gutta - percha .
it has been demonstrated that zoe - based sealers have lower bond strength
to dentin , when compared to epoxy - based sealers , especially in presence of smear
layer .
therefore , the concepts of root canal filling materials have changed since materials
with adhesive properties have been evaluated . a synthetic polymer composite commercially
known as resilon ( pentron ,
wallingford , ct , usa ) has been suggested as a gutta - percha
substitute .
this filling material is used in association with a dual curable , polymer ,
composite sealer ( epyphany sealer , pentron ) which is able to bond to both core material
and dentin forming a " monoblock "
obturation . the philosophy of adhesive root canal filling and the results obtained with
resilon / epiphany showing its ability to prevent mainly coronal microleakage , seems to be strongly altering the concepts of endodontics and the
choice for filling materials .
it can be seen by the number of studies
and by the launching of new filling materials , such as resin - coated gutta - percha cones
and dual - cure root canal sealers ,
with the specific focus on obtaining a monoblock obturation .
another example of these
adhesives system is endorez ( ultradent , south jordan , ut , usa ) .
this system establishes
a bond between a polybutadiene - diisocyanate - methacrylate resin - coated gutta - percha core
material and a self - priming sealer with an active ingredient of urethane
dimethacrylate .
the purpose of this study was to evaluate the bond strength of different sealers to
dentin , in presence or absence of smear layer , using push - out tests .
it was considered
the hypotheses that bond strength of resin - based sealers is similar among them , but
higher than that of zoe - based sealer , and that bond strength of all sealers is higher in
the absence of smear layer .
forty extracted single - rooted human teeth were used in this study , after approval by the
research ethics committee of the university of passo fundo , rs , brazil ( process
# 246/2006 ) .
the crowns of the specimens were removed at the cement - enamel junction using
a diamonded disk in a low - speed hand piece .
the working length was determined by
introducing a # 15k file until it reached the apical foramen , subtracting 1 mm from this
length .
the canals were enlarged with rotary ni - ti files ( race , fkg ,
la - chaux - des - fonds , switzerland ) , up to file # 40 at the working length .
the coronal and
middle thirds of the canals were shaped with a 1.50 mm post drill ( fibrekor post system ,
pentron ) , followed by a final flush with 3 ml of 17% edta ( pulpdent corporation ,
watertown , ma , usa ) . in group
b the same procedures were repeated using only saline solution ( 0.9% nacl ,
aqualite , chicago il , usa ) as irrigating .
then , all samples subdivided once again , into four groups ( n=5 ) and filled with
different root canal sealers : group i , epiphany ( pentron ) , group ii ,
endorez ( ultradent ) , group iii , ah 26 ( dentsply - detrey , konstanz , germany ) ; and group
iv , grossman 's sealer ( endo fill , dentsply ind . e com . ltda . , rio de janeiro , rj ,
brazil ) .
the sealers were mixed
according manufacturers ' specifications and introduced into the root canals using a
lentulo spiral # 40 in low - speed handpiece . in the epiphany 's group ,
primer ( epiphany primer , pentron , ) was applied on the root
canal walls using a paper point previously to the sealer fulfillment .
after that , the
sealer was light cured for 40 s in the root canal entrance .
after 2 weeks of storage in 100% humidity at 37c , all teeth were sectioned
transversally into 2-mm - thick discs using a diamond saw ( isomet , buehler , lake bluff ,
il , usa ) .
push - out tests were performed at a crosshead speed of 1 mm / min using a
universal testing machine ( instron 4411 , instron ltd .
the
maximum load at failure ( fmax ) was recorded in n and the bonding surface ( a ) was
calculated using the equation : where is the constant 3.14 , r is the root canal space radius , and
h is the thickness of the slice in mm .
then , the bond strength ( ) ,
expressed in mpa , was calculated using the equation : the data were recorded and submitted to statistical analysis by two - way anova and
tukey 's test using the software spss 14.0 .
the epiphany 's group presented the highest bond strength ( p < 0.01 ) of all other
sealers , when using both 2.5 naocl and 17% edta or saline solution .
irrigation only with
saline decreased the bond strength to dentin of all sealers , in comparison to 2.5 naocl
and 17% edta irrigation ( p<0.05 ) .
mean values ( sd ) expressed in mpa ( n=15 ) are shown
in table 1 .
means with similar superscript symbols
indicate non - significant differences ( p<0,01 ) means with similar superscript symbols indicate no statistically significant
differences ( p<0.01 )
ideally , one of the key roles of the sealer is to aggregate the root filling material
and maintain it as compact mass with no gaps , which adheres to the canal walls and
provides a single block configuration that seals hermetically the canal space .
new materials have been developed in order to increase the sealing ability of endodontic
filling materials .
the goal is to create a better interface between root canal walls and
sealer , resulting in less microleakage .
although no correlation has been found so far between microleakage by the root canal
filling material and the strength of the bond of the sealer to dentin in
vitro , the assumption that it would reduce the leakage and also improve the
stability of root canal filling are always correlated .
shear
strength , microtensile5 and even pull - out or
push - out tests have been described as reproducible and
effective for direct comparison of the results .
however , it is clear that test models can not reproduce the exact clinical conditions ,
mainly because root dentin is not uniform and the surface of the canal walls prepared
during the endodontic treatment differ considerably .
the thickness of
dentin used for push - out tests has been also variable in several studies .
thin slices , around 1.0 mm thick ,
seem to be preferable in order to create a larger number of samples and also when high
bond strength values are expected . otherwise , there is a risk of sealer detachment while
slicing , as reported by gesi , et al .
2-mm - thick slices were used in order to prevent premature
debonding and also in accordance to kreimer , et al .
it was assumed that the area of bonded surface would be
calculated and taken into account during the bond strength values ( mpa ) calculations .
although the model used in this study does not simulate clinical conditions , we tried to
be as closer as possible to the reality by using root canal dentin instead of coronal
dentin .
the use of coronal
dentin could mask some results due to the structural differences between coronal and
intra - radicular dentin .
another important point is that the coronal and middle thirds of the root were prepared
with the same 1.5-mm - diameter post drill , making sure to avoid the influence of
anatomical variations over the results .
we strongly believe that it is one of the
factors that could have influenced the results presented by gesi , et al .
( 2005 ) , and are clearly visible on these
authors ' images . on the other hand , in the present study , all samples were filled only
with sealers without core material ( gutta - percha or resilon ) , which could explain the
different results from those achieved by gesi , et al .
( 2005 ) were epiphany sealer had the lowest bond strength
values and from fisher , et al .
( 2004 )
were both epiphany and endorez had lower bond strength values , compared to an
epoxy - resin based sealer ( ah plus ) .
a hypothetic explanation for our results is that the absence of the core material could
allow the root canal sealer to achieve its full expansion without to be affected by the
weak interface between the sealer and the core material .
it could also explain the
higher values obtained in this study when compared to the studies that used the same
method but included the core material ( gutta - percha or resilon ) , indicating that the failure on adhesion could be mainly affected in
the interface sealer / core material .
current literature has shown the superiority of epoxy - resin based sealers in comparison
to zoe - based sealers , in terms of bonding .
our results are in agreement with those
findings and partially confirm our first hypothesis .
grossman 's sealer showed the lowest
bond strength to dentin in absence or presence of smear layer , when compared to the
resin based sealers .
the bond strength values decreased when smear layer was present ,
independently of the sealers ' composition , which is in accordance with other
authors and confirm our second hypothesis . in the present study ,
the bond strength values of epiphany were higher than those of other sealers , rejecting
the hypothesis that all resin - based sealers would have similar bond strength to dentin .
epiphany 's results might be explained by the bonding agent used to penetrate into de
dentin tubules , forming tags .
research on the endorez obturation
system disclosed good hydrophilic properties , thus helping create long resin tags in
radicular dentin .
however , these
gaps appeared unbounded and exhibited insufficient adhesive strength , resulting in gap
formation between sealer and canal walls .
further studies including the core materials and cyclic fatigue are being performed in
order to clarify the doubts resulted from this study .
epiphany sealer presented higher bond strength values to dentin in both irrigating
protocols , and the use of 2.5% naocl and 17% edta increased the bond strength values for
all sealers .
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### Summary:
: objectivethe aim of this in vitro study was to evaluate the bond strength
of different root canal sealers to dentin .
material and methodsforty extracted single - rooted human teeth were examined and the coronal and middle
thirds of the canals were prepared with a 1.50 mm post drill ( fibrekor post
system , pentron ) .
the teeth were allocated in two experimental groups , irrigated
with 2.5% naocl+17% edta or saline solution ( control group ) and instrumented using
race rotary files ( fkg ) to a size # 40 at the working length .
then , the groups were
divided into four subgroups and filled with epiphany sealer ( group 1 ) , endorez
( group 2 ) , ah26 ( group 3 ) and grossman 's sealer ( group 4 ) .
after 2 weeks of
storage in 100% humidity at 37c , all teeth were sectioned transversally into
2-mm - thick discs .
push - out tests were performed at a cross - head speed of 1 mm / min
using a universal testing machine .
the maximum load at failure was recorded and
expressed in mpa .
resultsmeans ( sd ) in root canals irrigated with 2.5% naocl and 17% edta were : g1
( 21.66.0 ) , g2 ( 15.23.7 ) , g3 ( 14.64.5 ) and g4 ( 11.74.1).two - way anova and
tukey 's test showed the highest bond strength for the epiphany 's group ( p <
0.01 ) when compared to the other tested sealers . saline solution decreased the
values of bond - strength ( p<0.05 ) for all sealers .
conclusionepiphany sealer presented higher bond strength values to dentin in both irrigating
protocols , and the use of 2.5% naocl and 17% edta increased the bond strength
values for all sealers .
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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 anthropological literature , the perforation of coronoid - olecranon septum in the humerus has also been called : supratrochlear foramen , intercondylar foramen , septal aperture , etc . recently
, this perforation has been of special interest to clinicians.14 the significance of the presence of coronoid - olecranon septal perforation was not clinically in atypical fracture pattern of distal humerus in teenaged boys.13 during a study performed on the humerus medullary canal for the nailing , akpinar et al . also observed that the humerus with perforation is of different canal from the normal.2 the ancient and recent studies reported the variable occurrence of perforation and to be more common on the left side and in females .
to our knowledge , there has been no study regarding coronoid - olecranon septal aperture in the living subjects . to compare with the results obtained from the skeletal material ,
an extensive work was planned on the plain and computed tomography ( ct ) radiographs of elbow region from turkish individuals with known age and sex .
plain radiographs of the elbows were obtained by multix pro / top ( version 0.5 , g05og type , siemens , germany ) . as stated below ,
ct ( hitachi japan ) scans with 2 mm cuts were also used for the case needed . since thin lamellae of bone
might have been mistaken for this apertures and vice versa , the voltage and amperage used were balanced by a technical expert , according to the weight and the age of the cases .
the present study reviewed 709 subjects ( 367 males , 342 females ) , all of whom were volunteers ( university students and medical / paramedical staff ) possessing no metabolic disease , trauma history , and complaint of upper extremity ( pain , paraesthesia etc . ) .
the x - rays were evaluated by the authors of this study together with an experienced orthopedic surgeon . when the perforation was discovered or suspected , ct scan of the arm was obtained , since less number of perforation than actual may be scored in the cases where it is small and/or trabecular bone on septa is missed on x - ray .
the cases having the coronoid - olecranon perforation were classified according to sex ( male - female ) and laterality ( bilateral , unilateral - right , unilateral - left ) .
z test was used in comparison of two sexes ( female - male ) . for age groups , duncan ( multiple comparison ) test
p value of 0.05 and less was considered as statistically significant for all analyses and comparisons .
apart from the possibility that our cases having humeral septa less than 2 mm thick mistakenly score perforation , 61 ( 8.6 % ) coronoid - olecranon perforation were found in our series of 709 subjects [ figures 1 and 2 ] . bilateral occurrence was found to be more common than both unilateral right and left occurrences [ table 1 ] , which was statistically significant ( p<0.05 ) .
our cases with bilateral perforation were found to be 55% . in our study , the greater number of humeri was from the persons in the fourth decade ( 40 - 49 ages , 188 humeri ) [ table 2 ] .
however , the highest observation ( n=26 ) and percentage ( 15% ) of the perforation were found in the 20 - 29 ages group [ figure 3 ] [ table 2 ] .
the lateral column in distal humerus with aperture was observed to be very strong in all cases .
bilateral coronoid - olecranon perforation of a 25 year old male subject ct scan of the right humerus in a 25 year old male subjectfnx01 , coronoid - olecranon perforation distribution of the coronoid - olecranon perforation in our study by sex and side distribution and percentage of the coronoid - olecranon perforation ( sa ) in the present study , according to sex and age groups changes with age in frequency of the coronoid - olecranon perforation of a male and a female
to discuss our findings , we failed to find a comparable study performed on the living subjects . in the anthropological literature ,
the frequency of this perforation has been reported with the sharp differences , as : between 12.6% and 47% in negroid subjects , 4.3% and 6.1% in the whites.56 in turkish population , an anthropological study with unknown age and sex ( n=114 ) reported the prevalence as 12%.7 we feel that our data might be compared directly with those obtained from the study with dry bones from our population .
( 8.6% versus 12%).7 simons8 stated that focal bony resorption and exposure of trabecular bone on septa without apertures may occur at the time of death to form an aperture .
similarly , some apertures on fine bony lamella might have occurred after death , artificially deflating its frequency in living subjects . in the anthropological literature , the female dominance and the left asymmetry
were commonly observed.6910 we found both the sexual asymmetry and the left occurrence to be statistically insignificant , however , bilateral occurrence to be significant [ table 1 ] .
some of the mechanisms explaining the presence of this perforation in the humerus are : an atavistic character , a mechanical reaction to hyperextension of the elbow , weak development of the bone , and a disturbance in the calcium metabolism .
hirdlika11 predicted that the bilateral occurrence might suggest gene differences among different populations , which seems to be an acceptable commentary .
the reason for the high incidence in the second decades and the lowest in the first and the fourth decades from our study are unclear .
trotter proposed that the individuals possessing the aperture die earlier.6 if so , the lowest occurrence of the perforation should occur in the later decades .
in the present study , the occurrence of the perforation in seventh decade ( 20% , n=2 ) was not included in the discussion due to its small sample size . an unusual ( divergent single - column ) fracture pattern seen in the distal part of the humerus with the septal aperture
was first reported in few.13 the authors pointed out the possible risk for the fracture in the contralateral humerus .
it suggests that since the bilateral occurrence is 55% in the living persons ( the present study ) , when a fracture occurs , the risk for the fracture at the other humerus is predicted . during a morphometric study on the humerus for intramedullary fixation , akpinar et al . found that the humerus bones with septal aperture have very narrow medullary canal and extreme anterolateral bowing at proximal and/or extreme anterolateral compressed surface at distal part .
it is unclear that the morphology of the distal humerus with septal perforation might make nailing through a retrograde technique more difficult or possibly with an increased risk of iatrogenic fracture at the site of insertion .
glanville5 found a relation between the higher frequency of the perforation and a greater range of movement ( rom ) at the elbow in african skeletal sample .
recent evidence indicates that the perforation is a response to hyperflexion , not hyperextension of the elbow .
the apertures form predominantly by resorption of the humeral septum at a point at which the coronoid process of the ulna would potentially make contact in full flexion.8 further clinical studies might be needed to explain some clinical questions , for example : a ) whether the elbows of these cases have more valgus ; b ) do they have more rom ?
although previous reports mentioned here , and the present study , confirm the significance of this variation , the clinical bit is yet unclear .
we await further clinical studies concerning its clinical significance , which would be of interest .
the present study suggests female preponderance and left asymmetry in case of septal perforation . bilateral occurrence from our study
although the current study represent original frequency data , future work using ct scans with cuts less than 2 mm would be useful to obtain actual data
. it may be worthwhile to investigate this trait in families , in a future view of possibility that it may represent an epigenetic character .
an unusual ( divergent single - column ) fracture pattern seen in the distal part of the humerus with the septal aperture was first reported in few.13 the authors pointed out the possible risk for the fracture in the contralateral humerus .
it suggests that since the bilateral occurrence is 55% in the living persons ( the present study ) , when a fracture occurs , the risk for the fracture at the other humerus is predicted . during a morphometric study on the humerus for intramedullary fixation , akpinar et al
. found that the humerus bones with septal aperture have very narrow medullary canal and extreme anterolateral bowing at proximal and/or extreme anterolateral compressed surface at distal part .
it is unclear that the morphology of the distal humerus with septal perforation might make nailing through a retrograde technique more difficult or possibly with an increased risk of iatrogenic fracture at the site of insertion .
glanville5 found a relation between the higher frequency of the perforation and a greater range of movement ( rom ) at the elbow in african skeletal sample .
recent evidence indicates that the perforation is a response to hyperflexion , not hyperextension of the elbow .
the apertures form predominantly by resorption of the humeral septum at a point at which the coronoid process of the ulna would potentially make contact in full flexion.8 further clinical studies might be needed to explain some clinical questions , for example : a ) whether the elbows of these cases have more valgus ; b ) do they have more rom ?
although previous reports mentioned here , and the present study , confirm the significance of this variation , the clinical bit is yet unclear .
we await further clinical studies concerning its clinical significance , which would be of interest .
the present study suggests female preponderance and left asymmetry in case of septal perforation . bilateral occurrence from our study
although the current study represent original frequency data , future work using ct scans with cuts less than 2 mm would be useful to obtain actual data
. it may be worthwhile to investigate this trait in families , in a future view of possibility that it may represent an epigenetic character .
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### Summary:
: background : the humerus bone with coronoid - olecranon septal aperture have very narrow medullary canal and extreme anterolateral bowing proximally and/or extreme anterolateral compressed surface at distal part .
septal perforation might make nailing through a retrograde technique more difficult or possibly with an increased risk of iatrogenic fracture at the site of insertion .
coronoid - olecranon perforation might be very important in preoperative planning for successful nailing .
since the data available has been obtained from the ancient studies using the skeletal material , the present study is aimed at investigating originally the presence of the coronoid - olecranon septum perforation in the living subjects , using a radiographic method.materials and methods : the study was performed on direct radiograms and computed tomography of the elbow obtained from the 709 volunteers ( 367 males , 342 females).results : the incidence of the perforation was found to be 8.6 % .
bilateral occurrence was found to be more common significantly .
the highest incidence occurred in second decade.conclusion:the present study suggests female prepronounced and left asymmetry in case of septal perforation . bilateral occurrence from our study might be peculiar to the clinician .
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