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perforation of the biliary system occurs
most frequently in the gallbladder , usually associated with ( and complicating
upto 10% cases of ) acute cholecystitis .
perforation of the extrahepatic biliary
tree is a rare entity , accounting for less than 10% of intraperitoneal biliary
rupture .
bile duct perforation is most commonly described in infants related to congenital
biliary system anomalies .
aetiology in the adult is commonly attributable to
intramural infection , necrosis of the wall of the bile duct secondary to
thrombosis , increased intraductal pressure secondary to obstruction , cirrhosis ,
and direct erosion by calculi .
overall , 70% of cases are related to calculi
. the incidence of biliary tract disease during pregnancy ranges from 0.050.3% . despite these apparent low
figures , complications from gallstones
represent the most common general surgical condition
requiring surgical intervention , second only to appendicitis .
indications for intervention of gallstones during pregnancy
include obstructive jaundice , acute cholecystitis , or pancreatitis failing
medical management .
we present the case of a young woman diagnosed with
gallstones in late pregnancy , complicated by acute gallstone pancreatitis and
subsequently spontaneous common bile duct perforation .
a twenty - year - old primigravida woman was
planned for elective caesarean section due to breech presentation .
the patient
had a past medical history of -thalassemia trait , but was not
normally on regular medication .
her mother had previously undergone a
cholecystectomy for gallstones . at 34 weeks gestation , she presented
acutely with a two - week history of worsening abdominal pain localised to the
epigastric region , associated with vomiting . on examination ,
blood results revealed raised inflammatory markers ( wbc 14.4 [ 4.011.0 ] ,
neutrophils 11.9 [ 2.07.5 ] , crp 60
[ 07.5 ] ) and evidence of pancreatitis ( amylase 1369
iu / l [ 36128 ] ) , mildly
raised bilirubin ( 24 mol / l [ 020 ] ) and raised alkaline phosphatase ( 183
an abdominal ultrasound revealed multiple small gallstones and a
thickened gallbladder wall , but no evidence of a dilated intra or extrahepatic
biliary system .
the patient was treated conservatively , rapidly improved , and liver function tests
normalised .
an emergency caesarean
section was performed and a term baby delivered , but no obvious cause was found
to explain her clinical condition .
the following day her clinical condition worsened , with progressive abdominal pain
and a metabolic acidosis .
she required aggressive resuscitation , inotropic , and ventilatory support and was ,
therefore , admitted to the intensive care unit .
a computed tomography ( ct )
revealed extensive free peritoneal fluid and gas of which the aetiology was not
apparent .
the patient underwent a prompt laparotomy and was found to have
generalised biliary peritonitis .
the gallbladder was intact but a 2 mm
perforation was found on the anterior surface of a dilated common
bile duct ( 12 mm ) . on table
cholangiography suggested obstruction of the distal
common bile duct caused by a 5 mm gallstone impacted within the distal common
bile duct .
the calculus was removed , and the duct was repaired over a t - tube .
a t - tube cholangiogram was performed
after 4 weeks , and the tube was uneventfully removed ( figure 1 ) .
although the pathogenesis of spontaneous biliary perforation is poorly understood ,
recognised mechanisms include the following : calculous perforation at the site
of impaction ; calculous erosion without impaction ; increased canalicular
pressure due to obstruction by tumour , stone , or spasm of the sphincter of
oddi ; intramural infection ; mural vessel infarction leading to mural necrosis ;
or rupture of a biliary tract anomaly such as cyst or diverticulum .
thus ,
because perforation of the biliary system is a recognised complication of
cholelithiasis , the diagnosis should be suspected if a perihepatic abscess or
peritonitis is combined with biliary stone disease . as early as 1882 , freeland reported the first case of extrahepatic biliary system rupture in an adult ( diagnosed at autopsy ) , an entity that was
subsequently first described in pregnancy by piotrowski et al . over a
century later . since this time ,
very few cases of spontaneous common bile duct
perforation in adults have been reported in the literature , with cases
occurring during pregnancy being even more scarce .
the importance of this clinical
scenario lies in the potential serious morbidity and not infrequent mortality
associated with missed biliary system perforation .
petrozza
et al . described two cases of gallbladder perforation due to cholelithiasis in
the early postpartum period .
both cases presented a diagnostic dilemma , and it
was concluded that a history of cholelithiasis in a patient with persistent
intra - abdominal symptoms in the postpartum period must alert to prompt
investigation and early management .
,
one patient was found to have suffered gallbladder rupture as a result of
cholecystitis , and in the second , a common bile duct perforation was found at
laparotomy with no obvious precipitating cause .
. also drew
attention to the similarity of symptoms of gallbladder disease in pregnancy to
mild pre - eclampsia , having in common hypertension , epigastric pain , and mildly
deranged liver function tests .
these cases highlight the importance of
recognising the possibility of delayed diagnosis of cholelithiasis as a result
of nonspecific abdominal symptoms during pregnancy and indicate early
investigation and treatment in order to reduce serious morbidity .
.
block and kelly reported the optimum time for surgical management of
gallstone pancreatitis to be in the second trimester or early postpartum
period , in order to minimise maternal / fetal mortality and recurrent
pancreatitis .
unfortunately , in those women presenting
late in pregnancy ( as in the case described ) , the balance of risk favours
watchful waiting until after delivery followed by elective cholecystectomy .
certainly , this risks early recurrence of acute pancreatitis , as well as rare but severe
consequences such as biliary peritonitis .
whether an early endoscopic retrograde cholangiopancreaticography ( ercp )
and sphincterotomy in those cases presenting with gallstone pancreatitis can be
an acceptable temporary preventive measure is unclear , but undertaking ercp is
not without risk , and the potential risks should be considered carefully in
individual cases . in this particular case ,
it is impossible to know whether the eroding calculus had been present during the
initial episode of pancreatitis .
magnetic resonance scanning is a commonly used
imaging modality in obstetrics , considered to be safe and avoiding the use of
ionising radiation .
therefore , magnetic resonance cholangiopancreatography
( mrcp ) would have been a reasonable next investigation during this patient s
initial presentation , and if a ductal stone had been revealed , then the indication
for ercp may have been clearer .
on the other hand , neonatal and postnatal
care of babies born early have progressed significantly , suggesting the
possibility of induction of labour perhaps at 3638 weeks
gestation in severely symptomatic or high - risk patients .
of course , every case
must be considered individually , taking into account maternal and fetal
history and health .
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spontaneous perforation of the extrahepatic biliary system is a rare presentation of ductal stones .
we report the case of a twenty - year - old woman presenting at term with biliary peritonitis caused by common bile duct ( cbd ) perforation due to an impacted stone in the distal common bile duct .
the patient had suffered a single herald episode of acute gallstone pancreatitis during the third trimester .
the patient underwent an emergency laparotomy , bile duct exploration , and removal of the ductal stone .
the postoperative course was uneventful .
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1. INTRODUCTION
2. CASE PRESENTATION
3. DISCUSSION
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two male patients with type 2 diabetes ( t2d ) and coronary heart disease had plasma levels of brain natriuretic peptide ( bnp ) and n - terminal probrain natriuretic peptide ( nt - probnp ) measured as part of routine evaluation .
their glomerular filtration rate was normal ( > 75 ml / min per 1.73 m ) , hba1c was < 7% with metformin , and c - reactive protein ( crp ) was < 1 mg / dl in both .
patient a was 71 years old and had suffered an anterior myocardial infarction three years ago with st - segment elevation , which was initially treated with fibrinolytics and 24 h later using percutaneous coronary intervention with a drug eluting stent on the anterior coronary descending artery .
he presented with a > 70% stenosis on a diagonal artery , which was not treated and showed no significant stenosis in the remaining coronary arteries .
his bmi was 34.8 kg / m , waist circumference 116 cm and was stable without chest pain in nyha class i. the echocardiogram showed apical and lateral hypokinesia with left ventricular ejection fraction ( lvef ) of 58% .
plasma bnp and nt - probnp were 72 and 100 pg / ml , respectively ( reference values for age and sex : bnp median 28 pg / ml ( percentile 2575th , 1058 pg / ml ) ; nt - probnp median 45 pg / ml ( percentile 595th , 14140 pg / ml ) ) .
patient b , 58 years of age , had suffered a non - st - elevation myocardial infarction two years earlier , and had received standard treatment .
his bmi was 44.3 kg / m and his waist circumference 137 cm .
the echocardiogram showed mild hypokinesia of the basal segment of the inferior wall and mild dilation of left ventricle with eccentric hypertrophy .
lvef was 66% and plasma bnp and nt - probnp were 10 and < 20 pg / ml , respectively ( reference values for age and sex : bnp median 31 pg / ml , percentile 2575th , 14 - -49 pg / ml ; nt - probnp median 25 pg / ml , percentile 595th , 588 pg / ml ) .
these findings posed the question as to why it is that in some patients the plasma levels of cardiac natriuretic peptides ( cnp ) are unexpectedly low , and what is their value in the prognosis for these patients ?
the cnp act as a basic functional link between cardiovascular system homeostasis , inflammation and certain metabolic functions ( fig .
1 ) . increased secretion of cnp is a result of both mechanical and neurohumoral stimuli ( 1 , 2 ) . the main mechanical stimulus for the secretion of cnp is the increased pressure in the cardiac chambers leading to stretching of the myocardial fibers .
neurohumoral stimuli include endothelin-1 , angiotensin ii , adrenergic agonists and various cytokines ( 4 ) . increased left ventricular end - diastolic wall stress and left ventricular end - systolic wall stress correlate with an increase in plasma cnp in heart failure ( 5 , 6 ) .
however , studies on cardiac transplant patients have shown that plasma cnp levels remain high even after intra - cardiac pressures normalize following transplantation ( 7 ) . during an acute cardiac allograft rejection episode , bnp but not atrial natriuretic peptide ( anp )
plasma levels increase significantly above pre - rejection values independently of the surgical technique used ( 8) .
plasma bnp levels during acute rejection episodes do not correlate with hemodynamic variables but correlate with the levels of regulated on activation , normal t expressed and secreted , insulin growth factor binding protein-1 and neutrophil activating protein-2 ( 4 ) . in non - rejecting transplanted patients , despite the normalization of endothelin-1 plasma levels and diastolic and systolic functions , bnp remains high by comparison with control subjects ( 9 ) .
measuring cnp is useful as a diagnostic and prognostic tool ( 10 , 11 , 12 ) .
high plasma levels of cnp ( e.g. bnp > 63pg / ml or nt - probnp > 206 pg / ml ) can quite precisely predict which patients are at risk for events such as hospitalization due to systolic heart failure or cardiovascular death ( 13 , 14 , 15 , 16 , 17 , 18 ) .
obese patients may have strikingly low levels of plasma cnp ( 19 , 20 , 21 , 22 ) due to multiple mechanisms that might include increased neprilysin - neutral endopeptidase activity resulting in increased degradation of circulating cnp and increased adipose tissue expression of the np clearance receptor c ( nprc ) .
it has been proposed that suppression of probnp1 - 108 prohormone processing due to o - glycosylation at its cleavage site where furine or corin convertases act , prevents the formation of bnp77 - 108 ( functionally active ) and nt - probnp1 - 76 ( inactive ) fragments , an event that is purportedly more frequent in diabetics and in insulin - resistant states ( 23 , 24 , 25 ) . in heart failure patients ,
the precursor pro - hormone probnp1 - 108 is found circulating at lower than normal levels ( 26 , 27 ) .
recently , the paradigm - hf trial showed that angiotensin receptor - neprilysin inhibition using the compound lcz-696 , 200 mg twice daily , compared with enalapril at 10 mg twice daily significantly reduced the risk of cardiovascular death and hospitalization in patients with heart failure with an lvef 40% .
however , death rates from cardiovascular causes were similar among diabetics compared with non - diabetics ( 28 ) .
although this interesting finding could be an accidental one , other heart failure trials found that the benefit of this therapy in diabetics seems to be less than that in non - diabetics ( 29 , 30 , 31 ) .
this finding merits further research , since diabetics comprise 2535% of the subjects in most studies ( 29 , 30 , 31 , 32 ) .
the obese are differentiated from the metabolically healthy obese by an unhealthy metabolic profile ( 33 ) . the latter is defined by increased waist circumference ( > 94 cm in men and > 80 cm in women ) or bmi 30 kg / m accompanied by two or more of the following : hypertriglyceridemia ( 1.7 mmol / l ) , low hdl cholesterol ( < 1.03 mmol / l in men and < 1.29 mmol / l in women ) , hyperglycemia ( > 11.1 mmol / l or a diagnosis of diabetes ) , hypertension ( 130/85 mmhg ) or medication for high blood pressure ( 34 , 35 ) . in a 12-year follow - up of 61 299 subjects free from cardiovascular disease at baseline mrkedal et al . ( 36 ) observed that systolic heart failure development was similar among
metabolically healthy compared to non - metabolically healthy obese subjects , meaning that obesity per se creates a higher risk for developing systolic heart failure , especially if it is long - lasting and severe ( bmi > 40 kg / m ) .
recently , it was reported that subjects with high plasma levels of nt - probnp are at a greater risk of developing systolic heart failure whether they are obese or non - obese . however , unlike the non - obese who show a direct linear relationship between levels of nt - probnp and systolic heart failure , the obese show a u - shaped relationship ; i.e. those who have the lowest plasma levels are at just as much risk of developing systolic heart failure as those with the highest plasma levels ( 37 ) .
in contrast , the pathological weight loss caused by anorexia nervosa seems to be related to high plasma levels of anp ( 38 ) . in severe obesity ,
bariatric surgery reduces the bmi and improves control of diabetes but it is not yet known if it reduces the risk of cardiovascular events ( 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ) . in patients with severe obesity ( bmi > 40 kg / m ) before gastric bypass surgery , the median level of nt - probnp was 54 pg / ml increasing by 125% after 1 year with no apparent relation to weight loss or glucometabolic parameters .
it was speculated that an improvement in secretory cardiac function following surgery was responsible for the increase in circulating nt - probnp ( 46 ) .
myocardial ischemia and cardiomyocyte stretch trigger the immediate release of cnp ( 47 , 48 ) even when the lvef is normal ( 49 , 50 ) . in a 9.2 year follow - up study of diabetic ( about 7% of the cohort ) and non - diabetic patients with chronic stable myocardial ischemia , high plasma levels of nt - probnp were significantly associated with mortality regardless of left ventricular function ( 51 ) .
recently , it was shown that in patients with stable coronary heart disease bnp and nt - probnp were strong predictors of long - term ( 6.53.3 years ) cardiovascular events and notably , when nt - probnp was added to the clinical predictors , it performed better than bnp in risk classification for adverse cardiovascular events ( 52 ) . serial measurement data for nt - probnp in patients with chronic stable angina have shown a wide intra - individual variation .
an increase by > 42% or a decrease by > 30% relative to baseline values is required to indicate a significant change ( 53 , 54 ) . in patients presenting with acute chest pain ,
cnp plasma levels help the diagnosis and prognosis when used together with a non - diagnostic ecg and a negative troponin .
cnp measured in these patients at rest predict future cardiac events at 30 and 180 days and at 1 year ( 55 , 56 , 57 , 58 ) .
if myocardial ischemia is evident during the stress test , an elevation of the plasma levels of nt - probnp detects ischemia and predicts cardiovascular events ( 59 ) .
likewise , in non - st - elevation acute coronary syndromes , cnp add prognostic information to the clinical indicators ( 60 , 61 , 62 , 63 ) ( table 1 ) . in a recent investigation ( 62 ) , bnp was shown to be an independent predictor of mortality on entering the study . at 1 year of
follow - up bnp plasma levels provided added value over the timi and grace scores .
cnp are stronger predictors of mortality than troponin in patients that will eventually develop myocardial infarction . in st - segment - elevation
acute coronary syndromes cnp plasma levels also add prognostic information independently of the lvef ( 50 , 64 , 65 ) and in addition , predict which patients with primary percutaneous coronary intervention ( pci ) may be discharged earlier thus saving health resources ( 66 ) .
it has been shown experimentally that anp is associated with salt - sensitive high blood pressure ( 67 ) . in humans
alleles associated with the highest levels of np were also associated with a lower risk of high blood pressure ( 68 , 69 ) . in keeping with these findings
, another study showed a relative deficiency of cnp at all the different stages of high blood pressure in humans consisting of low levels of probnp1 - 108 and anp99 - 126 .
low plasma levels of bnp76 - 108 and nt - probnp1 - 76 were observed in the first hypertensive stages together with a reduction of nt - anp1 - 98 in stage i ( 70 ) .
a possible therapeutic modality to supplement cnp in those cases in which circulating cnp are deemed deficient ( like in hypertension or heart failure ) is suggested by the development of a recombinant human serum albumin - atrial natriuretic factor ( anf ) ( 71 ) molecule .
this compound , when injected into mice increased circulating cgmp and decreased blood pressure demonstrated a half - life of > 80 min , which is considerably longer than the 510 min half - life for native anf ( 71 , 72 , 73 ) . from the preceding , it may be surmised that elevated cnp levels are strong markers of future cardiovascular events , especially cardiovascular death . on the other hand , cnp plasma levels lower than expected in obese and diabetic patients
the two patients discussed above had similar metabolic profiles , lvef > 50% but a different bmi and cnp profile .
patient a was not severely obese and had slight residual myocardial ischemia with bnp and nt - probnp within low to moderate values expected for systolic heart failure and cardiovascular mortality on follow - up .
patient b suffered from severe obesity , with very low plasma levels of cnp with a prognosis related to his bmi of > 40
kg / m and probably also to a deficit of cnp , placing him in the high - risk category for developing systolic heart failure and eventual cardiovascular death .
our patient a has markedly higher bnp and nt - probnp levels compared to patient b. this can largely be explained by the better ejection fraction of patient b , but there might also be other contributing factors .
for example , recent studies suggest an inverse relationship between circulating cnp levels and bodyweight as well as with insulin resistance and t2d ( 19 , 74 , 75 , 76 , 77 , 78 ) ( table 1 ) . this correlation can also be observed in patients with congestive heart failure , despite increased cnp levels , due to cardiac wall stress ( 79 ) .
cnp are cleared and degraded by neutral endopeptidase neprilysin and natriuretic peptide receptor c ( nprc ) ( 80 , 81 ) .
natriuretic peptide receptor a ( npra ) and nprc have been identified in human adipose tissue in abundance , implying that adipose tissue sustains a regulatory function on the np system ( 82 , 83 , 84 ) .
interestingly , compared to non - obese and normotensive individuals , nprc is increased in adipose tissue of obese hypertensive patients ( 85 ) .
insulin has been observed to induce nprc expression in human adipocytes ( 84 ) and monocytes ( 83 ) , and might , hence , link conditions associated with hyperinsulinemia ( e.g. obesity and insulin resistance ) , to a relative np deficit
. additionally , neprilysin , the np degrading endopeptidase , is expressed at increased levels in obesity ( 86 ) .
these data argue for obesity and insulin resistance being conditions in which cnp are degraded at an accelerated pace .
second , very recent experimental data also suggest that myocardial bnp expression is markedly decreased in mice fed a high fat diet ( 87 ) , an observation that warrants clinical confirmation .
a cnp deficit in patients with components of the metabolic syndrome might be of clinical relevance .
obese individuals have a higher prevalence of arterial hypertension compared to lean subjects ( 88 ) .
although obesity - related arterial hypertension has been intensively studied , not all mechanisms are well understood ( 89 , 90 ) . by reduced vasodilatory and sodium - excretion activity , as well as
aldosterone - system ( raas ) , a cnp deficit might contribute to obesity related hypertension .
interestingly , in lean subjects , application of a sodium load induces myocardial cnp secretion and stimulates natriuresis ( 91 , 92 , 93 , 94 ) , a response which is blunted in patients with obesity ( 95 ) .
together , these data argue that obesity promotes hypertension partly through reduced vascular and renal np responses as well as through impaired np - mediated raas inhibition .
second , cnp also have beneficial actions on cardiac remodelling in essential hypertension , reducing left ventricular hypertrophy ( 96 ) .
conversely , conditions with a cnp deficit are associated with cardiac hypertrophy in hypertensive patients . in this
regard , hypertensive patients with the metabolic syndrome present with lower anp and nt - probnp levels and increased left ventricular mass compared to hypertensive patients without the metabolic syndrome and insulin resistance ( 97 ) .
finally , the cnp deficit in patients with the metabolic syndrome might be part of a vicious circle which maintains metabolic disease .
for instance , cnp exert lipolytic properties mediated by a cgmp - dependent protein kinase g activating pathway .
cgmp - activated protein kinase g ( gk - i ) activates perilipin a and hormone sensitive lipase mediated triglyceride hydrolysis ( 98 , 99 , 100 , 101 ) . interestingly , these effects seem not to interact with the lipolytic effects of catecholamines ( 99 , 102 ) and the effect seems to be independent of the regulation of insulin ( 103 ) . besides a direct activating effect on lipolysis and lipid oxidation , cnp also control secretion of the insulin sensitizing adipokine adiponectin . in humans , anp acutely increases systemic levels of total and high molecular weight adiponectin ( 104 ) .
these findings are in line with some observational studies showing positive associations between systemic cnp and adiponectin concentrations , as for example in heart failure patients ( 105 , 106 ) .
this finding might also explain the adiponectin paradox in patients with congestive heart failure .
cnp also exert other relevant metabolic actions on adipose tissue . treating a human derived adipose cell line with anp results in the uncoupling of cellular respiration ( 107 ) as well as
the response seems to be mediated by p38 map kinase , which increases uncoupling protein 1 ( ucp1 ) transcription ( 107 ) . upon cold exposure , systemic np concentrations increase and nprc expression in
similarly , forced pkg expression in primary adipocytes leads to an increase in ucp1 expression and activates a thermogenic program .
administration of anp acutely increases lipid oxidation ( 102 , 109 ) and postprandial energy expenditure in healthy individuals ( 110 ) . circulating -hydroxybutyrate increases , indicating enhanced hepatic lipid oxidation .
apart from acute effects on lipid oxidation ( 110 ) , anp and bnp induce skeletal muscle mitochondrial biogenesis , respiration and lipid oxidation in human cells and in rodents , in vitro and in vivo
( 111 , 112 ) .
chronic overexpression of bnp and gk - i each led to increased muscle mitochondrial content , oxidative capacity and lipid oxidation in rodents ( 111 ) .
enhanced oxidative metabolism is associated with protection from diet induced obesity and insulin resistance ( 113 ) .
heterozygous npra knockout mice are prone to gaining weight and become insulin resistant ( 111 ) .
the mechanism linking np signalling to mitochondrial biogenesis and lipid oxidation in skeletal muscle includes activation of the co - transcriptional activator peroxisome proliferator activated receptor coactivator ( pgc)-1 and peroxisome proliferator activated receptor- , both of which are important factors of mitochondrial biogenesis in skeletal muscle ( 111 ) . in human myotubes , we observed that cnp stimulate pgc-1 , maximal mitochondrial respiratory capacity and lipid oxidation ( 112 ) .
moreover , npra expression positively correlates with pgc-1 expression in the skeletal muscle of individuals after a chronic physical training program .
similarly , cell culture studies show that cgmp restores glucose and insulin induced mitochondrial dysfunction in cultured c2c12 myotubes ( 114 ) , nitric oxide signalling via cgmp mediates activation of pgc-1 , and mitochondrial biogenesis in various murine tissues ( 115 ) .
hepatic and skeletal muscle lipid content has been associated with insulin resistance ( 113 ) . in liver and skeletal muscle ,
insulin resistance develops when bioactive lipid species accumulate , such as intracellular diacylglycerol ( 113 ) . in obesity and the metabolic syndrome , this lipid accumulation is primarily due to excessive caloric intake that exceeds the capacity of hepatocytes and myocytes to metabolize or export fatty acids , while refining mitochondrial respiration and enhancing lipid oxidation have been proved to improve lipid utilization and insulin sensitivity ( 116 , 117 , 118 ) . so far , there is no evidence that cnp directly interact with the insulin signalling cascade ( 109 , 119 ) .
it is tempting to speculate that cnp could ameliorate lipid - induced insulin resistance through improvements in hepatic ( 110 ) and muscular ( 112 ) lipid oxidation .
in line with this notion , cnp preserves mitochondrial function and insulin sensitivity in high fat diet mice ( 111 ) . cross sectional studies support the hypothesis that cnp protect from the development of obesity and t2d in patients ( 78 , 120 , 121,122 ) .
conversely , data from the framingham heart study and the malm diet and cancer study show that reduced cnp concentrations correlate with a higher probability of insulin resistance in lean and obese individuals ( 76 ) .
moreover , in the latter study low cnp concentrations are predictive of new - onset diabetes ( 123 ) .
together , these data suggest that a cnp deficit , as observed in obese patients with the metabolic syndrome , contributes and aggravates metabolic vascular disease , and thus , prognosis .
life style interventions as well as pharmacological approaches might be of benefit in this regard ( 28 , 124 ) .
while physical activity increases cnp levels acutely and augments npra expression in skeletal muscle cells ( 112 ) , physical activity coupled with a low calorie diet seems to increase cnp levels chronically ( 125 ) ; an observation that seems to depend on the amount of weight loss ( 126 , 127 ) .
experimental data further suggests that the incretin glucagon like peptide 1 ( glp1 ) might be of relevance in the regulation of np secretion .
the glp1 receptor agonist liraglutide , which is widely used for the treatment of t2d , has been shown to induce cardiac anp release in mice , leading to enhanced natriuresis and vasodilatation ( 128 ) without inducing congestive heart failure .
so far 25 clinical studies failed to demonstrate a similar effect of liraglutide when administered acutely ( 129 ) or sub - chronically to patients ( 130 ) .
chronic liraglutide treatment , accompanied by weight loss , however , seems to increase circulating anp as well as bnp concentrations in diabetic patients ( 131 ) .
clearly , future studies need to address the important question how a cnp deficit in obesity and t2d can be reversed most efficiently ( 132 ) .
the authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review .
this work was supported by a grant from the secretara de ciencia y tecnologa de la universidad nacional de crdoba ( grant number 69/08 ) to h r ramos , a grant from the german research foundation ( grant number bi1292/4 - 2 ) to a l birkenfeld and by funds from the university of ottawa to a j de bold .
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since their discovery in 1981 , the cardiac natriuretic peptides ( cnp ) atrial natriuretic peptide ( also referred to as atrial natriuretic factor ) and brain natriuretic peptide have been well characterised in terms of their renal and cardiovascular actions .
in addition , it has been shown that cnp plasma levels are strong predictors of cardiovascular events and mortality in populations with no apparent heart disease as well as in patients with established cardiac pathology .
cnp secretion from the heart is increased by humoral and mechanical stimuli .
the clinical significance of cnp plasma levels has been shown to differ in obese and non - obese subjects .
recent lines of evidence suggest important metabolic effects of the cnp system , which has been shown to activate lipolysis , enhance lipid oxidation and mitochondrial respiration .
clinically , these properties lead to browning of white adipose tissue and to increased muscular oxidative capacity . in human association studies in patients without heart disease
higher cnp concentrations were observed in lean , insulin - sensitive subjects .
highly elevated cnp levels are generally observed in patients with systolic heart failure or high blood pressure , while obese and type-2 diabetics display reduced cnp levels .
together , these observations suggest that the cnp system plays a role in the pathophysiology of metabolic vascular disease . understanding
this role should help define novel principles in the treatment of cardiometabolic disease .
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Introduction
The cardiologist's perspective
The endocrinologist's perspective
Declaration of interest
Funding
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stress cardiomyopathy ( scm ) , a disease with many names like the broken heart syndrome ,
takotsubo cardiomyopathy , and apical ballooning syndrome , is characterized by regional myocardial dysfunction , typically occurring in the wake of a significant physical or emotional stressor .
the pathophysiology of the condition remains incompletely understood , yet the effects of catecholamines on select portions of myocardium are thought to play an integral role .
the degree of cardiac dysfunction in this condition is variable , and in the largest contemporary registry of patients with scm , only 9.9% developed cardiogenic shock .
although uncommon , this severe presentation of the disease is critical to appreciate , and we present a case of the disease at its extreme , with a patient in cardiogenic shock .
a 79-year - old woman with a history of an infratentorial meningioma was admitted to the coronary care unit in cardiogenic shock . the morning of admission
her past medical history was significant only for modest essential hypertension and no known coronary ischemia or dysrhythmias .
following routine induction of anesthesia with securement of the airway and institution of mechanical ventilation , sinus bradycardia associated with profound hypotension ( 70/40 mm hg ) ensued , and this hemodynamic perturbation subsequently progressed to cardiac standstill with absence of peripheral pulses .
cardiopulmonary resuscitation ( cpr ) was initiated and return of spontaneous circulation ( rosc ) was achieved after 90 s with one round of cpr and 1 mg of intravenous epinephrine .
after rosc , her vital signs were notable for sinus bradycardia with a systolic blood pressure initially between 140 and 170 mm hg , which quickly declined to less than 90 mm hg despite continuous infusions of high - dose norepinephrine ( 3 g / kg / min ) and dopamine ( 20 g / kg / min ) . the surface electrocardiogram post - rosc revealed new t - wave inversions in the precordial leads .
intra - operative transthoracic echocardiography shortly after cardiac arrest demonstrated a left ventricular ejection fraction ( lvef ) of 15 - 20% with severely hypokinetic mid and distal segments and a hyperkinetic left ventricular base consistent with scm ( fig . 1 and supplementary video 1 , www.cardiologyres.org ) .
in the setting of her continued hemodynamic instability , left heart catheterization was performed and an intra - aortic balloon pump was placed .
the coronary anatomy was notable for only mild , non - obstructive disease ( fig .
the right coronary artery has minimal disease , and supplies the posterior descending artery ( c ) . in the subsequent 6 h
serum troponin i levels peaked at 1.67 ng / ml and a newly prolonged qt interval developed ( fig .
3 ) . inotropic and mechanical supports were rapidly weaned off over the following 6 h and she was successfully extubated .
repeat echocardiography 12 h after the initial study revealed a lvef of 75 - 80% , near cavity obliteration during systole , and no regional wall motion abnormalities ( supplementary video 2 , www.cardiologyres.org ) . at 6-month follow - up
, the patient denied any symptoms of heart failure and her ef normalized to 55% .
note the low voltages , inferior and lateral precordial lead st segment depressions , and the prolonged qt interval .
this case highlights many of the classic elements of scm : a post - menopausal female with a primary neurologic disease ; a temporal correlation with significant stress and exposure to catecholamines ; prolongation of the qt interval ; low - level cardiac enzyme elevations ; and reversible , often transient left ventricular dysfunction , which at the extreme , results in cardiogenic shock .
although reversal of left ventricular dysfunction is the norm in scm , the time course of this patient s improvement is remarkable .
most studies of scm cite echocardiographic and symptom improvement occurring within days to weeks of diagnosis , and to our knowledge , the earliest reported echocardiographic resolution occurred 5 days following diagnosis in these case series [ 2 , 3 ] .
scm has been associated with administration of catecholamines ( i.e. dobutamine during stress testing or epinephrine for treatment of anaphylaxis ) , and has occurred in the wake of cpr , which we believe occurred in this case . from a pathophysiological standpoint , a catecholamine surge , iatrogenic or otherwise , can impair myocyte contractility , particularly at the apex where the highest concentrations of adrenergic receptors are localized . in summary ,
we describe a case of transient , albeit severe scm that reversed rapidly . to our knowledge , this is the fastest recovery ever reported .
this case highlights the role of catecholaminergic excess , one of the proposed mechanisms underlying the disease s pathophysiology , and also reinforces the need of aggressive supportive therapy early in the disease .
the authors declare that there are no conflicts of interest regarding the publication of this paper .
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we report the case of a 79-year - old woman who presented to our hospital for elective removal of an infratentorial meningioma and suffered a periprocedural cardiac arrest . shortly after uncomplicated induction of anesthesia prior to the surgery ,
the patient became hypotensive and bradycardic , culminating ultimately in a cardiac arrest with pulseless electrical activity .
return of spontaneous circulation occurred within 90 seconds of arrest , but the patient remained dependent on maximal doses of epinephrine and dopamine for hemodynamic support .
echocardiography performed on the day of cardiac arrest revealed a newly depressed left ventricular ejection fraction ( lvef ) of 15 - 20% with an apical ballooning pattern . left heart catheterization showed no obstructive coronary lesions to explain her depressed ejection fraction .
a diagnosis of stress cardiomyopathy ( scm ) was made given the echocardiographic findings and absence of concomitant coronary disease . within the next 24 hours
, the patient was liberated from inotropic support , and at 6-month follow - up , her lvef returned to 55% and she had no heart failure symptoms .
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Introduction
Case Report
Discussion
Funding Sources
Conflicts of Interest
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appropriate management of moderate postoperative pain is well achieved associating several analgesic drugs with adjuvant agents through synergistic interaction .
the potential advantage of this combined therapy is related to the minimization of the incidences of adverse effects of each drug and to the improvement of the outcome .
postoperative clinical situations , such as difficult patient extubation , respiratory depression due to opioids , and cardiovascular side effects , require a combined therapy to improve analgesia quality and decrease adverse effects of each drug when used alone .
this has led to administering pain drugs in continuous intravenous ( iv ) infusion with different mechanisms and sites of action , together with adjuvant agents .
tramadol hydrochloride ( hcl ) and ketorolac tromethamine are analgesic drugs commonly used in combination in postoperative pain management .
tramadol hcl is a synthetic , centrally acting analgesic with no anti - inflammatory activity and one of the most interesting and useful weak opioids for treatment of moderate to moderately severe pain with weak -receptor agonist properties and noradrenergic and serotonergic neurotransmission effects.[39 ] ketorolac tromethamine is a potent nonsteroidal anti - inflammatory drug ( nsaid ) with analgesic efficacy similar to opioids.[289 ] this drug is administered to treat moderate pain or , combined with reduced opioid doses , for severe pain . according to some studies , metoclopramide hcl as an adjuvant agent can improve analgesia and decrease the need for other pain drugs ; it is a dopamine and 5-ht receptor antagonist , commonly used as a prokinetic and antiemetic .
also , this has been recently investigated as an agent that can enhance the efficacy of analgesic drugs.[91113 ] some studies have also suggested a role of magnesium sulfate ( mgso4 ) as an adjuvant agent , an n - methyl - d - aspartate receptor antagonist , in the management of postoperative pain . the perioperative administration of iv mgso 4 is associated with smaller analgesic requirements , and magnesium sulfate could be of interest as an adjuvant to postoperative analgesia.[1416 ] the aim of this study was to investigate the chemical stability of tramadol hcl combined with ketorolac tromethamine and metoclopramide hcl in solution for 48 h ( 25c ) and 5 days ( 5c ) , with the presence of mgso4 .
milan , italy ) 2 mg / ml , tramadol hcl ( contramal ; grnenthal , gmbh , stolberg , germany ) 20 mg / ml , and ketorolac tromethamine ( lixidol ; roche s.p.a . , milan , italy ) 6 mg / ml stock solutions were prepared in high - performance liquid chromatographic ( hplc)-grade deionized water and stored at 4c during experimental assay .
well - defined volume samples were drawn from each stock solution , joined , and diluted in deionized water to produce 5 working standard solutions , with concentrations in the range of 0.51.5 g / ml for metoclopramide hcl , 2060 g / ml for tramadol hcl , and 39 g / ml for ketorolac tromethamine .
every 48 h the working standard solutions were prepared from stock solutions and stored at 4c .
limit of quantitation ( loq ) values were found to be 1 , 0.5 , and 0.1 g / ml for tramadol , ketorolac , and metoclopramide , respectively .
limit of detection ( lod ) values were 0.05 , 0.2 , and 0.1 g / ml for tramadol , ketorolac , and metoclopramide .
precision and accuracy were determined on spiked samples at 4 concentrations with respect to a calibration graph prepared every day ( n = 3 ) .
the precision of the method was evaluated as the intra- and interday relative standard deviation ( rsd ) of the measured peak areas by assaying spiked samples at 4 different concentrations .
all samples for these purposes were freshly prepared , including preparing the standard solution from the same stock solution .
six drug admixtures were prepared by transferring the contents of one ampule of metoclopramide hcl , 4 ampules of tramadol hcl , 2 ampules of ketorolac tromethamine , and 4 ampules of mgso4 ( 1 g/10 ml ampule , magnesio solfato monico ; monico s.p.a . , venezia mestre , italy ) to give each a final volume of 52 ml .
all the solutions were prepared on different days , stored at 25c and assessed over a period of 48 h. solutions were stored in amber colored glass bottles with air - tight caps to protect them from direct light exposure .
the nominal concentration of each drug in all prepared solutions was 0.19 mg / ml for metoclopramide hcl , 7.69 mg / ml for tramadol hcl , and 1.15 mg / ml for ketorolac tromethamine .
all the drug admixtures were visually inspected immediately after preparation ( 0 h ) and at 24 and 48 h against a black and white background to ensure any physical changes ( eg , color , phase separation , precipitation ) .
a 100 l sample was drawn from each solution at intervals of 0 ( initial ) , 24 , and 48 h and diluted to 20 ml with deionized water ; we prepared solutions in triplicate at each time interval to have 54 samples .
twenty microliters of each sample was injected into the hplc system to determine concentration of each drug .
as previously described , 6 drug admixtures were prepared on different days , stored at 5c ( refrigerated ) , assessed , and visually inspected at intervals of 0 ( initial ) , 1 , 3 , and 5 days .
a 100 l of sample was drawn from each solution and diluted to 20 ml with deionized water ; we prepared solutions in triplicate at each time interval to have 72 samples .
twenty microliters of each sample was injected into the hplc system to determine concentration of each drug . the hplc method developed by kk et al
was modified for use in this study.[1718 ] the instrumentation included a binary pump ( model g1312a ; agilent technologies ; hewlett - packard , waldbronn , germany ) and an ultraviolet ( uv)variable wavelength detector ( model g1314a ; agilent ) . at the beginning of our study
, we looked for the maximum uv absorption wavelength for each drug solution on the basis of uv spectra for each solution . as we used uv
variable wavelength detector , and metoclopramide and tramadol retention times were very close reciprocally , we found that 271 nm was the best wavelength for both drugs to have good sensitivity and maximum signal / noise ratio . for ketorolac drug solutions
separation was achieved using a reversed - phase c18 5 m particle size column ( luna c18 ( 2 ) 100a , 150 4.6 mm ; chemtek analytica srl , anzola emilia ( bo ) , italy ) , equipped with a 2-cm precolumn , which was maintained at 25c with a column temperature controller ( thermosphere ts-130 ; phenomenex , torrance , california ) .
hplc - gradient analysis were performed using the following mobile phase : 0.01 m phosphate buffer , potassium dihydrogen phosphate [ kh2po4 ] ultra for molecular biology ( fluka and riedel - de han , buchs sg , switzerland ) and acetonitrile ( sigma - aldrich supelco , bellefonte , pennsylvania ) ( 75:25 , v / v ) with the addition of 0.1% triethylamine , adjusted to ph 3 with phosphoric acid ( solvent a ) and h2o acetonitrile ( 50:50 , v / v , solvent b ) .
0% b , 610 min 80% b , 1015 min 0% b [ table 1 ] .
the elution - gradient program each mobile phase was prepared fresh daily , filtered through a 0.45 m 47 mm nylon membrane filter ( supelco , bellefonte , pennsylvania nylon 66 filter membranes pore size 0.20 m , diameter 47 mm ) , and degassed ultrasonically for 20 min before use .
the flow rate was 1 ml / min , and the injected volume was 20 l .
the run time was 15 min and the approximate retention times for metoclopramide , tramadol , and ketorolac were 2.8 , 3.4 , and 13.4 min , respectively [ figure 1 ] .
uv chromatogram of metoclopramide hydrochloride ( a ) , tramadol hydrochloride ( b ) , and ketorolac tromethamine ( c ) , eluted at 2.8 , 3.4 , and 13.4 min , respectively .
calibration curves were produced using linear regression of the peak area against concentration of each drug [ table 2 ] .
we obtained 5 calibration curves for each drug and all the curves were linear over the concentration ranges considered for each drug : metoclopramide hcl r = 0.991 ; tramadol hcl r = 0.995 ; ketorolac tromethamine r = 0.961 .
the results were averaged and analyzed by linear simple regression model of y = mx + q by the least - squares method .
the t test was used to examine the concentration difference at each time , and the significance level of error was less than 0.001 .
linear simple regression model ( y = mx + q ) by the least - squares method all the data reported in tables 3 and 4 were submitted to anova and differences analyzed by tukey 's honestly significant differences test .
no significant admixture and time - dependent effect interactions were observed ( p 0.05 ) .
percentage % sd of metoclopramide hydrochloride , tramadol hydrochloride , and ketorolac tromethamine remaining in the admixtures with magnesium sulfate after storage at 25c for 48 h percentage % sd of metoclopramide hydrochloride , tramadol hydrochloride , and ketorolac tromethamine remaining in the admixtures with magnesium sulfate stored at 5c for 5 days
milan , italy ) 2 mg / ml , tramadol hcl ( contramal ; grnenthal , gmbh , stolberg , germany ) 20 mg / ml , and ketorolac tromethamine ( lixidol ; roche s.p.a . , milan , italy ) 6 mg / ml stock solutions were prepared in high - performance liquid chromatographic ( hplc)-grade deionized water and stored at 4c during experimental assay .
well - defined volume samples were drawn from each stock solution , joined , and diluted in deionized water to produce 5 working standard solutions , with concentrations in the range of 0.51.5 g / ml for metoclopramide hcl , 2060 g / ml for tramadol hcl , and 39 g / ml for ketorolac tromethamine .
every 48 h the working standard solutions were prepared from stock solutions and stored at 4c .
limit of quantitation ( loq ) values were found to be 1 , 0.5 , and 0.1 g / ml for tramadol , ketorolac , and metoclopramide , respectively .
limit of detection ( lod ) values were 0.05 , 0.2 , and 0.1 g / ml for tramadol , ketorolac , and metoclopramide .
precision and accuracy were determined on spiked samples at 4 concentrations with respect to a calibration graph prepared every day ( n = 3 ) .
the precision of the method was evaluated as the intra- and interday relative standard deviation ( rsd ) of the measured peak areas by assaying spiked samples at 4 different concentrations .
all samples for these purposes were freshly prepared , including preparing the standard solution from the same stock solution .
six drug admixtures were prepared by transferring the contents of one ampule of metoclopramide hcl , 4 ampules of tramadol hcl , 2 ampules of ketorolac tromethamine , and 4 ampules of mgso4 ( 1 g/10 ml ampule , magnesio solfato monico ; monico s.p.a . , venezia mestre , italy ) to give each a final volume of 52 ml .
all the solutions were prepared on different days , stored at 25c and assessed over a period of 48 h. solutions were stored in amber colored glass bottles with air - tight caps to protect them from direct light exposure .
the nominal concentration of each drug in all prepared solutions was 0.19 mg / ml for metoclopramide hcl , 7.69 mg / ml for tramadol hcl , and 1.15 mg / ml for ketorolac tromethamine .
all the drug admixtures were visually inspected immediately after preparation ( 0 h ) and at 24 and 48 h against a black and white background to ensure any physical changes ( eg , color , phase separation , precipitation ) .
a 100 l sample was drawn from each solution at intervals of 0 ( initial ) , 24 , and 48 h and diluted to 20 ml with deionized water ; we prepared solutions in triplicate at each time interval to have 54 samples .
twenty microliters of each sample was injected into the hplc system to determine concentration of each drug .
as previously described , 6 drug admixtures were prepared on different days , stored at 5c ( refrigerated ) , assessed , and visually inspected at intervals of 0 ( initial ) , 1 , 3 , and 5 days .
a 100 l of sample was drawn from each solution and diluted to 20 ml with deionized water ; we prepared solutions in triplicate at each time interval to have 72 samples .
twenty microliters of each sample was injected into the hplc system to determine concentration of each drug .
the hplc method developed by kk et al was modified for use in this study.[1718 ] the instrumentation included a binary pump ( model g1312a ; agilent technologies ; hewlett - packard , waldbronn , germany ) and an ultraviolet ( uv)variable wavelength detector ( model g1314a ; agilent ) . at the beginning of our study
, we looked for the maximum uv absorption wavelength for each drug solution on the basis of uv spectra for each solution . as we used uv
variable wavelength detector , and metoclopramide and tramadol retention times were very close reciprocally , we found that 271 nm was the best wavelength for both drugs to have good sensitivity and maximum signal / noise ratio . for ketorolac drug solutions , we found that 323 nm was the best absorption wavelength .
separation was achieved using a reversed - phase c18 5 m particle size column ( luna c18 ( 2 ) 100a , 150 4.6 mm ; chemtek analytica srl , anzola emilia ( bo ) , italy ) , equipped with a 2-cm precolumn , which was maintained at 25c with a column temperature controller ( thermosphere ts-130 ; phenomenex , torrance , california ) .
hplc - gradient analysis were performed using the following mobile phase : 0.01 m phosphate buffer , potassium dihydrogen phosphate [ kh2po4 ] ultra for molecular biology ( fluka and riedel - de han , buchs sg , switzerland ) and acetonitrile ( sigma - aldrich supelco , bellefonte , pennsylvania ) ( 75:25 , v / v ) with the addition of 0.1% triethylamine , adjusted to ph 3 with phosphoric acid ( solvent a ) and h2o acetonitrile ( 50:50 , v / v , solvent b ) .
the elution - gradient program was 06 min 0% b , 610 min 80% b , 1015 min 0% b [ table 1 ] .
the elution - gradient program each mobile phase was prepared fresh daily , filtered through a 0.45 m 47 mm nylon membrane filter ( supelco , bellefonte , pennsylvania nylon 66 filter membranes pore size 0.20 m , diameter 47 mm ) , and degassed ultrasonically for 20 min before use .
the flow rate was 1 ml / min , and the injected volume was 20 l .
the run time was 15 min and the approximate retention times for metoclopramide , tramadol , and ketorolac were 2.8 , 3.4 , and 13.4 min , respectively [ figure 1 ] .
uv chromatogram of metoclopramide hydrochloride ( a ) , tramadol hydrochloride ( b ) , and ketorolac tromethamine ( c ) , eluted at 2.8 , 3.4 , and 13.4 min , respectively .
calibration curves were produced using linear regression of the peak area against concentration of each drug [ table 2 ] .
we obtained 5 calibration curves for each drug and all the curves were linear over the concentration ranges considered for each drug : metoclopramide hcl r = 0.991 ; tramadol hcl r = 0.995 ; ketorolac tromethamine r = 0.961 .
the results were averaged and analyzed by linear simple regression model of y = mx + q by the least - squares method .
the t test was used to examine the concentration difference at each time , and the significance level of error was less than 0.001 . linear simple regression model ( y = mx + q ) by the least - squares method all the data reported in tables 3 and 4
no significant admixture and time - dependent effect interactions were observed ( p 0.05 ) .
percentage % sd of metoclopramide hydrochloride , tramadol hydrochloride , and ketorolac tromethamine remaining in the admixtures with magnesium sulfate after storage at 25c for 48 h percentage % sd of metoclopramide hydrochloride , tramadol hydrochloride , and ketorolac tromethamine remaining in the admixtures with magnesium sulfate stored at 5c for 5 days
at the mediterranean institute for transplantation and highly specialized therapies ( ismett , palermo , italy ) is already using an experimental protocol for the treatment of moderate to severe pain , which involves the administration of intravenous mixture of tramadol ( 7.69 mg / ml ) , metoclopramide ( 0.19 mg / ml ) , ketorolac ( 1.15 mg / ml ) , and magnesium sulfate ( 77 mg / ml ) . to use this drug combination
is necessary that the drugs are compatible with each other and the mixture is stable over time .
table 3 shows drugs solution concentration after storage period up to 48 h. the data obtained are in agreement with data reported in the literature regarding a mixture of tramadol , ketorolac , metoclopramide , and ranitidine in a solution for intravenous perfusion .
data reported in table 4 show the remaining percentage of drug concentrations in all admixtures prepared and assessed over a period of 5 days .
it is possible to observe constant percentage concentrations remaining for all the 3 drugs at 1 , 3 , and 5 days when stored at 5c .
we believe that the information has clinical utility in facilitating the preparation and dispensing of the tramadol , metoclopramide , ketorolac , and magnesium sulfate mixture in postoperative pain management . on the basis of our results ,
the mixture may be considered for a possible commercial formulation , at the concentrations listed .
in this study , precise and accurate hplc method suitable for stability evaluation of tramadol hcl combined with ketorolac tromethamine and metoclopramide hcl is described .
the physical appearance of the solutions remained constant during the study period , without the formation of any visible discoloration , cloudiness , or precipitation . in admixtures containing mgso4 and stored at 25c , each drug , at the same time , reached at least 98% of the initial concentration during 48 h. solutions prepared adding mgso4 assessed over a period of 5 days at 5c show the lower confidence limit of the estimated regression line of the concentration at 98% of the initial concentration . within these limits , for the purpose of pre - preparing drug admixtures to use with confidence , tramadol hcl infusions may be prepared in advance and then thawed before use in clinical units .
moreover , information about the chemical stability of the drugs could be utilized in further investigations focused on iv infusion solutions .
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background : tramadol hydrochloride ( hcl ) and ketorolac tromethamine are analgesic drugs , which are commonly used in combination in postoperative pain management . according to some studies , metoclopramide and magnesium sulfate ( mgso4 ) as adjuvant agents can improve analgesia and decrease the need for other pain drugs.materials and methods : the chemical stability of tramadol hcl combined with ketorolac tromethamine and metoclopramide hcl has been studied using a stability - indicating high - performance liquid chromatographic assay method .
calibration curves were produced using linear regression of the peak area against concentration of each drug , with an r2 value 0.96 .
our aim was to investigate the stability of admixture solution of tramadol hcl combined with ketorolac tromethamine and metoclopramide hcl for 48 h ( 25c ) and 5 days ( 5c ) , with mgso4 , which has never been assessed.results:data obtained for admixtures prepared and stored at temperatures of 25c and 5c , show that all drugs have reached at least 98% of the initial concentration.conclusions:for the purpose of pre - preparing drug admixtures to use with confidence , tramadol hcl infusions may be prepared in advance and then thawed before use in clinical units . on the basis of our results , the intravenous mixture of tramadol ( 7.69 mg / ml ) , metoclopramide (
0.19 mg / ml ) , ketorolac ( 1.15 mg / ml ) , and magnesium sulfate ( 77 mg / ml ) may be considered for a possible commercial formulation .
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INTRODUCTION
MATERIALS AND METHODS
Preparation of stock solutions
Admixture preparation and analysis
High-performance liquid chromatography
Data analysis
RESULTS AND DISCUSSION
CONCLUSIONS
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antiphospholipid syndrome ( aps ) may predispose the patient to deep vein thrombosis ( dvt ) , pulmonary thromboembolism ( pte ) , pulmonary hypertension and pulmonary infarction , and occasionally progress to pulmonary cavitations .
corticosteroid and immunosuppressive therapy directed at reducing antibody are not advised routinely . in a special situation ,
recognized as catastrophic apl syndrome with recurrent pte along with anticoagulant therapy , the recommendations is to start therapy with immunosuppressive agents .
however , treatment with corticosteroid and other immunosuppressive agents predispose the patients to diabetes mellitus and opportunistic infections such as fungal infection .
opportunistic fungal infection such as mucormycosis and invasive aspergilosis are almost always reported in patients with major risk factors such as diabetic ketoacidosis , long term neutropenia , post transplantation , and high dose long term corticosteroid treatment .
these infections are aggressive , rapidly progressive , angioinvasive , and life threatening diseases .
pulmonary mucormycosis has a rapid progressive course and result in lung cavitations with high a mortality rate .
some less common condition resulting in catastrophic condition are surgical procedures , anticoagulation withdrawal , medications , obstetric complications , neoplasia and systemic lopus erythmatosus ( sle ) flares .
the present case is one of the unique presentations of apl syndrome complicated with catastrophic flare up in a young woman , who died after a possible of fungal infection and immunosuppressive withdrawal .
a 35-year - old woman presented to respiratory clinic because of acute onset of fever , dyspnea exacerbation , hemoptesis , and aggravated bilateral lower limbs edema .
she had two significant episodes of dvt 12 and 10 years earlier after each childbearing .
her first infant suffered from congenital heart disease , and died at the age of 5 months .
afterwards , her condition progressed to pulmonary hypertension and right sided heart failure gradually in the last years . in spite of conventional treatment for dvt and pulmonary thromboembolism
, her condition had developed to severe pulmonary hypertension , severe dyspnea and severe lower limb edema .
she had high serum concentration of antiphospholipid antibodies ( igg : 22 gpl , igm : 17 mpl ) and anticardiolipine antibody ( igg : 25gpl , igm : 21mpl ) , but normal rheumatologic tests including antinuclear antibody ( ana ) , rheumatoid factor ( rf ) , and anti - neutrophil cytoplasmic antibodies ( anca ) .
perfusion lung scanning demonstrated perfusion defects , which was interpreted as high probability of pulmonary thromboembolism ( figure 1 ) .
perfusion lung scan : multiple segmental perfusion defects compatible with the presence of pulmonary thromboembolism .
she started receiving warfarin aiming at an international normalized ratio ( inr ) of 3 to 4 .
the measurement of serum levels of antiphospholipid antibodies was repeated on the occasion of deciding about immunosuppressive therapy . assuming the presence of multiple deep vein thrombosis , pulmonary thromboembolism , progressive pulmonary hypertension and positive antiphospholipid antibodies , prednisolone ( 60 mg / day ) and azathioprine ( 50 mg twice a day ) started hoping to prevent more catastrophic events .
she was on treatment with warfarine , azathioprine and prednisolon for 12 months , after which corticosteroid was tapered and discontinued because of hyperglycemia .
the patient then continued to receive azathioprine , warfarine and oral glucose lowering agents , and felt well until recently .
last year , she suffered from several attacks of paroxsismal atrial tachycardia ; therefore , she was admitted to the hospital . because of poor compliance , glycemic control was poor .
there was no history of any serious infection during the last four years , and serial assays for complete blood count was normal . at the last presentation ,
the laboratory findings were as follows : urea ; 55 mg / dl , creatinine ; 1.1 mg / dl , glucose ; 350 mg / dl , prothromobine time ; 25 seconds , inr ; 4.4 , wbc ; 10000/l / with 75% segment and 20% lymphocyte .
microscopic examination of urine showed : wbc ; 4 - 5/high power field , rbc ; 4 - 5/high power field and negative for bacteria .
chest computer tomography ( ct ) scan showed cavity in the medial segment of left lower lobe and a cavity in the apical segment of right lower lobe ( figure 3 ) .
blood culture for bacterial infections , and sputum smear for acid fast bacillus ( afb ) were negative .
the patient was in poor condition , and semi invasive or invasive procedures were not performed .
liposomal amphotricine was not available ; therefore , amphotricin b started empirically for possible invasive fungal infection of lung , and azathioprine was discontinued .
blood glucose remained in an acceptable range by regular insulin therapy . at the end of the first week
, the patient continued to be much better , and blood sugar , urea and creatinine were remained in acceptable range .
after two weeks of treatment , the patient was discharged and amphotricine was replaced by oral itraconasol . because of recurrent paroxysmal atrial tachycardia , the patient was readmitted on day 7 after discharge . at this admission ,
the patient succumbed to severe dyspnea , increased urea ( 192 mg / dl ) and creatinine ( 4.4 mg / dl ) , state of confusion , and was transferred to icu on the day 5 of the admission .
the portable chest radiography was not remarkable for complications such as pneumothorax or new infection .
the patient failed to improve , and died on the second day of icu care with multi organ failure and homodynamic instability .
chest computed tomography showing a cavity in the medial segment of left lower lobe and a cavity in the apical segment of right lower lobe ( arrows ) .
the patients did have the criteria for apl syndrome such as recurrent venous thrombosis , pte , pulmonary hypertension , and pregnancy morbidity as well as the presence of high serum levels of antiphospholipid antibody and anticardiolipine . as it occurred in the present case , pulmonary thromboembolism accompanied by dvt
anticoagulant therapies with heparin followed by life - long warfarine is the optimal prophylactic treatment .
since apl syndrome was not suspected in the present patient , anticoagulant was discontinued at the end of 6 month ; therefore , subsequent multiple thromboembolic events resulted in pulmonary hypertension .
as this case illustrates , apl syndrome can be associated with chronic thromboembolic pulmonary hypertension .
the prevalence of pulmonary hypertension in patient with apl syndrome is estimated to be 2 to 4% .
on the other hand , the prevalence of apl in patients with chronic thromboembolic pulmonary hypertension is around 10 to 20% .
primary non - thromboembolic pulmonary hypertension was also reported in patients with primary apl syndrome .
however , the prevalence of apl has been reported more frequently in thrombembolic type than in primary non - thromboembolic type of pulmonary hypertension .
there is also evidence that apl may contribute to the pathogenesis of pulmonary hypertension in patients with connective tissue diseases .
some cases of apl syndrome fall into a catastrophic situation , which is characterized by overwhelming small vessel occlusive disease simultaneously affecting many organs in a short period of time .
the catastrophic situation represents less than 1% of all patients with apl syndrome , and is usually life - threatening with a 50% mortality rate .
cerebral and cardiac involvements are the main causes of death in catastrophic variant of the syndrome , followed by bacterial and fungal infections . because of highly - suspected fungal infection in the present case , azathioprine was discontinued .
this might have predisposed the patient to flare up of catastrophic syndrome , which was presented as stupor , hemodynamic instability and renal failure after an initial improvement in the condition of patient due to amphotricine therapy .
infections ( 22% ) and surgical procedures ( 10% ) are the most common precipitating factors of catastrophic syndrome reported in catastrophic antiphospholipid syndrome registry followed by anticoagulation withdrawal or low inr ( 8% ) , medications ( 7% ) , obstetric complications ( 7% ) , neoplasia ( 5% ) and sle flare up ( 3% ) . in the present case ,
pulmonary cavitations in patients with apl syndrome are rare , and there are only few case reports of the condition caused by pulmonary embolism and infarction followed by cavitations
. it might be important to mention that the lung cavitations in the present case could not be due to microthrombosis , which is one of the major features of catastrophic syndrome .
however constellation of long term uncontrolled hyperglycemia state , immunosuppressive therapy , and severely decompensated pulmonary circulation , could be predisposing the patient into opportunistic angioinvasive fungal infection such as mucurmycosis .
pulmonary mucormycosis is most often encountered in patients with diabetic ketoacidosis , uncontrolled diabetes , hematological malignancy , severe burn , and after solid organ transplantation .
the definite diagnosis of pulmonary mucormycosis is usually difficult and ante - mortem diagnosis has been made infrequently . because of ill and decompensated condition in the present case , invasive diagnostic procedures such as bronchoscopy either percutaneous or open lung biopsy , were not possible .
the signs and symptoms of the present case might suggest that physicians should be aware of flare up of a catastrophic situation in patients with apl syndrome , if they decide to taper or discontinue the immunosuppressive or corticosteroid regimens .
besides , as the infection may be a possible cause of flare up or relapse , close observation of any infectious condition must be considered .
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antiphospholipid syndrome ( aps ) is a systemic disease that causes venous and arterial thrombosis in virtually any organ .
sometimes it is complicated into pulmonary infarction and cavitation , pulmonary hypertension , and catastrophic course with high morbidity and mortality .
the present case is a 35-year - old woman with one episode of postpartum deep veins thrombosis ( dvt ) 12 years earlier and the second one after the second labor two years later . in spite of usual therapy for each episode of dvt
, the condition had progressed into severe pulmonary hypertension . the diagnosis of primary apl syndrome was confirmed four years ago .
she had been on warfarin , low dose of steroid , and azathioprine since the diagnosis of apl syndrome .
after one year treatment with steroid and azathiprine the patient showed progressive well being ; however , because of hyperglycemia the steroid tapered and discontinued .
she had several attacks of paroxismal atrial tachycardia in the last year .
on the last time , she presented with severe dyspnea , hemoptesis , and lower limbs edema .
chest radiography and lung ct scan demonsterated the presence of lung cavitations .
because of high suspicious for fungal pulmonary infection , azathioprine was also discontinued . however , constellation renal failure , hemodynamic instability , and confusion caused the patient to succumb to death .
the definite diagnosis of lung cavitations was not obtained .
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Introduction
Case Description
Discussion
Conclusion
None
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the patients in the african - heritage ( n = 9 ) and caucasian - heritage ( n = 11 ) groups had similar distributions of sex , age , and duration of diabetes ( male 75 vs. 70% , p = 0.89 ; mean sd age 53.3 7.2 vs. 55.2 4.6 years , p = 0.50 ; and duration 10.3 10.7 vs. 6.8 6.4 years , p = 0.37 , respectively ) .
systolic blood pressure and diastolic blood pressure were 124.4 vs. 122.1 mmhg ( p = 0.75 ) and 77.0 vs. 76.1 mmhg ( p = 0.81 ) , respectively .
the patients were nave to antihypertensive therapy , and equal numbers in each group received metformin ( n = 6 ) and insulin ( n = 2 ) .
a1c and urinary albumin were measured by high - pressure liquid chromatography ( ha 8 - 121 ; biomen , berkshire , u.k . ) and immunoturbidimetry , respectively .
microalbuminuria was excluded on the basis of three consecutive albumin - to - creatinine ratios <3 mg / mmol in sterile , early - morning urine samples and a urinary albumin excretion rate < 30 mg / day .
renal plasma flow ( rpf ) was measured by the constant infusion method ( 6,7 ) .
a bolus dose of 8 mg / kg paraminohippurate ( merck , sharp & dohme , hoddesdon , u.k . ) was given with a 20 mg / min infusion .
after a 90-min equilibration period , the concentration of the infusate was multiplied by the infusion flow rate and divided by the mean of duplicate plasma samples at this and subsequent time points .
plasma paraminohippurate was assayed after deproteinizing the samples with 6% trichloroacetic acid for 10 min at 70c and sequentially adding sodium nitrite , ammonium sulfamate , and n-1-naphthylethylenediamine using a cobas mira ( roche , lewes , u.k . ) .
after initial equilibration , an amino acid mixture ( vamin ; pharamcia & upjohn , milton keynes , u.k . ) was infused ( 0.043 ml kg min ) .
rpf was assessed 80 min later , and then l - nmma ( clinalfa , laufelfingen , switzerland ) was begun at the nonpressor dose of 20 g kg min .
both infusions were continued for a further 20 min , after which a final rpf measurement was made . during the studies ,
blood pressure was monitored automatically ( dinamap ; critikon , basingstoke , u.k . ) , and whole blood was sampled from a venflon in a hand vein to measure glucose by the oxidase method ( one touch ; lifescan , high wycombe , u.k . ) every 10 min .
mean arterial pressure ( map ) was calculated as the diastolic blood pressure plus one - third of the pulse pressure .
renal blood flow ( rbf ) was calculated by dividing the rpf by 1 hematocrit and renal vascular resistance ( rvr ) by dividing map by rbf .
the study was approved by the ethics committee of the whittington hospital national health service trust .
analyses between or within the groups were performed using spss for windows ( version 10 ; spss , chicago , il ) .
continuous variables were compared with parametric or nonparametric tests and associations tested with spearman 's rank correlation test or pearson 's x test according to their distribution .
categorical variables were compared using a test with continuity correction or fisher 's exact test .
clearance and rpf measurements were corrected for a body surface area of 1.73 m. data are expressed as means sd unless otherwise stated .
analyses between or within the groups were performed using spss for windows ( version 10 ; spss , chicago , il ) .
continuous variables were compared with parametric or nonparametric tests and associations tested with spearman 's rank correlation test or pearson 's x test according to their distribution .
categorical variables were compared using a test with continuity correction or fisher 's exact test .
clearance and rpf measurements were corrected for a body surface area of 1.73 m. data are expressed as means sd unless otherwise stated .
comparative baseline measurements of rpf and systolic and diastolic blood pressures were similar between the african - heritage and caucasian - heritage groups ( rpf 533.7 174.7 vs. 565.3 260.8 ml / min per 1.73 m , p = 0.78 ; systolic 124.9 23.7 vs. 121.6 12.3 mmhg , p = 0.29 ; and diastolic 77.1 9.5 vs. 76.3 5.7 mmhg , p = 0.81 , respectively ) .
there were no differences in creatinine clearance or median urinary albumin excretion rate ( 93.7 19.9 vs. 98.9 19.5 ml / min per 1.73 m , p = 0.57 , and 12.6 [ 4.125.0 ] vs. 14.0 [ interquartile range 8.524.1 ] mg / day , p = 0.79 ) .
averaged blood glucose was similar ( 6.7 0.9 vs. 7.4 0.9 mmol / l ; p = 0.14 ) .
a1c was lower in the african - heritage than in the caucasian - heritage group ( 6.8 0.69 vs. 8.0 0.94% ; p = 0.005 ) .
the l - nmma infusion was associated with significant changes in systolic blood pressure in the african - heritage group ( fig .
relative to the baseline and post amino acid measurements , there was a mean rise of 10.0 mmhg ( 95% ci 2.317.9 ; p = 0.017 ) and 7.3 mmhg ( 1.013.7 ; p = 0.03 ) , respectively , in the african - heritage group and 4.3 mmhg ( 1.8 to 10.4 ; p = 0.23 ) and 2.4 mmhg ( 3.5 to 8.3 ; p = 0.38 ) in the caucasian - heritage group .
final blood pressure was higher in the african - heritage group ( 137.5 9.0 vs. 123.4 14.2 mmhg ; p < 0.05 ) and was associated with a fall in rbf ( 46.0 ml / min per 1.73 m ; p < 0.05 ) and a rise in rvr ( from 0.12 0.06 to 0.14 0.04 mmhg ml / min per 1.73 m ; p = 0.036 ) .
the changes in rvr correlated with map ( r = 0.77 ; p = 0.004 ) .
in this study , patients without hypertension or renal disease of african heritage had an increased sensitivity to the renal vasoconstrictive effect of no synthase ( nos ) inhibition .
these data suggest that a reduction in no bioavailability may adversely affect autoregulatory processes that could potentially increase vulnerability to renal damage ( 8) .
we used the amino acid infusion to optimize renal blood flow and suppress tubuloglomerular feedback as a contributor to vasoconstriction .
therefore , the reduction in renal blood flow that we observed was probably due to an effect of nos inhibition on the renovascular smooth muscle .
early in the course of diabetes , no production is necessary to forestall a rise in blood pressure .
hypertension is associated with the generation of no - quenching free radicals and is a prerequisite for the development of renal disease ( 1012 ) .
furthermore , the renal expression of nos in patients with diabetes is related to the degree of vasculopathy ( 13 ) .
it could therefore be considered that upregulation of no production in patients of african heritage is related to a mechanism that opposes an enhanced vasoconstrictor tendency .
although consistent with experimental studies , these outcomes require caution before being generalized . confirmatory studies in patients with and without diabetes with greater power and the evaluation of the role of vasoconstrictive cytokines , angiotensin
|
objective we compared the renal and systemic vascular ( renovascular ) response to a reduction of bioavailable nitric oxide ( no ) in type 2 diabetic patients without nephropathy and of african and caucasian heritage.research design and methods under euglycemic conditions , renal blood flow was determined by a constant infusion of paraminohippurate and changes in blood pressure and renal vascular resistance estimated before and after an infusion of l-ng-monomethyl-l-arginine.resultsin the african - heritage group , there was a significant fall in renal blood flow ( 46.0 ml / min per 1.73 m2 ; p < 0.05 ) and rise in systolic blood pressure ( 10.0 mmhg [ 95% ci 2.317.9 ] ; p = 0.017 ) , which correlated with an increase in renal vascular resistance ( r2 = 0.77 ; p = 0.004).conclusions the renal vasoconstrictive response associated with no synthase inhibition in this study may be of relevance to the observed vulnerability to renal injury in patients of african heritage .
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RESEARCH DESIGN AND METHODS
Statistical analysis
RESULTS
CONCLUSIONS
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following exposure of a population to radiation , concern about the risk of radiation - induced cancer can be a major source of anxiety,1,2 particularly for parents concerned about the future health of their children.3 despite the obvious importance of preventing accidental radiation exposure and reducing exposure levels , it is not currently known whether there is a practical way to specifically mitigate radiation - induced cancer risk once exposure has occurred.4,5 post - exposure measures to increase survival from acute radiation are available for individuals needing intensive care after high - dose exposure ; however , for large populations exposed to low radiation doses , there are no medical interventions which are currently advised to reduce the probability of a radiation - induced malignancy later in life .
research into chemical and biologic radio - protectors has been ongoing for many decades,6 and while some agents have been found to confer a certain degree of protection against acute effects when delivered within a short period after irradiation , many need to be administered prior to exposure in order to be effective . in the absence of a specific medical countermeasure , a consensus regarding other strategies proven to be effective in minimizing radiation - induced cancer risk and/or cancer risk more generally , would likely be a valuable public health tool .
in addition to direct effects on cancer burden , empowering individuals in exposed populations by providing safe , proven methods to lower their cancer risk could assist in decreasing anxiety and improving coping skills.7 one candidate for such an approach is caloric restriction ( cr ) .
controlled dietary intake has long been studied in terms of its effects on increasing longevity and reducing cancer incidence.8 cr has also been investigated for its potential as an adjuvant cancer treatment , to slow the growth of existing tumors.9,10 although many specific mechanisms of cr have been documented , it has effects on a wide range of physiological and cellular systems , not all of which are understood .
in fact , the levels of cr required to produce the greatest longevity effects in experimental animals are perhaps beyond what could be reasonably maintained by most people , and certainly would not be advised for children or young people during their developmental years.11 yet , understanding the kinetics of how cancer preventative / suppressive approaches can be instigated long after the time of irradiation affects the risk of radiation - induced cancer can help us to determine the utility of such approaches , and whether they can specifically prevent or merely offset radiation - induced cancer risk .
seven weeks after 1-week - old mice were subjected to 3.8 gy irradiation , they were fed either a diet equivalent to their ad libitum calorie intake ( 95 kcal / mouse / week ) or switched to a nutritionally - balanced diet limited to approximately 1/3 fewer calories ( 65 kcal / mouse / week).12 the results showed that irradiation alone decreased tumor - free lifespan , cr alone increased tumor - free lifespan , and initiating cr after irradiation was able to partially mitigate radiation - induced cancer . separating the data by cause of death revealed that different tumor types / sites responded differently to cr , with radiation - induced lymphomas showing little to no response , while a clear effect could be seen for late - occurring solid tumors .
here , we analysed the pathology results further to identify cases of lethal solid tumors and applied a multistage mathematical model of carcinogenesis to the data13 in order to gain mechanistic insight into the protective effect of cr , specifically as it relates to radiation - induced cancers .
we used lifespan data from male b6c3f1 mice published by shang et al.12 briefly , mice were either irradiated with 3.8 gy of x - rays at 1 week of age , or were sham - irradiated .
this radiation dose was chosen because it is known to efficiently induce both haematopoietic and various solid tumors in the b6c3f1 mouse strain , providing the opportunity to examine whether cr would have differential effects by tumor type . at 7 weeks of age ,
irradiated and unirradiated mice were switched from an ad libitum diet to either a diet limited to 95 kcal / week / mouse ( equivalent to ad libitum ) or to a nutrient - balanced but calorically restricted diet of 65 kcal / week / mouse ( a caloric reduction of approximately one - third ) . at this age , mice are fully developed adults but have not yet reached their peak body weight , allowing the mice to physiologically adapt to long - term cr without interrupting normal development or inducing a sharp decline in body weight .
the four groups were monitored over their natural lifespan , with detailed autopsy and pathology analysis for each mouse . tumor spectrum and latency , and their effects on overall lifespan , were used as measures of the interaction between radiation - induced carcinogenesis and cr . in the original study ,
lifespans were compared based on tumors that the mice harboured at the time of autopsy . however , as such tumors could be either incidental or lethal , the age of the mouse at the time of death may not have been directly related to any one of the tumors discovered at autopsy.14 thus , we elected to use data only from mice with tumor(s ) that were diagnosed as lethal , with the autopsy and pathology records re - evaluated by a veterinary pathologist .
this approach allowed us to compare the age - specific tumor mortality in a manner analogous to that used in human cancer epidemiology .
since cr was not observed to have a significant effect on leukaemia / lymphoma , we limited our analyses to deaths due to any solid tumor ( except sarcoma , which was rare ) , and then further analysed deaths due to lethal hepatocellular carcinoma ( hcc ) , lethal lung tumor , or lethal hemangioma .
we used a simple implementation of the armitage - doll model,13 which postulates that a normal single cell must undergo several critical steps , such as mutations or other rate - limiting events , to become a malignant cell .
armitage and doll used this model to explain the temporal variation in the death rate for solid cancer , and it has since been used across a large number of epidemiological studies to estimate the stages of cancers at many sites.15,16 the mortality rate of cancer at age t , i(t ) ( tumor deaths / mouse - day ) , is related to the probabilities of the transition between each step , p ( transitions per unit time ) . because the transitions must proceed in a unique , sequential order , i(t ) is expressed as shown in equation ( 1 ) , below , where k is the number of critical stages in the course of carcinogenesis a cell needs to pass through before becoming fully malignant , t is the age of the mice , and pi is the probability of a transition from the ( i1 ) to the i
change ( i k ) .
( 1)i(t)=p1p2pk(k-1)tk-1the logarithm of i(t ) is directly proportional to the logarithm of age , as shown in equation ( 2 ) , where a is a constant representing the product of the transition ( pk ) rates divided by ( k1 ) ! , and t
( in our analysis ) is the mid - point of age divided into 200-day increments .
( 2)log i(t)=a+(k-1)logtby plotting the log of age - specific mortality rate , i(t ) , against the log of age ( t ) obtained from the lifespan and pathology data , we used a linear fit ( estimated using the non - linear least squares method with r software version 3.1.3 ) to calculate the intercept ( a ) and slope ( k1 ) for each of the three site - specific tumors and all solid tumors to derive the model parameters pk and k. an estimate of the per - stage transition rate , pk , was calculated from the product of the transition rates , pk .
figure 1 shows the model fit for all solid tumors for the four treatment groups , with the model parameters for all solid tumor data and for the three site - specific analyses shown in table 1 .
the data clearly show a more rapid increase in the mortality rate with age in the two 65 kcal groups ( cr ) compared to the mortality rate of mice on the 95 kcal diet .
this is consistent with the increased lifespan associated with cr reported in the original data , since , although there is a stronger effect of age on the increase in the mortality rate , the mortality rate starts at a lower point and remains lower for most of the animals lifespans , exceeding that of the standard diet only at the most advanced ages , by which time few animals remain alive .
the increase in the slope and thus in the model parameter k with cr is significant for all solid tumors , hcc , and lung tumor deaths ( table 2 ) , but is not significant for hemangioma . for
all solid tumors and hcc , the increase in k associated with cr was equivalent in irradiated and unirradiated mice . on the contrary
, irradiation did not change the estimate of k , with no significant change in the slopes of the graphs of solid tumor deaths or any of the site - specific data . for each of the four treatment groups ,
the age - specific mortality data for all solid tumors shows an increase with age that is consistent with the power function characteristic of the simple armitage - doll model ( r > 0.98 ) .
hcc represented between 27% to 56% of the diagnoses for solid tumor death in each group , and the model for the hcc data ( r > 0.93 ) was very consistent with the all - solid tumor model .
although the model fits were reasonable ( r > 0.88 ) , there were too few cases of lung cancer to provide a model fit for each group , and the model fit was poor for hemangioma ( r > 0.38 ) .
both the pooled solid tumor and hcc models showed a significant increase in k with cr .
an increase in k of around 3 reflects a more rapid increase in the mortality rate in aging mice on the lower calorie diet , albeit starting from a lower baseline mortality rate . according to the tenets of the model
the carcinogenic process which delay the onset of tumors but also allow for the accumulation of cells in the penultimate stages of tumor formation .
the reduction in the product of the transition rates with cr could be the result of an overarching effect common to all of the steps ( such as a decrease in the spontaneous mutation rate ) , or the result of a specific effect which alters the probability of one particular transition .
the results presented here confirm that solid tumor mortality is indeed lower when mice are subjected to cr for most of their lifespan , and excludes artefacts due to variations in tumor stage or accelerated discovery of incidental tumors due to earlier death caused by another tumor type .
the similarity in the effect of cr on both parameters between the irradiated and unirradiated groups may suggest that there is no or little interaction between the detrimental effects of irradiation and the beneficial effects of the dietary regimen .
it is thus possible that cr offsets both spontaneous and radiation - induced carcinogenesis in a similar fashion .
this could mean that existing data on the optimal levels , duration , and timing of cr may be applicable to individuals who have previously been exposed to radiation .
interestingly , although the products of the transition rates did increase , the modelled values of k were not significantly lower in the irradiated mice , consistent with the notion that the probability of mutations was altered without concomitant alterations in the oncogenic pathway .
it may be that a radiation - induced dna mutation , such as inactivation of a tumor suppressor gene , might instantaneously move cells one or more steps forward through a multistage progression towards carcinogenesis , effectively removing the step(s ) .
although not significant , the effect of irradiation on the values of k were estimated to be in the range of a loss of a single step , and , thus , such an explanation is not excluded by our data . since radiation may act on the carcinogenic process by inducing genomic instability , stimulating tissue regeneration following radiation - induced apoptosis , and other physiological changes , as well as introducing dna mutations , it is plausible that the overall effect of irradiation on age - specific mortality would affect both the number of steps and the transition rate . here , the effects of radiation and cr were not included in the model itself , since a sufficient quantity of data are not currently available to formalize the relationship .
however , having demonstrated an effect of cr on both the parameters of this simple model , we can begin to consider the types of experimental data that would be valuable for incorporating radiation exposure and cr directly into the model .
the most pertinent questions pertaining to cr would be :
what is the relationship between the level of cr and the induction of protective effects , and is there a threshold? what is the effect of the interval between radiation exposure and the onset of cr? what is the effect of the duration of cr ?
what is the relationship between the level of cr and the induction of protective effects , and is there a threshold ? what is the effect of the interval between radiation exposure and the onset of cr ? what is the effect of the duration of cr ? in one study , adult trp53 mice ( which are highly predisposed to cancer development )
were assigned to either a calorie - restricted diet or a one - day - a - week fasting regimen , and both diets were associated with a delay in cancer - related death.17 as discussed above , if radiation - mediated cancer induction and cr - mediated cancer suppression are indeed independent of one another , existing data on cr regimens could be used to formulate a model to examine optimal strategies for offsetting both radiation - induced and spontaneous cancer risk .
such approaches have been used to model lung cancer risk after smoking cessation to understand the competing effects of smoking levels , duration , and time since quitting.18 analogously , comparing the effectiveness of long - term / lifetime cr versus short - term intense cr after irradiation might provide insight into the nature of the additional steps implied by the model discussed here , and such animal experiments are now being undertaken .
ultimately , the impractical nature of extreme cr gives rise to the question of whether complementary stressors or mimetics could be used instead .
much research has been undertaken to find cr mimetics,19 and candidates which prove effective will likely be applicable to post - radiation risk mitigation .
we are investigating the effect of addition of dietary supplements ( such as the plant phenol resveratrol , one candidate cr mimetic20 ) to the standard laboratory diet of mice . we are also undertaking experiments to determine whether radiation - induced tumors arising in calorie - restricted and -unrestricted animals show any differences in key carcinogenic pathways at the molecular level .
any differences in tumor phenotype may indicate pathways where cr interacts with the accumulation or selection of mutations . in parallel , we have established experiments utilizing environmental enrichment for laboratory mice ( play equipment , increased housing space , nesting materials ) following radiation exposure to explore whether other simple lifestyle changes may mitigate radiation - induced cancer . it is not expected that any one of these measures alone will have a dramatic impact on cancer incidence , but lifestyle changes that are safe , simple , and beneficial represent low - hanging fruit that might be included in post - disaster counselling and public health campaigns .
human populations invariably have additional cancer risk factors,21 such as smoking , alcohol consumption , sedentary lifestyles , and associated obesity , which are difficult to reproduce in experimental animals .
however , it is likely that existing public health recommendations for reducing cancer risk will be similarly effective in offsetting or mitigating low dose radiation - induced cancer risk . ultimately , at the radiation exposure levels relevant to large populations in the wake of environmental contamination , the increased risk to the individual is small compared to the background risk of cancer in the population .
simple lifestyle changes which can be proven to help offset both spontaneous and radiation - induced risk might provide significant public health benefits , both in terms of decreased cancer burden and improved mental health and well - being .
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the risk of radiation - induced cancer adds to anxiety in low - dose exposed populations .
safe and effective lifestyle changes which can help mitigate excess cancer risk might provide exposed individuals the opportunity to pro - actively reduce their cancer risk , and improve mental health and well - being . here
, we applied a mathematical multi - stage carcinogenesis model to the mouse lifespan data using adult - onset caloric restriction following irradiation in early life .
we re - evaluated autopsy records with a veterinary pathologist to determine which tumors were the probable causes of death in order to calculate age - specific mortality .
the model revealed that in both irradiated and unirradiated mice , caloric restriction reduced the age - specific mortality of all solid tumors and hepatocellular carcinomas across most of the lifespan , with the mortality rate dependent more on age owing to an increase in the number of predicted rate - limiting steps .
conversely , irradiation did not significantly alter the number of steps , but did increase the overall transition rate between the steps .
we show that the extent of the protective effect of caloric restriction is independent of the induction of cancer from radiation exposure , and discuss future avenues of research to explore the utility of caloric restriction as an example of a potential post - irradiation mitigation strategy .
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INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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exacerbations of copd are associated with accelerated loss of lung function , poor quality of life , and mortality.1,2 these events can be predicted by numerous clinical factors , including prior exacerbations , airflow obstruction , symptom burden , gastroesophageal reflux , and leukocytosis.3 it is important to detect copd exacerbations early and minimize their severity .
patients with copd frequently experience significant decreases in oxygen saturation during exercise , attributed to the imbalance between oxygen delivery and exercise - induced demand.4 exercise - induced oxygen desaturation ( eid ) is reported to be associated with hospitalization and mortality in patients with copd.5 the 6-minute walking test ( 6mwt ) has been suggested as the preferred measure to identify patients with copd and eid.6 eid occurs frequently during the 6mwt in patients with copd.7 eid has been related to forced expiratory volume in 1 second ( fev1 ) , diffusion capacity of lung carbon monoxide ( dlco ) , amount of emphysema , and baseline oxygen saturation.810 pulmonary hypertension ( ph ) is an important factor contributing to acute exacerbation of copd.11 ph appears when airflow limitation is severe , and is associated with chronic hypoxemia .
pulmonary vascular remodeling in copd is the main cause of increased pulmonary artery ( pa ) pressure , and is thought to result from the combined effects of hypoxia , inflammation , and capillary loss in severe emphysema.12 the presence of ph has been shown to increase the hospitalization rate and mortality of patients with copd.13,14 computed tomography ( ct)-detected pa enlargement is independently associated with acute exacerbations of copd.15 the pa - to - aorta ( pa : a ) ratio measured by ct scan outperforms echocardiography for diagnosing resting ph in patients with severe copd.16 a pa : a > 1 indicates lower oxygen saturation at rest than a pa : a < 1.15 however , there are no reports on the association between pa : a and eid in patients with copd .
we hypothesized that pa : a correlates with the presence of eid and that 6mwt results are useful for predicting the risk of having a pa : a > 1 .
the present study aimed to examine the relationship between pa : a and eid and develop a simple screening tool by determining the appropriate cutoff score on the 6mwt to predict a pa : a > 1 in patients with copd .
this study analyzed regularly treated outpatients with copd between 2014 and 2015 at the kobe city medical center west hospital .
a total of 64 patients with copd were included after applying the exclusion criteria in this study ( figure 1 ) .
the criteria for diagnosing copd were a smoking history ( 20 pack - years ) and postbronchodilator fev1/forced vital capacity ( fvc ) < 70% .
furthermore , we used the following inclusion criteria to define copd clinically , all of which had to be fulfilled : symptoms , including cough , sputum production , wheezing , dyspnea , smoking history ( 20 pack - years ) , existence of emphysema on chest ct , and a physician diagnosis of copd.1721 study - exclusion criteria were as follows : history of lung surgical procedures , exacerbation - related hospitalization 3 months before 6mwt , and patients on long - term oxygen therapy .
this examination included an assessment of body weight , height , and medical history ( eg , pulmonary embolism and sleep apnea syndrome ) , gold ( global initiative for chronic obstructive lung disease ) grade 04 , history of acute exacerbations of copd within the previous year , copd assessment test , level of dyspnea ( using the modified medical research council dyspnea scale ) , postbronchodilator spirometry , dlco , 6mwt ( according to international recommendations ) , emphysema area , and pa enlargement on ct .
body mass index ( bmi ) was calculated as weight in kilograms divided by height in meters squared .
gold 0 was defined as current and former smokers with a normal postbronchodilator ratio of fev1:fvc exceeding 0.7 and an fev1 of at least 80% , symptoms , including cough , sputum production , wheezing , and dyspnea , smoking history ( 20 pack - years ) , existence of emphysema on chest ct , and a physician diagnosis of copd.1721 the 6mwt was performed according to the 2002 american thoracic society guidelines.22 participants were asked to walk indoors on a flat , round , 25 m walking course supervised by a physician and physical therapist .
a pulse oximeter ( wristox 3150 ; nonin medical , plymouth , mn , usa ) with a finger probe measured peripheral oxygen saturation ( spo2 ) during 6mwt , and 6mwt - analysis software ( wristox 2 ; star product , tokyo , japan ) was used . in addition , a modified borg scale was used to quantify the levels of dyspnea perceived by subjects at each minute during the 6mwt .
eid was defined as a nadir spo2 < 90% , spo2 88% , and spo2 4%.2325 one reviewer , blinded to hemodynamic information , analyzed ct scans ( optima ct 660 discovery ; ge healthcare , little chalfont , uk ) .
measurements of the diameter of the main pa and the diameter of the aorta at the level of the bifurcation were used to calculate the pa : a ratio , as previously reported.1416 in cases where the aorta was not uniform in diameter , two measurements were taken 90 apart and the larger diameter used .
pa was measured on the line that joins the origin of the left pa and the center of the adjacent ascending aorta on the axial section at the level of pa bifurcation.26 ct - measured relative pa enlargement was defined as pa : a > 1 ( figure 2).1416 results are expressed as counts or median ( interquartile range ) .
cohen s -coefficient measured intraobserver and interobserver agreements for ct measurements of the pa : a ratio .
bivariate analyses were performed with the use of pearson s test for categorical data and the mann
spearman s rank - correlation coefficient was determined for relationships between the pa : a ratio , lung - function parameters , 6mwt parameters , and ct parameters .
receiver operating characteristic ( roc ) curves were used to determine the threshold values with the best sensitivity and specificity to predict pa : a > 1 , with the best being defined as the point on the roc curve with the shortest distance from the upper - left corner .
sensitivity , specificity , positive / negative predictive value , and positive / negative likelihood were calculated for lung - function parameters and 6mwt parameters of exacerbation - risk factors on the basis of a previous study.6,27,28 all statistical analyses were performed with ezr ( saitama medical center , jichi medical university , saitama , japan ) , which is a graphical user interface for the r project ( r foundation for statistical computing , vienna , austria).29 more precisely , it is a modified version of r commander designed to add statistical functions frequently used in biostatistics , and p - values < 0.05 were considered statistically significant .
this study analyzed regularly treated outpatients with copd between 2014 and 2015 at the kobe city medical center west hospital .
a total of 64 patients with copd were included after applying the exclusion criteria in this study ( figure 1 ) .
the criteria for diagnosing copd were a smoking history ( 20 pack - years ) and postbronchodilator fev1/forced vital capacity ( fvc ) < 70% .
furthermore , we used the following inclusion criteria to define copd clinically , all of which had to be fulfilled : symptoms , including cough , sputum production , wheezing , dyspnea , smoking history ( 20 pack - years ) , existence of emphysema on chest ct , and a physician diagnosis of copd.1721 study - exclusion criteria were as follows : history of lung surgical procedures , exacerbation - related hospitalization 3 months before 6mwt , and patients on long - term oxygen therapy .
this examination included an assessment of body weight , height , and medical history ( eg , pulmonary embolism and sleep apnea syndrome ) , gold ( global initiative for chronic obstructive lung disease ) grade 04 , history of acute exacerbations of copd within the previous year , copd assessment test , level of dyspnea ( using the modified medical research council dyspnea scale ) , postbronchodilator spirometry , dlco , 6mwt ( according to international recommendations ) , emphysema area , and pa enlargement on ct .
body mass index ( bmi ) was calculated as weight in kilograms divided by height in meters squared .
gold 0 was defined as current and former smokers with a normal postbronchodilator ratio of fev1:fvc exceeding 0.7 and an fev1 of at least 80% , symptoms , including cough , sputum production , wheezing , and dyspnea , smoking history ( 20 pack - years ) , existence of emphysema on chest ct , and a physician diagnosis of copd.1721 the 6mwt was performed according to the 2002 american thoracic society guidelines.22 participants were asked to walk indoors on a flat , round , 25 m walking course supervised by a physician and physical therapist .
subjects were encouraged using standard methodology every minute of the 6mwt . a pulse oximeter ( wristox 3150 ; nonin medical , plymouth , mn , usa ) with a finger probe measured peripheral oxygen saturation ( spo2 ) during 6mwt , and 6mwt - analysis software ( wristox 2 ; star product , tokyo , japan ) was used .
in addition , a modified borg scale was used to quantify the levels of dyspnea perceived by subjects at each minute during the 6mwt .
90% , spo2 88% , and spo2 4%.2325 one reviewer , blinded to hemodynamic information , analyzed ct scans ( optima ct 660 discovery ; ge healthcare , little chalfont , uk ) .
measurements of the diameter of the main pa and the diameter of the aorta at the level of the bifurcation were used to calculate the pa : a ratio , as previously reported.1416 in cases where the aorta was not uniform in diameter , two measurements were taken 90 apart and the larger diameter used .
pa was measured on the line that joins the origin of the left pa and the center of the adjacent ascending aorta on the axial section at the level of pa bifurcation.26 ct - measured relative pa enlargement was defined as pa : a > 1 ( figure 2).1416
this examination included an assessment of body weight , height , and medical history ( eg , pulmonary embolism and sleep apnea syndrome ) , gold ( global initiative for chronic obstructive lung disease ) grade 04 , history of acute exacerbations of copd within the previous year , copd assessment test , level of dyspnea ( using the modified medical research council dyspnea scale ) , postbronchodilator spirometry , dlco , 6mwt ( according to international recommendations ) , emphysema area , and pa enlargement on ct .
body mass index ( bmi ) was calculated as weight in kilograms divided by height in meters squared .
gold 0 was defined as current and former smokers with a normal postbronchodilator ratio of fev1:fvc exceeding 0.7 and an fev1 of at least 80% , symptoms , including cough , sputum production , wheezing , and dyspnea , smoking history ( 20 pack - years ) , existence of emphysema on chest ct , and a physician diagnosis of copd.1721
the 6mwt was performed according to the 2002 american thoracic society guidelines.22 participants were asked to walk indoors on a flat , round , 25 m walking course supervised by a physician and physical therapist .
a pulse oximeter ( wristox 3150 ; nonin medical , plymouth , mn , usa ) with a finger probe measured peripheral oxygen saturation ( spo2 ) during 6mwt , and 6mwt - analysis software ( wristox 2 ; star product , tokyo , japan ) was used .
in addition , a modified borg scale was used to quantify the levels of dyspnea perceived by subjects at each minute during the 6mwt .
one reviewer , blinded to hemodynamic information , analyzed ct scans ( optima ct 660 discovery ; ge healthcare , little chalfont , uk ) .
measurements of the diameter of the main pa and the diameter of the aorta at the level of the bifurcation were used to calculate the pa : a ratio , as previously reported.1416 in cases where the aorta was not uniform in diameter , two measurements were taken 90 apart and the larger diameter used .
pa was measured on the line that joins the origin of the left pa and the center of the adjacent ascending aorta on the axial section at the level of pa bifurcation.26 ct - measured relative pa enlargement was defined as pa : a > 1 ( figure 2).1416
cohen s -coefficient measured intraobserver and interobserver agreements for ct measurements of the pa : a ratio .
bivariate analyses were performed with the use of pearson s test for categorical data and the mann
spearman s rank - correlation coefficient was determined for relationships between the pa : a ratio , lung - function parameters , 6mwt parameters , and ct parameters .
receiver operating characteristic ( roc ) curves were used to determine the threshold values with the best sensitivity and specificity to predict pa : a > 1 , with the best being defined as the point on the roc curve with the shortest distance from the upper - left corner .
sensitivity , specificity , positive / negative predictive value , and positive / negative likelihood were calculated for lung - function parameters and 6mwt parameters of exacerbation - risk factors on the basis of a previous study.6,27,28 all statistical analyses were performed with ezr ( saitama medical center , jichi medical university , saitama , japan ) , which is a graphical user interface for the r project ( r foundation for statistical computing , vienna , austria).29 more precisely , it is a modified version of r commander designed to add statistical functions frequently used in biostatistics , and p - values < 0.05 were considered statistically significant .
the current analysis comprised 64 patients who were separated into groups on the basis of pa : a > 1 ( n=29 ) and 1 ( n=35 ) .
the -values for intraobserver and interobserver agreements for detecting pa : a > 1 were 0.87 ( 95% confidence interval [ ci ] 0.740.99 ) and 0.75 ( 95% ci 0.580.91 ) , respectively .
differences in the pa : a ratio between both groups were driven by the diameter of pa ( 2.9 [ 2.73.3 ] cm in pa : a 1 vs 3.7 [ 3.53.9 ] cm in pa : a > 1 , p=0.002 ) , because no differences were detected in the diameter of aortae ( 3.7 [ 3.43.9 ] cm vs 3.5 [ 3.33.7 ] cm , p=0.20 ) .
there were no significant differences between the two groups with regard to age , sex , bmi , pack - years , modified medical research council dyspnea scale , gold , copd assessment test , baseline pulse rate , or baseline modified borg scale ( p>0.05 ) .
on the other hand , there were significant differences between the two groups with regard to fev1 ( 71.6% [ 60.5%80.8% ] vs 52.6% [ 39.6%72.1% ] , p=0.013 ) , fvc ( 82.3% [ 50.3%93.6% ] vs 75.8% [ 42.7%86% ] , p=0.04 ) , fev1:fvc ratio ( 68% [ 61%73.3% ] vs 53.8% [ 48.8%69.4% ] , p=0.023 ) , dlco ( 72.5% [ 55.5%82.9% ] vs 44.6% [ 37.7%49.6% ] , p=0.005 ) , bode ( bmi , obstruction [ airflow ] , dyspnea , and exercise performance ) index ( 2 [ 13 ] vs 4 [ 25 ] , p<0.001 ) , 6mw distance ( 6mwd ; 450 m [ 400510.5 ] vs 325 m [ 238466 ] , p<0.001 ) , baseline spo2 ( 97% [ 95%97.5% ] vs 95% [ 93%96% ] , p=0.001 ) , lowest spo2 ( 92% [ 91%94% ] vs 86% [ 84%88% ] , p<0.001 ) , highest modified borg scale result ( 2 [ 05 ] vs 5 [ 25 ] , p=0.04 ) , low - attenuation area ( laa ; 6.8% [ 2.8%14.7% ] vs 25.4% [ 11.3%33.4% ] , p<0.001 ) , and history of acute exacerbations of copd within the previous year ( 1 [ 2.9% ] vs 7 [ 24.1% ] , p=0.019 ) ( table 1 ) .
the pa : a ratio demonstrated a significant linear correlation with lowest spo2 ( r=0.68 , r=0.46 ; p<0.001 ) , dlco ( r=0.61 , r=0.37 ; p<0.001 ) , 6mwd ( r=0.43 , r=0.18 ; p<0.001 ) , bode index ( r=0.41 , r=0.17 ; p<0.001 ) , baseline spo2 ( r=0.36 , r=0.13 ; p=0.003 ) , laa ( r=0.36 , r=0.13 ; p=0.004 ) , fvc ( r=0.34 , r=0.12 ; p=0.006 ) , fev1 ( r=0.29 , r=0.08 ; p=0.019 ) , and highest pulse rate ( r=0.26 , r=0.07 ; p=0.035 ) ( table 2 ) .
using roc curves , the threshold values with the best cutoff point , sensitivity , and specificity to predict pa : a > 1 were determined for spo2 during the 6mwt ( best cutoff point 89% , area under curve [ auc ] 0.94 , 95% ci 0.881 ) , dlco ( best cutoff point 51% , auc 0.87 , 95% ci 0.780.96 ) , 6mwd ( best cutoff point 388 m , auc 0.75 , 95% ci 0.620.87 ) , and bode index ( best cutoff points 4 , auc 0.74 , 95% ci 0.610.87 ) ( table 3 , figure 3 ) .
the performance data on the 6mwt and lung function for predicting pa enlargement are depicted in table 4 .
spo2 < 90% , spo2 88% , and spo2 4% during 6mwt were 94.3 ( 80.899.3 ) , 97.1 ( 85.199.9 ) , and 45.7 ( 28.863.4 ) , respectively , for specificity , 93.1 ( 77.299.2 ) , 95.8 ( 78.999.9 ) , and 59.6 ( 44.373.6 ) , respectively , for positive predictive value , and 16.2 ( 4.262.8 ) , 27.7 ( 4193.3 ) , and 1.8 ( 1.32.4 ) , respectively , for positive likelihood ratios .
first , we found a strong association between the pa : a ratio and lowest spo2 during the 6mwt .
for this reason , a consistent finding in patients with copd is the close relationship between severity of hypoxemia and pa pressure or pulmonary vascular resistance , supporting a major role for alveolar hypoxia.30 alveolar hypoxia causes constriction of the resistance pas , and sustained alveolar hypoxia induces pulmonary vascular remodeling.28 pathological studies of lung specimens from patients with copd have shown extensive pulmonary vascular remodeling , with prominent intimal thickening and medial hypertrophy . for this reason , chronic alveolar
hypoxia plays an important role in pulmonary vascular remodeling.28 in a previous study , patients with pa : a > 1 showed lower resting spo2 , higher usage rates of supplemental oxygen , and an indirect association with eid.15 in the present study , the lowest spo2 during the 6mwt to predict pa : a > 1 was considered to be a beneficial result based on the roc curves .
these results suggest that the lowest spo2 during the 6mwt is a very helpful measure and screening test for the pa : a ratio .
for example , it might be possible to easily screen for pulmonary artery expansion by means of the six - minute walking test in a home - care situation , where it would be difficult to perform ct imaging .
second , with regard to the relationship between pa : a ratio and lung function , correlations were observed among fev1 , dlco , and laa .
one of the factors that may play a role in causing ph to advance in patients with copd is the destruction of lung parenchyma , leading to loss of part of the pulmonary vascular bed,30,31 and the burden of airway remodeling influencing pa - pressure increase.28 a previous study included patients with airflow - obstruction severity greater than moderate , and our study included mild airflow obstruction and smokers with normal spirometry.15 therefore , regardless of the severity of airflow obstruction , pa enlargement may be progressing .
undiagnosed copd is a problem worldwide.18 gold 0 has been reported to be an exacerbation risk ; therefore,18 early detection and not just spirometry evaluation is important from multiple perspectives.18,32 from the viewpoint of early detection of pa enlargement , a definition of eid as spo2 < 90% may be a good start .
however , these findings may imply that pa : a > 1 is one of the multiple risk factors for acute copd exacerbations .
one reason for this is that pa : a is associated with ph16 and ph is also a risk factor for acute copd exacerbations.33 furthermore , a previous study reported an association between the pa : a ratio and acute copd exacerbation.15 these results suggest that screening for the pa : a ratio without ct using the 6mwt may indicate the risk of acute copd exacerbations at an early stage .
this study had some limitations , including small size , single - center experience , and retrospective design .
in addition , this study also included copd subjects who did not fit the gold criteria .
furthermore , because healthy controls do not have respiratory symptoms and there are no control data for the measurement items pertaining to such individuals , healthy controls were not included in the present study .
however , it has been reported that the presence of clinical symptoms and low dlco in smokers , even with normal spirometry , increases the risk of progression to airflow obstruction in copd.1720 therefore , the present study s results during the 6mwt could be useful to screen for ph at an early copd stage , even in gold 0 patients . finally , according to a previous study , left ventricular dysfunction causes pa enlargement .
however , echocardiography was not performed in all subjects , and this information could not be included because it was unavailable from the medical history , although we observed clinically relevant associations between ct - measured pa : a ratios and 6mwt results .
the current study s findings suggest that there is a strong association between pa : a ratio and lowest spo2 during the 6mwt .
lowest spo2 during the 6mwt is a very helpful measurement to predict pa : a ratios on ct , and lowest spo2 of < 89% during the 6mwt is excellent to screen for ph in copd .
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purposepulmonary hypertension and exercise - induced oxygen desaturation ( eid ) influence acute exacerbation of copd .
computed tomography ( ct)-detected pulmonary artery ( pa ) enlargement is independently associated with acute copd exacerbations .
associations between pa to aorta ( pa : a ) ratio and eid in patients with copd have not been reported .
we hypothesized that the pa : a ratio correlated with eid and that results of the 6-minute walk test ( 6mwt ) would be useful for predicting the risk associated with pa : a > 1.patients and methodswe retrospectively measured lung function , 6mwt , emphysema area , and pa enlargement on ct in 64 patients with copd .
the patients were classified into groups with pa : a 1 and > 1 .
receiver - operating characteristic curves were used to determine the threshold values with the best cutoff points to predict patients with pa : a > 1.resultsthe pa : a > 1 group had lower forced expiratory volume in 1 second ( fev1 ) , forced vital capacity ( fvc ) , fev1:fvc ratio , diffusion capacity of lung carbon monoxide , 6mw distance , and baseline peripheral oxygen saturation ( spo2 ) , lowest spo2 , highest modified borg scale results , percentage low - attenuation area , and history of acute copd exacerbations 1 year , and worse bode ( body mass index , airflow obstruction , dyspnea , and exercise ) index results ( p<0.05 ) . predicted pa : a > 1 was determined for spo2 during 6mwt ( best cutoff point 89% , area under the curve 0.94 , 95% confidence interval 0.881 ) .
spo2 < 90% during 6mwt showed a sensitivity of 93.1 , specificity of 94.3 , positive predictive value of 93.1 , negative predictive value of 94.3 , positive likelihood ratio of 16.2 , and negative likelihood ratio of 0.07.conclusionlowest spo2 during 6mwt may predict ct - measured pa : a , and lowest spo2 < 89% during 6mwt is excellent for detecting pulmonary hypertension in copd .
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Introduction
Patients and methods
Study design and patient selection
Clinical characterization
Assessments
Six-minute walking test
Measuring the PA:A ratio
Statistical analysis
Results
Discussion
Limitations
Conclusion
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patients with a preexisting episcleral encircling element who underwent implantation of a silicone agv to treat intractable glaucoma during january 2009 to september 2010 at a large , tertiary care ophthalmic hospital were identified by means of operative records .
postsurgical follow - up of less than 6 weeks and inability to measure intraocular pressure ( iop ) were the exclusion criteria .
the conjunctival incision was made at the corneal limbus or at 4 - 5 mm behind and parallel to the limbus , at the operating surgeon 's discretion , for approximately 100 in the supero - temporal quadrant .
the agv ( model fp7 , new world medical , rancho cucamonga , la , usa ) was primed by injecting 1 - 2 ml balanced salt solution .
the plate of agv was placed over the episcleral encircling element ; either encircling band or scleral buckle [ figure 1 ] .
the plate was secured to the underlying sclera with 8 - 0 nylon suture material ( m / s gn corporation ltd . ,
yamanashi , japan ) such that its anterior edge lied 8 mm behind the corneal limbus .
this was followed by placement of the silicone tube into anterior chamber or pars plana region through a 23-gauge needle track .
the anterior part of the tube was covered with previously prepared human donor scleral patch graft .
fibrin sealant ( tisseel kit , baxter ag , vienna , austria ) or 8 - 0 nylon suture material was used to secure the scleral patch graft .
the overlying conjunctiva was sutured with 8 - 0 polyglactin suture material ( ethicon inc . ,
if there was limited mobility of the conjunctiva due to prior surgeries , relaxing incisions were given in the conjunctiva and/or amniotic membrane transplantation was considered .
the eye was inspected for any leaks after the anterior chamber was inflated using balanced salt solution .
the base plate of ahmed glaucoma valve being placed over the episcleral encircling element that is indicated by arrows the donor scleral tissue preserved in absolute alcohol was used in every case .
the tissue was cleaned of all the uveal tissue attachments , washed thoroughly with balanced salt solution and cut into the desired size ( 4 - 5 4 - 5 mm ) .
the data collection included information on patient demography , diagnosis of glaucoma , prior ocular surgeries , measurement of visual acuity , iop , number of antiglaucoma medications at pre - agv and every post - agv follow - up visit , duration between placement of episcleral encircling element and agv , and complications , if any .
we measured iop either by applanation tonometer , namely , goldmann tonometer ( haag - streit , switzerland ) , a hand - held perkin 's tonometer ( haag - streit , essex , uk ) , or by tonopen xl ( reichert ophthalmic instruments , walden ave .
the cause ( s ) for low vision and postoperative reduction in visual acuity , if any , were also recorded .
surgical success was defined as a final iop between 5 and 22 mmhg without ( complete success ) or with topical antiglaucoma medication ( s ) ( qualified success ) and without any vision threatening complication .
paired t - test was used to compare measurements of iop and number of antiglaucoma medications at the preoperative and the final visits .
data analysis was done using spss software version 15.0 for windows ( spss inc . ,
patients with a preexisting episcleral encircling element who underwent implantation of a silicone agv to treat intractable glaucoma during january 2009 to september 2010 at a large , tertiary care ophthalmic hospital were identified by means of operative records .
postsurgical follow - up of less than 6 weeks and inability to measure intraocular pressure ( iop ) were the exclusion criteria .
the conjunctival incision was made at the corneal limbus or at 4 - 5 mm behind and parallel to the limbus , at the operating surgeon 's discretion , for approximately 100 in the supero - temporal quadrant .
the agv ( model fp7 , new world medical , rancho cucamonga , la , usa ) was primed by injecting 1 - 2 ml balanced salt solution .
the plate of agv was placed over the episcleral encircling element ; either encircling band or scleral buckle [ figure 1 ] .
the plate was secured to the underlying sclera with 8 - 0 nylon suture material ( m / s gn corporation ltd . ,
yamanashi , japan ) such that its anterior edge lied 8 mm behind the corneal limbus .
this was followed by placement of the silicone tube into anterior chamber or pars plana region through a 23-gauge needle track .
the anterior part of the tube was covered with previously prepared human donor scleral patch graft .
fibrin sealant ( tisseel kit , baxter ag , vienna , austria ) or 8 - 0 nylon suture material was used to secure the scleral patch graft .
the overlying conjunctiva was sutured with 8 - 0 polyglactin suture material ( ethicon inc . , aurangabad , india ) .
if there was limited mobility of the conjunctiva due to prior surgeries , relaxing incisions were given in the conjunctiva and/or amniotic membrane transplantation was considered .
the eye was inspected for any leaks after the anterior chamber was inflated using balanced salt solution .
the base plate of ahmed glaucoma valve being placed over the episcleral encircling element that is indicated by arrows
the tissue was cleaned of all the uveal tissue attachments , washed thoroughly with balanced salt solution and cut into the desired size ( 4 - 5 4 - 5 mm ) .
the data collection included information on patient demography , diagnosis of glaucoma , prior ocular surgeries , measurement of visual acuity , iop , number of antiglaucoma medications at pre - agv and every post - agv follow - up visit , duration between placement of episcleral encircling element and agv , and complications , if any .
we measured iop either by applanation tonometer , namely , goldmann tonometer ( haag - streit , switzerland ) , a hand - held perkin 's tonometer ( haag - streit , essex , uk ) , or by tonopen xl ( reichert ophthalmic instruments , walden ave .
the cause ( s ) for low vision and postoperative reduction in visual acuity , if any , were also recorded .
surgical success was defined as a final iop between 5 and 22 mmhg without ( complete success ) or with topical antiglaucoma medication ( s ) ( qualified success ) and without any vision threatening complication .
paired t - test was used to compare measurements of iop and number of antiglaucoma medications at the preoperative and the final visits .
data analysis was done using spss software version 15.0 for windows ( spss inc . ,
fourteen patients underwent implantation of agv in eyes with a preexisting episcleral encircling element during the study period .
two eyes ( 16.6% ) had undergone placement of a circumferential scleral buckle in the supero - temporal quadrant . in one of these eyes with scleral buckle
the shunt plate was additionally covered with two layers of cryo - preserved human amniotic membrane to reduce the chances of exposure of this implant in the postoperative period .
the mean ( standard deviation ) duration between placement of episcleral encircling element and implantation of agv was 30.5 ( 33.8 ) months ; median , 11.5 months .
the mean follow - up was 37.4 ( 22.9 ) weeks ; median , 33.5 weeks .
the mean preoperative iop was 31.4 ( 7.9 ) mmhg ; median , 32mmhg with an average of 2.8 ; median , 3 medications . at last postoperative follow - up , the mean iop decreased to 12.5 ( 3.5 ) mmhg
the postoperative reduction in iop and in number of antiglaucoma medications was statistically significant ( p < 0.001 , paired t - test ) .
demographic / pre - operative data corneal graft failure occurred in three eyes in late postoperative period following implantation of agv ( cases 4 , 7 , 9 ) . in one of these eyes , the agv tube was placed in the pars plana region . in the remaining two eyes ,
the agv tube was placed in the anterior segment , however , there was no tube - cornea touch .
the mean duration between placement of agv and corneal graft failure was 7.3 ( 5.3 ) months ; median , 8.5 months .
tube erosion occurred in another two eyes in late postoperative period ( cases 10 , 11 ) .
case 12 reported reduced vision at sixth postoperative week and was found to have a rhegmatogenous retinal detachment .
in this series , we describe implantation of the silicone plate agv in eyes with a preexisting episcleral encircling element
. this novel use of ahmed valve can be helpful in the management of intractable glaucoma after the encircling procedure .
described the use of a silicone tube to shunt aqueous from the anterior segment to the fibrous capsule surrounding a previously placed episcleral encircling element . using the existent fibrous capsule around the encircling element as an aqueous reservoir obviated the need for temporary restriction of the aqueous flow to allow encapsulation .
early postoperative complications attributable to hypotony were few and self - limiting . however , eight instances of fibrous obstruction of the distal tube opening occurred within 4 months of the initial procedure .
suh et al . also reported high overall success rate with the same technique , but they studied only seven eyes .
modified the technique by using a valved ( plate less ) krupin - denver tube . no case of early postoperative hypotony occurred , although two ( 29% ) of seven eyes experienced distal tube occlusion necessitating surgical revision .
scott et al . described an alternative approach to manage refractory glaucoma in eyes with a preexisting encircling band .
they inserted 250- ( 7 eyes [ 44% ] ) or 350-mm ( 9 eyes [ 56% ] ) baerveldt drainage devices behind or over a preexisting encircling band and over the adjacent recti muscles .
the fibrous capsule overlying the encircling band was excised in the quadrant of surgical implantation .
nine patients ( 56% ) achieved complete success and seven patients ( 44% ) achieved qualified success at 1 year postoperatively .
implant migration or exposure and diplopia did not develop in any patient over the median follow - up of 22.9 months .
however , it might be unsafe to insert a large sized implant in the presence of an encircling band in all four quadrants due to the effects of crowding
. it may be that this study with limited number of patients does not reflect the true outcome . the incidence of postoperative diplopia has been shown to be significantly higher with the baerveldt than any other implant .
this is the reason smith et al . trimmed the wings of baerveldt implants to debulk them before insertion in eyes with a preexisting episcleral encircling element .
the valve abutted against the anterior portion of the scleral band and was sutured into position .
the valve function of the implant was retained to reduce postoperative hypotony . however , the reduction in the surface area of the trimmed drainage implant is of concern as the extent of iop reduction with glaucoma drainage implants has been demonstrated to be directly proportional to the surface area of the fibrous capsule .
additionally , it may be difficult to mobilize adequate conjunctiva to cover the implant in eyes with a preexisting episcleral encircling element , especially a scleral buckle .
an implant with minimum - sized end - plate that is sufficient to achieve iop control is preferable in such eyes . increasing the surface area of
a randomized controlled clinical trial showed comparable failure rates at 1-year for both agv and 350 mm baerveldt implants .
therefore , agv should be preferred over baerveldt implant in eyes with a preexisting episcleral encircling element .
moreover , the base plate of the newer silicone ahmed valve ( model fp7 ) is thinner ( 0.9 mm ) and has the same surface area ( 184 mm ) compared with the earlier polypropylene model s2 ( thickness 1.9 mm ) .
the silicone base plate is also flexible and has a tapered profile for easy insertion .
these features allowed us to insert a silicone agv over the episcleral element in our patients .
one can also make use of a long , curved surgical scissor for better access to the supero - temporal quadrant , and guide the base plate of the agv into position over the partly open blades of the scissor .
two patients in our series had preexisting scleral buckle in the supero - temporal quadrant ( cases 8 and 12 ) .
however , the procedure was difficult in one eye ( case 12 ) due to multiple prior surgeries .
we gave a couple of relaxing incisions in the surrounding conjunctiva for adequate wound closure .
the shunt plate was additionally covered with two layers of cryo - preserved human amniotic membrane , as described by amini et al .
to reduce the chances of exposure of the implant in the postoperative period . despite these efforts , the anterior edge of the scleral patch graft covering the implant tube did expose in the early postoperative period
one of them had prior corneal graft failure ( case 9 ) . in two of these three eyes ,
the agv tube was placed in the anterior segment , however , there was no demonstrable tube - cornea touch .
found corneal graft failure in 24 ( 43.6% ) out of 55 eyes that had undergone both penetrating keratoplasty ( pk ) and either baerveldt or ahmed glaucoma implant .
also found poor long - term survival of corneal grafts in their study of 77 eyes that underwent pk following agv implantation .
the grafted corneas failed in 46 [ 59.1% , ( 95% confidence interval : 47.5 - 71.2% ) ] eyes at 3 years .
prior pk and stromal vessels , but not tube - cornea touch , did increase the risk of graft failure .
erosion of drainage tube through the overlying conjunctiva was seen in two eyes despite meticulous conjunctival closure and the use of a scleral patch graft .
both eyes underwent early repair as tube erosion carries with it increased risk of endophthalmitis .
he was a high myope , suffered from posttraumatic retinal detachment and developed secondary glaucoma following retinal detachment repair .
retinal detachment as a complication of glaucoma drainage device has been reported in as many as 16% cases with varied risk factors . nevertheless ,
considering the presence of multiple risk factors for retinal detachment , the complication may not necessarily be related to the implantation of agv in our case .
conventional filtration surgery such as trabeculectomy was either not possible or carried an unacceptably high risk of failure in these eyes .
known frequent complications such as early postoperative hypotony , shallow anterior chamber , tube obstruction , and conjunctival wound leak were not detected in this series .
even so , the overall postsurgical complications do appear frequent in this series ; however , many patients maintained useful vision that they could potentially have lost since all had uncontrolled glaucoma prior to surgery .
the retrospective design and the heterogeneity of the cases are major limitations of this study .
the sample size is small and therefore , we did not analyze complete and qualified success separately .
however , the clinical situations in which the procedures were done were extremely severe and until now none of the proposed treatments have gained general acceptance .
this study , for the first time , shows that the silicone , flexi - plate ahmed valve can be effectively implanted in eyes with a preexisting episcleral encircling element keeping in mind the possibility of significant postoperative complications .
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background : to describe the use of ahmed glaucoma valve ( agv ) in the management of intractable glaucoma in eyes with a preexisting episcleral encircling element.materials and methods : this is a retrospective , consecutive , noncomparative study .
the study included 12 eyes of 12 patients with a preexisting episcleral encircling element that underwent implantation of silicone agv to treat intractable glaucoma during january 2009 to september 2010.results:the mean patient age was 25.6 ( standard deviation 17.1 ) years .
five ( 41.6% ) patients were monocular .
the indications for agv were varied .
the mean duration between placement of episcleral encircling element and implantation of agv was 30.5 ( 33.8 ) months .
the mean follow - up was 37.4 ( 22.9 ) weeks .
preoperatively , the mean intraocular pressure ( iop ) was 31.4 ( 7.9 ) mmhg and the mean antiglaucoma medications were 2.8 . at the final postoperative follow - up , the mean iop was 12.5 ( 3.5 ) mmhg and the mean number of antiglaucoma medications was 0.8 ( p < 0.001 ) .
the complications observed over the follow - up period did include corneal graft failure in three eyes , tube erosion in two eyes and rhegmatogenous retinal detachment in one eye.conclusion:agv is an effective option in the management of intractable glaucoma in eyes with a preexisting episcleral encircling element keeping in mind the possibility of significant postoperative complications .
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Materials and Methods
Study design
Surgical procedure
Preparation of donor scleral graft
Data collection and analysis
Results
Discussion
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hydroxyl radical attack on dna most frequently leads to base damages that result in generating a range of derivatives [ 13 ] .
aerobic organisms , within the course of evolution , developed a range of adaptive mechanisms inducing synthesis of anti - oxidative enzymes and/or enzymes repairing oxidative damages of dna [ 57 ] .
oxidative damage to nucleic acid has been associated with a number of pathologies including cancer and neurodegenerative and cardiovascular diseases [ 810 ] . to date , more than 20 different types of oxidative modifications of bases have been identified .
of all the modified bases , the processes which repair 8-oxogua are perhaps best understood , and may be regarded as a template for the processes which repair other lesions . to combat the deleterious biological effect of the presence of 8-oxogua , cells have developed specific mechanisms to remove this lesion from cellular dna . in mammalian cells ,
the first level of this protection is human mut t homologue ( hmth1 ) which hydrolyses 8-oxodgtp ( a potential substrate for dna polymerase ) , thereby eliminating it from the nucleotide pool .
the second level of defence is specific glycosylases that initiate base excision repair ( ber ) .
finally , human mut y homologue ( hmyh ) removes adenine that is mis - paired with 8-oxogua .
most recently , we proposed that nucleotide excision repair ( ner ) , which involves the removal of a lesion - containing oligonucleotide , may compliment the go system , based upon evidence that oxidative dna damage may be repaired by this route .
however , there is very little evidence that 8-oxodg is a direct product of dna repair itself ( ie , released as the deoxynucleoside , rather than the base , from dna ) .
it is generally accepted that products of cellular repair of oxidatively damaged dna , such as modified bases and nucleosides : 8-oxo-7,8-dihydroguanine ( 8-oxogua ) and 8-oxo-7,8-dihydro-2-deoxyguanosine ( 8-oxodg ) are excreted in urine .
an assay was performed to analyze levels of 8-oxogua and 8-xoxdg in urine samples with regard to diet . in case of the examined group
, a conclusion was drawn that diet does not determine excretion of these biomolecules in urine . in another study , different amounts ( up to 25 mg ) of 15n labeled oxidatively modified dna were absorbed orally by volunteers . throughout 2 weeks , blood and urine samples were collected .
no 15n 8-oxogua or 8-oxodg were detected either in urine and or in dna of monoclonal cells in venous blood obtained from the same subjects taking part in the study , demonstrating that diet has no influence on the level of these damages . in both known works by faure et al . and erhola et al . , no rise of levels in 8-oxodg excretion in urine was observed despite unequivocal evidence for mass reduction of treated tumors . in certain reports , a clear rise of 8-oxodg in urine excretion was observed after radio - chemotherapy or radiotherapy itself [ 2123 ] .
however , measuring excretion of repair product in urine exclusively may be misleading since it provides no information on the oxidative state of the organism ( damage rate vs. repair rate ) in cellular dna and reports only the mean value of damage repair in the past .
the aim of the work was to investigate whether the levels of markers of oxidative damages of dna : excreted in urine 8-oxo-7,8-dyhydro-2-deoxyguanosine ( 8-oxodg ) and 8-oxo-7,8-dyhydroguanine ( 8-oxogua ) as well as the level of 8-oxodg in dna of venous blood leukocytes differ in a population of healthy subjects when compared with cancer patients .
hydroxyl radical attack on dna most frequently leads to base damages that result in generating a range of derivatives [ 13 ] .
aerobic organisms , within the course of evolution , developed a range of adaptive mechanisms inducing synthesis of anti - oxidative enzymes and/or enzymes repairing oxidative damages of dna [ 57 ] .
oxidative damage to nucleic acid has been associated with a number of pathologies including cancer and neurodegenerative and cardiovascular diseases [ 810 ] . to date , more than 20 different types of oxidative modifications of bases have been identified .
of all the modified bases , the processes which repair 8-oxogua are perhaps best understood , and may be regarded as a template for the processes which repair other lesions . to combat the deleterious biological effect of the presence of 8-oxogua , cells have developed specific mechanisms to remove this lesion from cellular dna . in mammalian cells ,
the first level of this protection is human mut t homologue ( hmth1 ) which hydrolyses 8-oxodgtp ( a potential substrate for dna polymerase ) , thereby eliminating it from the nucleotide pool .
the second level of defence is specific glycosylases that initiate base excision repair ( ber ) .
finally , human mut y homologue ( hmyh ) removes adenine that is mis - paired with 8-oxogua .
most recently , we proposed that nucleotide excision repair ( ner ) , which involves the removal of a lesion - containing oligonucleotide , may compliment the go system , based upon evidence that oxidative dna damage may be repaired by this route .
however , there is very little evidence that 8-oxodg is a direct product of dna repair itself ( ie , released as the deoxynucleoside , rather than the base , from dna ) .
it is generally accepted that products of cellular repair of oxidatively damaged dna , such as modified bases and nucleosides : 8-oxo-7,8-dihydroguanine ( 8-oxogua ) and 8-oxo-7,8-dihydro-2-deoxyguanosine ( 8-oxodg ) are excreted in urine .
an assay was performed to analyze levels of 8-oxogua and 8-xoxdg in urine samples with regard to diet . in case of the examined group
, a conclusion was drawn that diet does not determine excretion of these biomolecules in urine . in another study , different amounts ( up to 25 mg ) of 15n labeled oxidatively modified dna were absorbed orally by volunteers . throughout 2 weeks , blood and urine samples were collected .
no 15n 8-oxogua or 8-oxodg were detected either in urine and or in dna of monoclonal cells in venous blood obtained from the same subjects taking part in the study , demonstrating that diet has no influence on the level of these damages .
, no rise of levels in 8-oxodg excretion in urine was observed despite unequivocal evidence for mass reduction of treated tumors . in certain reports , a clear rise of 8-oxodg in urine excretion was observed after radio - chemotherapy or radiotherapy itself [ 2123 ] .
however , measuring excretion of repair product in urine exclusively may be misleading since it provides no information on the oxidative state of the organism ( damage rate vs. repair rate ) in cellular dna and reports only the mean value of damage repair in the past .
the aim of the work was to investigate whether the levels of markers of oxidative damages of dna : excreted in urine 8-oxo-7,8-dyhydro-2-deoxyguanosine ( 8-oxodg ) and 8-oxo-7,8-dyhydroguanine ( 8-oxogua ) as well as the level of 8-oxodg in dna of venous blood leukocytes differ in a population of healthy subjects when compared with cancer patients .
analysis of daily excretion of 8-oxogua and 8-oxodg with urine was done in a study group consisting of 222 patients with malignant cancer ( iii and iv degree of clinical stage ) .
leukocytes from peripheral blood samples for analysis of 8-oxodg level were obtained from 179 patients from among the study group .
control peripheral blood samples for analysis of 8-oxodg in leukocytes were obtained from 134 healthy volunteers . from this group ,
85 urine samples were taken for the measurement of daily excretion of 8-oxogua and 8-oxodg in urine .
the patients had various malignant tumors : , head and neck cancer ( n=45 ) , breast cancer ( n=32 ) , colon cancer ( n=25 ) , lung cancer ( n=37 ) , uterine cancer ( n=15 ) , ovarian cancer ( n=39 ) , testicular cancer ( n=7 ) , prostate cancer ( n=11 ) , gastrointestinal cancer ( n=11 ) .
the patients were asked to abstain from vitamin supplementation for at least 1 month before the chemotherapy started and during the course of the treatment , and only these patients qualified .
the control group was chosen in such a way that the following criteria matched the patient group : eating habits , age , body weight , sex , and smoking status .
the study was approved by the medical ethics committee of the collegium medicum nicolaus copernicus university bydgoszcz , poland , ( in accordance with good clinical practice , warsaw 1998 ) , and all the patients gave informed consent .
venous blood samples ( 18 ml ) from the patient and volunteer groups were collected .
the blood was carefully applied on top of histopaque 1119 solution ( sigma - aldrich inc . ; st .
louis , mo ) and leukocytes were isolated by centrifugation according to the procedure specified by the manufacturer .
determination of 8-oxodg by the mean of hplc / ec technique was as described previously .
urine sample preparation , hplc purification and gc / ms analysis were conducted as described earlier .
mann - whitney testing for independent groups with abnormal distribution was performed . for normal distribution ,
analysis of daily excretion of 8-oxogua and 8-oxodg with urine was done in a study group consisting of 222 patients with malignant cancer ( iii and iv degree of clinical stage ) .
leukocytes from peripheral blood samples for analysis of 8-oxodg level were obtained from 179 patients from among the study group .
control peripheral blood samples for analysis of 8-oxodg in leukocytes were obtained from 134 healthy volunteers . from this group ,
85 urine samples were taken for the measurement of daily excretion of 8-oxogua and 8-oxodg in urine .
the patients had various malignant tumors : , head and neck cancer ( n=45 ) , breast cancer ( n=32 ) , colon cancer ( n=25 ) , lung cancer ( n=37 ) , uterine cancer ( n=15 ) , ovarian cancer ( n=39 ) , testicular cancer ( n=7 ) , prostate cancer ( n=11 ) , gastrointestinal cancer ( n=11 ) .
the patients were asked to abstain from vitamin supplementation for at least 1 month before the chemotherapy started and during the course of the treatment , and only these patients qualified .
the control group was chosen in such a way that the following criteria matched the patient group : eating habits , age , body weight , sex , and smoking status .
the study was approved by the medical ethics committee of the collegium medicum nicolaus copernicus university bydgoszcz , poland , ( in accordance with good clinical practice , warsaw 1998 ) , and all the patients gave informed consent .
venous blood samples ( 18 ml ) from the patient and volunteer groups were collected .
the blood was carefully applied on top of histopaque 1119 solution ( sigma - aldrich inc . ; st .
louis , mo ) and leukocytes were isolated by centrifugation according to the procedure specified by the manufacturer .
determination of 8-oxodg by the mean of hplc / ec technique was as described previously .
urine sample preparation , hplc purification and gc / ms analysis were conducted as described earlier .
mann - whitney testing for independent groups with abnormal distribution was performed . for normal distribution ,
significantly elevated levels of 8-oxogua and 8-oxodg excreted in urine daily as well as 8-oxodg in dna of leucocytes in venous blood were observed in cancer patients as compared with healthy subjects , with considerable statistic significance ( table 1 ) . for the whole patient population ( n=222 ) , the median values of 8-oxogua and 8-oxodg in urine samples were 12.44 ( interquartile range : 8.1420.33 ) [ nmol/24 hr ] and 6.05 ( 3.1215.38 ) [ nmol/24 hr ] , respectively .
the median values of 8-oxogua and 8-oxodg in urine samples of the control group ( n=85 ) were 7.7 ( 4.6510.15 ) [ nmol/24 hr ] and 2.2 ( 1.72.8 ) [ nmol/24 hr ] , respectively .
the level of 8-oxodg in dna isolated from leukocytes in the patient group ( n=179 ) and of the control group ( n=134 ) was 4.93 ( 3.469.27 ) per 10 dg and 4.46 ( 3.825.31 ) per 10 dg , respectively .
certain amounts of oxidatively modified bases are present in every cell , reflecting the balance between ros attacking dna in the course of many metabolic processes and damage repair of these molecules by specific enzymes repairing dna .
it is not known at present what is the endogenous level of these potentially mutagenic damages . according to the reports of authors applying different analytical techniques , the values range from 0.2 to several modifications/10 pairs of bases for healthy cells .
they are removed in the process of repair and excreted in urine in unchanged state .
a balance between producing ros which induce oxidative dna damages and removing these damages was observed in a cell ( background level ) . according to some authors , the levels of these modifications
it is possible to estimate the extent of repair on the level of the whole organism while analyzing the amount of oxidative dna damages in urine .
high values of oxidative damages of dna excreted in urine indicate an intensified level of oxidative stress , but they may also reflect high efficiency of repair systems of these damages ( oxidative stress may be high , yet repair mechanisms remove its effects ) . however , combining the background level specific for every patient and analyzing 8-oxogua and 8-oxodg in excreted urine may clearly reflect information about dna repair mechanisms .
the results presented in the present study comparing amounts of 8-oxogua and 8-oxodg excreted in urine daily as well as amounts of 8-oxodg in venous blood dna leucocytes in patients with diagnosed cancer when compared with healthy subjects demonstrate higher levels of these modifications in cancer patients ( figures 13 ) .
significantly elevated levels of analyzed markers of oxidative damage dna may reflect the oxidative stress situation which accompanies cancer .
several studies have analyzed 8-oxogua and 8-oxodg in urine in different types of cancer patients and control groups , reporting elevated level of 8-oxogua in urine of cancer patients and in a control group of smoking subjects , and the level of 8-oxodg in dna isolated from venous blood leucocytes was higher in the patient group .
these findings suggest that in cancer patients repair mechanisms of oxidative damage to dna are less efficient ( the concentration of modified nucleoside / base in urine reflects dna damages of the whole organism , and the level of 8-oxodg in cellular dna reflects balance between processes generating damages and the ability of their repair ) .
compared a group of cancer patients and healthy volunteers with regard to the amount of 8-oxogua and 8-oxodg excreted in urine , demonstrating elevated levels of oxidatively modified base in patients when compared with healthy subjects by 50% .
our work indicates the levels of these derivatives elevated to such an extent can not be related to its increase in cancer cells exclusively .
the results suggest that oxidative stress in patients with cancer , demonstrated by elevated levels of these modifications in urine , may be typical not only of affected tissue but also of other tissues and even the whole organism . from practical point of view , a test that would enable determination of background levels of basic markers of oxidative stress ( 8-oxogua and 8-oxodg in urine and 8-oxodg in dna in leukocytes ) , might be applied as an additional and helpful marker for early detection of the development of cancer .
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summarybackgroundthe broad spectrum of oxidative damage dna biomarkers : urinary excretion of 8-oxodg ( 8-oxo-7,8-dihydro-2-deoxyguanosine ) , 8-oxogua ( 8-oxo-7,8-dihydroguanine ) as well as the level of oxidative damage dna in leukocytes , was analyzed in cancer patients and healthy subjects.material/methods222 cancer patients and 134 healthy volunteers were included in the analysis , using methodologies which involve hplc ( high - performance liquid chromatography ) prepurification followed by gas chromatography with isotope dilution mass spectrometry detection and hplc / ec.resultsfor the whole patient population ( n=222 ) the median values of 8-oxogua and 8-oxodg in urine samples were 12.44 ( interquartile range : 8.1420.33 ) [ nmol/24 hr ] and 6.05 ( 3.1215.38 ) [ nmol/24 hr ] , respectively .
the median values of 8-oxogua and 8-oxodg in urine samples of the control group ( n=85 ) were 7.7 ( 4.6510.15 ) [ nmol/24 hr ] and 2.2 ( 1.72.8 ) [ nmol/24 hr ] , respectively .
the level of 8-oxodg in dna isolated from leukocytes of the patient population ( n=179 ) and of the control group ( n=134 ) was 4.93 ( 3.469.27 ) per 106 dg and 4.46 ( 3.825.31 ) per 106 dg , respectively.conclusionsthe results suggest that oxidative stress in cancer patients , demonstrated by augmented amounts of these modifications in urine , could be typical not only for affected tissue but also for other tissues and even the whole organism .
an assay that enables the determination of levels of basic markers of oxidative stress might be applied in clinical practice as an additional , helpful marker to diagnose cancer .
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Background
Oxidatively modified bases
Diet as a potential source of 8-oxoGua and 8-oxodG in urine
Cell death as a potential source of 8-oxoGua and 8-oxodG in urine
Purpose
Material and Methods
Patients
Isolation of leukocytes from venous blood
DNA isolation and 8-oxodG determination in DNA isolates
Urine analysis
Statistical analysis
Results
Discussion
Conclusions
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it is predicted that by 2025 , the prevalence of hypertension ( htn ) will increase by 60% to a total of 1.56 billion worldwide suggesting that htn remains a major public health problem .
htn in sub - saharan africa ( ssa ) has also been on the rise with reports indicating higher values in urban settings compared to rural settings [ 24 ] .
the prevalence of htn in ssa ranges between 14.5% in rural eritrea , 32.9% in semiurban ghana , and 40.1% in urban south africa .
likewise , adequate blood pressure ( bp ) control has been on the decline , ranging between 1.7% in rural ghana , 4% in urban slum dwellers in nigeria , and 21.5% in urban kenya . in cameroon
, the prevalence of htn spans from 5.7% in rural settings through 21.9% in semiurban to 47.5% in urban milieu , with a national average survey of 31.0% . despite the relatively better bp control in urban over rural settings , levels of adequate bp control as low as 2% to 27.5% ( in men ) and 38.7% ( in women )
even though much has been done so far to reduce the incidence of hypertension in urban areas , this has not been the same in rural areas , with public health policies aimed at controlling hypertension mainly directed towards the large cities .
most of the studies done so far in these urban areas can not therefore give a true estimate of the extent to which the rural population is affected by this major cardiovascular disease risk factor .
an analysis of hypertension and its risk factors in rural cameroon will therefore help guide health policy decisions and provide baseline data for future studies aimed at addressing this problem .
we therefore had the following as objectives : determining the prevalence of hypertension in the adult population in the moliwe health area in rural cameroon ; identifying the risk factors associated with htn in this rural setting ; determining the extent of bp control in known hypertensive patients in this locality .
a community - based cross - sectional descriptive and analytical study was conducted over a 6-month period ( june 20 to december 28 , 2013 ) in the moliwe health area ( mha ) .
this principally rural health area is found in the limbe health district of the south west region of cameroon .
a multistage sampling method was used to select participants from the 5 villages / settlements of the health area : bonadikombo , wotutu , ewongo , moliwe , and tomatal .
the sample selected was self - weighted through the probability proportional to size method used . the data of 2005 cameroon census was used as a guide to the sampling frame with households considered as the primary sampling units . using a random start
, a systematic sample of households was then selected from a list of the approximate cumulative number of households of all the villages .
this gave an estimate of the number of households to be selected from each village .
as the secondary sampling units , two participants were then recruited from each selected household by simple random sampling from a list of eligible households occupants produced by the respective household heads .
three hundred and twenty - nine participants were thus recruited from bonadikombo , 113 from wotutu , 112 from moliwe , 96 from ewongo , and 83 from tomatal .
a combined estimate of the prevalence of htn in rural rwanda , tanzania , and malawi of 22% was used .
we recruited 733 participants by systematic and simple random sampling methods . at each selected household ,
a questionnaire was administered to each recruited participant to collect information on age , sex , level of education , marital status , status of htn , treatment of htn , smoking , quantity of alcohol intake , physical activity , diabetes status , and family history of htn .
blood pressure measurements were also done at the home of the participants by a casually dressed clinician not in white coat .
two measurements ( in mmhg ) were taken on the right arm using an automated electronic bp machine ( omron m3 hem-7200-e omron matsusaka co. ltd . , kyoto , japan ) through the standard procedure ( jnc 7 recommendations ) . heights in meters ( m ) and weights in kilograms ( kg )
were measured using standard procedures and were used to determine the body mass index ( bmi ) as follows : bmi = weight ( kg)/[height ( m ) height ( m ) ] . who steps surveillance manual
the data was entered into epi info statistical software , version 7.0 ( cdc / who , atlanta , usa ) .
frequencies and means were obtained for appropriate variables ; chi - square and fischer 's exact tests were used as appropriate to test for associations between binary and categorical variables .
a logistic regression model was built to assess the effect of factors found to be significantly associated with hypertension while controlling for potential confounders .
an ethical clearance was obtained from the institutional review board of the faculty of health sciences , university of buea .
administrative approvals were obtained from the regional delegate of public health as well as from the local chiefs , quarter heads , and camp presidents concerned .
all patients found to have elevated blood pressure values were advised and referred to the nearest health facility for proper management and follow - up .
of the 733 participants , 479 ( 39.5% ) were between 20 and 29 years .
the male to female ratio was 1 : 1.2 , 35.9% had primary education , and 50.5% were married .
less than half of the participants ( 47.3% ) had normal bmi and 15% had sedentary life style . a small proportion , ( 2.9% )
were known diabetics and 32.7% reported a family history of hypertension ( table 1 ) .
of the 733 participants recruited , 228 were hypertensive , giving a prevalence of 31.1% ( 95% ci : 27.834.6 ) .
sixty - six of the 228 hypertensive participants ( 28.9% , 95% ci : 23.235.3 ) knew their status prior to our study .
of these 66 known hypertensive participants already aware of their status , 14 of them ( 21.2% , 95% ci : 12.133.3 ) had their blood pressures well controlled even though as high as 47 of them ( 71% , 95% ci : 58.781.7 ) were on antihypertensive treatment at that moment ( figure 1 ) .
age 40 and above , obesity , smoking , alcohol consumption , diabetes , low educational level , and marriage were found to be associated with hypertension ( table 2 ) . after adjusting for all significant factors using logistic regression , only age 40 and above , obesity , low educational level , and marriage
there was a progressive increase in the prevalence of htn with age when age below 40 was used as the reference : from 3 folds in the 4059 years , through 8.3 folds in the 6079 years , to 11.6 folds in 80 years age groups .
people who were obese had 2.8 times the odds of being hypertensive compared to the nonobese .
those who never went to school had 6.7 times the odds of having htn compared to those who had at least high school education ( table 3 ) . since the new recommendations for htn diagnosis and management by jnc 7 in 2003 , no study had been done in rural cameroon . the last published rural study on htn was as far back as 1998 .
the 31.1% prevalence of htn observed in the mha is similar to the 31.0% reported in cameroon by kingue et al . and the 32.9% reported by amoah in semiurban ghana but higher than that reported elsewhere [ 3 , 7 , 8 , 12 , 16 , 17 ] .
however , our value was lower than 44.7% reported by williams et al . in rural ghana and 40% reported by chow et al . in rural and urban high , middle , and low income countries .
our study revealed low hypertension awareness similar to the 32.3% observed in rural ghana by addo et al . and the 32.6% observed by dzudie et al . in urban cameroon .
however , this value is higher than the 11% reported in rural cameroon by mbanya et al .
this variation between rural and urban settings could be explained by poor knowledge of the disease , lesser access to health facilities , and poverty , in rural compared to urban communities .
age was identified to be strongly associated with htn , supporting the findings of other studies [ 9 , 12 , 2123 ] .
this is because as people get older , their blood vessels become harder and they are likely to have decreased baroreceptor sensitivity , increased responsiveness to sympathetic nervous system stimuli , altered renal and sodium metabolism , and an altered renin - aldosterone relationship thereby predisposing them to high blood pressure .
obesity , which is one of the common pathways between diabetes and htn , was also found to be strongly associated with htn in our study , as earlier documented [ 8 , 26 ] .
low educational status and being married were strongly linked with htn in our study as reported in previous studies [ 21 , 27 , 28 ] . a poor understanding of the disease and its risk factors and the stress experienced my married couples , respectively ,
could put these groups at a higher risk . on the other hand , gender , family history of htn , overweight , and physical inactivity
smoking , alcohol consumption , and diabetes mellitus which were associated with htn on bivariate analysis were not significantly associated with hypertension on multivariate analysis by logistic regression .
the proportion of known hypertensives who were currently on antihypertensive treatment in our study was similar to the 64.9% reported in ghana but much higher than the 12.5% reported in cameroon
. the high proportion on antihypertensives may be due to the increase in awareness of htn and the availability and access to antihypertensive medications in cameroon lately compared to 16 years ago . despite this considerable proportion of hypertensive patients being on treatment ,
reported as low as 3% in rural nigeria and yuvaraj et al . reported 12.5% in rural india
however , higher proportions have been reported ( 33.1% and 63.2% ) among hypertensives in urban and semiurban settings in cameroon , respectively , 56.8% in mexico , and 75.9% in urban india .
in this context noncompliance to treatment is multifactorial in aetiology with reasons such as inadequate knowledge of htn , intolerance of side effects of medications , and low purchasing power .
this study was cross - sectional which means participants declared hypertensive may not necessarily be hypertensive clinically .
also , our study was done in a small rural area whose findings may not necessarily apply to all rural cameroonian or sub - saharan african communities . moreover , some known risk factors such as dyslipidaemia , salt intake , and psychosocial and socioeconomic status were not assessed in our study .
nevertheless , the large sample size , varied sampling method , and execution of standard measurement procedures make the findings of this study robust and accurate .
also , the white coat effect which could potentially produce an overestimation of the actual prevalence of hypertension in this setting was minimized since the casually dressed clinician without a white coat did the measurements from the participants ' homes .
our study revealed that about one out of three adults in the moliwe health area could be hypertensive with only a quarter of them being aware of their status and a fifth of those on treatment having their blood pressure well controlled .
this reveals how very much a cardiovascular risk the rural population may be exposed to .
there is , therefore , need for massive improvement in awareness through education and repeated patient follow - up in these rural settings alongside the urban ones .
also , the importance of further research in other rural communities to assess trends and risk factors of hypertension and the extent of blood pressure control can not be overemphasized .
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background . despite the increasing trends suggesting that hypertension is a growing public health problem in developing countries , studies on its prevalence , associated risk factors , and extent of blood pressure control have been inequitably done in urban and rural communities in these countries .
we therefore aimed to determine the prevalence of hypertension and extent of blood pressure control in rural cameroon .
methods .
this was a community - based cross - sectional study conducted in rural cameroon ( the moliwe health area ) .
participants aged 21 years and above were recruited by a probability proportional to size multistage sampling method , using systematic sampling for household selection and random sampling for participant selection .
blood pressure , weight , and height were measured by standard methods .
hypertension was defined as bp 140/90 mmhg .
results .
the prevalence of hypertension among the 733 participants recruited was 31.1% ( 95% ci : 27.834.6 ) and 71% ( 95% ci : 58.781.7 ) of these hypertensive patients were newly diagnosed . only 21.2% ( 95% ci : 12.133.3 ) of known hypertensives had a well controlled bp .
age , obesity , low educational status , and being married were associated with htn after adjusting for confounders .
conclusions . the high prevalence of hypertension and inadequate bp control among known hypertensives in rural cameroon warrants greater sensitization and regular screening to reduce hypertension - related morbidity and mortality .
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1. Background
2. Materials and Methods
3. Results and Discussion
4. Conclusions
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granuloma annulare ( ga ) was first described in 1895 by colcott - fox who reported an 11-year - old girl with a ring eruption of the fingers .
the condition is a benign , usually self - limited granulomatous disease of the dermis and subcutaneous tissue .
clinically , the condition is characterized by asymptomatic , flesh - colored or erythematous - brown papules , frequently arranged in a ring or annular pattern on the distal extremities
. it may be skin - colored erythematous or violaceous measuring 1 - 5 cm in diameter .
several clinical variants of ga have been reported , namely localized , generalized or disseminated , targetoid , giant , subcutaneous and perforating ga .
we report an 18-month - old male child with multiple , progressive ga over the lower extremities .
an 18-month - old male child presented with multiple annular lesions over lower extremities and buttocks .
initially it started as a small papule over the left thigh , substantially attaining the present size .
there was no history of fever , pain , drug intake or recent vaccination . on examination ,
on cutaneous examination , closely set , skin - colored , firm , smooth papules 2 - 3 mm in size arranged in a ring - like fashion to form annular plaques measuring approximately 3 3 cm ( eight lesions ) were present over dorsal aspect of foot [ figures 1 and 2 ] , both legs and buttocks .
granuloma annulare over the left foot granuloma annulare over the right ankle routine hematological , biochemical and urine examinations were normal .
venereal disease research laboratory test , human immunodeficiency virus 1 and 2 , hepatitis surface antigen test were negative and a biopsy showed features consistent with ga .
ga is a benign , relatively common cutaneous disease that classically presents as closely set , skin - colored , firm , smooth papules 2 - 3 mm in size arranged in a ring - like fashion to form annular lesions .
most cases occur before the age of 30 years and it is approximately twice more common in females .
it often favors sacral sites such as the dorsa of the hands , elbows and feet but involvement of the palms appears to be rare .
occasional familial cases are described with the occurrence in twins , siblings , and members of successive generations .
attempts to identify an associated hla sub - type have yielded disparate results in different population groups .
linear ga , a follicular pustular form and popular umbilicated lesions in children have also been described .
the condition manifests as numerous ( at least 10 , often hundreds to thousands ) small , asymptomatic , erythematous , violaceous , brown- or skin - colored papules .
rarely , ga may be complicated by nerve involvement as a result of granulomatous inflammation surrounding cutaneous nerves and perineural infiltrates of histiocytes in the dermis .
the differential diagnoses of localized ga include tineacorporis , pityriasis rosea , pityriasis rotunda , erythema annulare centrifugum , nummular eczema , discoid lupus erythematosus , psoriasis , necrobiosis lipoidica , morphea , hypertrophic lichen planus and erythema chronicum migrans .
treatment options include topical or intralesional corticosteroids , imiquimod cream , topical calcineurin inhibitors ( tacrolimus , pimecrolimus ) , cryotherapy , and pulsed dye laser .
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granuloma annulare is a benign , self - limiting , inflammatory and granulomatous disease of unknown etiology occurring in both adults and children .
an 18-month - old male child had multiple progressive annular plaques over the lower extremities .
clinical and histopathological features were consistent with granuloma annulare .
localized granuloma annulare is the most common form in children .
we report a young child with multiple , progressive granuloma annulare over the lower extremities .
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Introduction
Case Report
Discussion
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we analyzed all 140 mrsa isolates we obtained during a previous study ( 2 ) and 50 other isolates selected from our collection of nosocomial mrsa isolates obtained in 2003 .
characteristics of these 190 isolates are shown in table 1 . * ni , nosocomial infection acquired at national taiwan university hospital ( ntuh ) ; nc , nosocomial colonization at ntuh ; ieoh , mrsa infection detected at ntuh within 48 h after transfer from another hospital .
bl , blood ; ur , urine ; sp , sputum ; pu , pus ; wo , wound ; ns , nostril ; ct , catheter tip ; st , stool .
pulsed - field gel electrophoresis patterns were interpreted according to procedures previously reported ( 7,8 ) .
thirty - four isolates belonged to pulsotype a , 49 to pulsotype b , 69 to pulsotype c , 6 to pulsotype d , 2 to pulsotype e , 3 to pulsotype f , 11 to pulsotype k , 5 to pulsotype l , 8 to pulsotype m , and 3 ( all isolated in 2003 ) to 3 minor pulsotypes .
all isolates were tested by sccmec element typing and multilocus sequence typing ( mlst ) ( 9 ) and were analyzed for the panton - valentine leukocidin ( pvl ) gene ( 10 ) and drug susceptibility to erythromycin , clindamycin , gentamicin , amikacin , ciprofloxacin , levofloxacin , tetracycline , trimethoprim - sulfamethoxazole , rifampin , and vancomycin by using the disk diffusion method ( 11 ) .
isolates with pulsotype a are sequence type 254 ( st254 ) ; those with pulsotype b are st241 ; those with pulsotypes c , k , and l are st239 ; and those with pulsotypes d , e , f , and m are st59 , st 254 , st30 , and st5 , respectively .
all mrsa isolates with pulsotypes a , d , e , and f have the type iv sccmec element .
however , only isolates with pulsotypes d and f , as well as 2 isolates from 2003 with 2 minor pulsotypes , have the pvl gene .
isolates with pulsotypes b and c have the type iii sccmec element , and isolates with pulsotype m have the type ii sccmec element . *
p , pulsotype ; scc , staphylococcal cassette chromosome ; mlst , multilocus sequence typing ; pvl , panton - valentine leukocidin ; n , no ; y , yes . ox , oxacillin ; em , erythromycin ; cl , clinidamycin ; gm , gentamicin ; am , amikacin ; cp , ciprofloxacin ; lv , levofloxacin ; tc , tetracycline ; ts , trimethoprim - sulfamethoxazole ; rf , rifampin ; va , vancomycin .
results of mlst and typing of sccmec elements of the 3 isolates with 3 minor pulsotypes obtained in 2003 are shown in table 2 .
the correlation between sccmec element typing and mlst in this study corresponds to findings of previous reports ( 6,1214 ) .
enright et al . identified st254-iv mrsa isolates in germany and the united kingdom ( 12 ) , and chongtrakool et al . identified st239-iii and st241-iii mrsa isolates in several asian countries ( 14 ) .
we demonstrate that the predominant mrsa clone at ntuh in early 1990s had the type iv sccmec element . however , the predominant mrsa clones at ntuh from 1994 to 2003 had the type iii sccmec element .
these findings differ from those of wisplinghoff et al . , who reported that that the sccmec element in predominant mrsa clones at their institute changed from type iii in 1984 to 1988 to type i in 1989 to 1998 ( 6 ) .
mrsa isolates of pulsotypes b and c are more resistant than isolates of pulsotype a to certain antimicrobial drugs , especially fluoroquinolones and trimethoprim - sulfamethoxazole ; mrsa isolates with pulsotype c are more resistant to clindamycin but less resistant to rifampin than those with pulsotype b ( table 2 ) . from 1993 through 2000 , annual use of fluoroquinolones increased 3 at ntuh ; however , use of trimethoprim - sulfamethoxazole , clindamycin , and rifampin did not change ( 15 ) .
therefore , the shift of predominant mrsa clones , which also led to the shift in types of sccmec elements at ntuh , might be caused by selective pressure from antimicrobial drugs , especially fluoroquinolones .
the mrsa clone ( pulsotype a ) that predominated in 1992 and 1993 at ntuh has the type iv sccmec element .
although the first study of mrsa with the type iv sccmec element reported that this element was found in community - acquired mrsa ( ca - mrsa ) ( 5 ) , some studies have reported mrsa isolates with this element in a hospital environment ( 12 ) . however , to our knowledge , these reports did not demonstrate that mrsa isolates with the type iv sccmec element became predominant among all mrsa isolates in an institution , especially before the mid-1990s .
furthermore , 4 st59 mrsa isolates obtained in 1994 and 1996 and 3 st30 mrsa isolates obtained in 1992 and 1993 have the type iv sccmec element and pvl gene .
recently , st59 mrsa isolates were found to cause ca - mrsa infection in taiwan ( 13 ) . among these st59
ca - mrsa isolates , some had the type iv sccmec element , and others had the type v sccmec element ( 13 ) . although the type iv sccmec element could be transferred to ca - mrsa clones with other genetic backgrounds , our finding supports the possibility that st59 mrsa isolates with the sccmec element type iv in taiwan may originate from hospital strains but transfer into ca - mrsa strains .
recently reported the results of sccmec typing of 615 mrsa isolates obtained in 1998 and 1999 from 11 asian countries ( 14 ) .
the st239-iii , st241-iii , st254-ii , and st5-ii mrsa isolates were prevalent in many asian countries .
however , the st254-iv , st30-iv , and st59-iv mrsa isolates from our study were not found in other asian countries .
in addition , st254-iv mrsa isolates have been found in germany and the united kingdom ( 12 ) . whether st254-iv mrsa isolates in our study
were transmitted from those in germany or the united kingdom by international travel requires further study .
the first mrsa isolate with the type iv sccmec element in our hospital appeared as early as 1992 . the sccmec element carried by predominant mrsa clones changed from type iv to type iii sccmec element during the period 19922003 at ntuh .
because the major mrsa clones isolated in 19942003 are more resistant to antimicrobial drugs , especially fluoroquinolones and trimethoprim - sulfamethoxazole , than those obtained in 1992 and 1993 , this shift may be caused by selective pressure from indiscriminate use of antimicrobial drugs .
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to determine the predominant staphylococcal cassette chromosome ( scc ) mec element in methicillin - resistant staphylococcus aureus , we typed 190 isolates from a hospital in taiwan .
we found a shift from type iv to type iii sccmec element during 19922003 , perhaps caused by selective pressure from indiscriminate use of antimicrobial drugs .
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The Study
Conclusions
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