The clustering of metabolic and cardiovascular risk factors is known as metabolic syndrome (MetS). The risk of having MetS is strongly associated with increased adiposity and can be further modified by smoking behavior. Apolipoproteins (apo) associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) may be altered in MetS. This study aimed to examine the association between smoking and the following parameters: MetS and its components, levels of apolipoproteins and estimated lipoprotein particle size, separately for men and women, and in different body mass index (BMI) classes.2). MetS was defined according to the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP:ATPIII) criteria. Blood pressure, anthropometric and lipid measurements were rigorously standardized, and the large sample size enabled a powerful estimate of quantitative changes. The association between smoking and the individual MetS components, and apoA1 and apoB, was tested with linear regression. Logistic regression was used to examine the effect of smoking and daily tobacco smoked on risk of having MetS. All models were age adjusted and stratified by sex and BMI class.We included 24,389 men and 35,078 women aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012; 5,685 men and 6,989 women were current smokers. Participants were categorized into three different body mass index (BMI) classes . Current smokers had lower levels of HDL cholesterol and apoA1, higher levels of triglycerides and apoB, and higher waist circumference than non-smokers . Smoking had no consistent association with blood pressure or fasting blood glucose. In all BMI classes, we found a dose-dependent association of daily tobacco consumption with MetS prevalence as well as with lower levels of HDL cholesterol, higher triglyceride levels and lower ratios of HDL cholesterol/apoA1 and, only in those with BMI <30, LDL cholesterol/apoB .Prevalence of MetS increased with higher BMI levels. A total of 64% of obese men and 42% of obese women had MetS. Current smoking was associated with a higher risk of MetS in both sexes and all BMI classes (odds ratio 1.7 to 2.4 for men, 1.8 to 2.3 for women, all Smoking is associated with an increased prevalence of MetS, independent of sex and BMI class. This increased risk is mainly related to lower HDL cholesterol, and higher triglycerides and waist circumference. In addition, smoking was associated with unfavorable changes in apoA1 and apoB, and in lipoprotein particle size.http://www.biomedcentral.com/1741-7015/11/196.Please see related commentary:  Metabolic syndrome (MetS) is a combination of unfavorable health factors including abdominal obesity, dyslipidemia, hypertension and glucose intolerance ,2 and isSmoking has also been implicated as a risk factor for MetS. Earlier studies have suggested that overall tobacco use is associated with an increased risk of MetS ,11, mostAlterations in the size and composition of low-density lipoprotein (LDL) particles and high-density lipoprotein (HDL) particles have been associated with metabolic syndrome , and areThe aim of the present study was to examine the association between smoking and the individual components of MetS in normal weight, overweight and obese subjects, in a very large population-based cohort study . We alsoThe LifeLines Cohort Study is a multidisciplinary prospective population-based cohort study that examines the health and health-related behaviors of participants living in the northeast of The Netherlands . It emplFor this cross-sectional study we included subjects of Western European origin (according to self-reported information in the questionnaire), aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012. Individuals who had missing data on BMI (n = 21), or on the variables needed to define MetS , or whose questionnaires were incomplete with regard to smoking behavior  were excluded from analysis. A total of 59,467 individuals were available for the current analysis.The anthropometric measurements height, weight, waist and hip circumference, and blood pressure were conducted by trained technicians using a standardized protocol. Body weight was measured without shoes with 0.1 kg precision. Height, waist and hip circumference were measured to the nearest 0.5 cm. Waist circumference was measured in standing position with a tape measure all around the body, at the level midway between the lower rib margin and the iliac crest. Systolic and diastolic blood pressures were measured every minute for a period of 10 minutes using an automated Dinamap Monitor . The size of the cuff was chosen according to the arm circumference. The average of the last three readings was recorded for each blood pressure parameter.At a second visit, blood was collected in the fasting state, between 8.00 and 10.00 a.m. The blood samples were transported under temperature-controlled conditions  to the LifeLines central laboratory facility. All measurements were performed the same day. Total and HDL cholesterol were measured using an enzymatic colorimetric method, triglycerides using a colorimetric UV method, and LDL-C using an enzymatic method, all on a Roche Modular P chemistry analyzer . Apolipoprotein A1 (apoA1) and apolipoprotein B (apoB) were measured by nephelometry . Fasting blood glucose was measured using a hexokinase method.2). We classified the subjects into three BMI categories: normal weight (BMI <25.0), overweight (BMI 25.0 to 30) or obese (BMI ≥30). Individuals with a BMI <30 were considered to have MetS if they satisfied at least three of the five criteria named in the revised National Cholesterol Education Program’s Adult Treatment Panel III  divided by height squared m. We clasDiagnosis of earlier myocardial infarction or hypertension was self-reported, as was the use of medication. Diagnosis of diabetes mellitus was based either on self-report, or on the finding of a fasting blood glucose >7 mmol/l. Information about smoking was collected from the self-administered questionnaires. Respondents were asked whether they smoked; whether they had smoked during the last month and whether they had ever smoked for an entire year; whether they had stopped smoking; which type of tobacco they currently smoked ; and the amount smoked . The subjects were classified according to smoking status as non-smoker, former smoker or current smoker. Subjects were defined as a non-smoker if they had not smoked during the last month and had also never smoked for longer than a year. Former smokers were those who had not smoked during the last month but reported to have smoked for longer than a year and had stopped smoking. Current smokers were subjects who reported to have smoked during the last month or those who reported to have smoked for longer than a year and had not stopped smoking. Estimation of current smokers’ total tobacco use and their classification into light, moderate and heavy smokers were based on the following quantities: one cigarette = 1 g tobacco, one cigarillo = 3 g tobacco and one cigar = 5 g tobacco. Light smoking was defined as 10 g/day or less, moderate as 11 to 20 g/day and heavy as more than 20 g/day.P value of ≤0.001 (0.05/48) was regarded as significant, given 48 independent tests . Since the analyses were performed separately for men and women, and also for each BMI class, we used six models. The eight traits were as follows: (1) systolic and diastolic blood pressure or hypertension; (2) fasting glucose level; (3) HDL-C level; (4) triglyceride level; (5) waist circumference; (6) apoA1 and apoB; (7) HDL-C/apoA1 and LDL-C/apoB ratios; and (8) MetS.All analyses were conducted using IBM SPSS Statistics version 20 . Data are presented as means ± SD, or geometric mean and interquartile range when they were not normally distributed. For comparisons between groups, analysis of variance was used where appropriate. Linear regression was used to examine the associations between smoking and the five components of MetS as well as between smoking and the apolipoprotein levels and the HDL-C/apoA1 and LDL-C/apoB ratios. Logistic regression was used to examine the effect of smoking and daily tobacco use on the risk of having MetS. This approach generated odds ratios that predicted the odds of having MetS for the different smoking statuses and different amounts of tobacco usage. Since distributions for triglyceride and fasting blood glucose were right skewed, before analysis we log-transformed  values to approximate normal distribution. All analyses were stratified for sex and BMI class, and were additionally adjusted for age. We applied a Bonferroni correction to account for the number of independent tests. A The baseline characteristics of the participants are summarized in Table For both sexes, former smokers were older and had higher levels of BMI, blood pressure, LDL-C, total cholesterol, waist circumference and glucose and were more frequently diagnosed with type 2 diabetes than non-smokers and current smokers Table . CurrentThe percentage of subjects with MetS according to smoking status and daily tobacco consumption are shown in Figure For all BMI classes and smoking statuses, the percentage of subjects with high blood pressure, elevated blood glucose and elevated triglyceride levels was higher in men than in women, whereas women were more likely than men to have a higher waist circumference Figure . In bothP <0.001). In addition, the HDL-C/apoA1 ratio was significantly lower for higher amount of tobacco smoked in all BMI classes, and the LDL-C/apoB ratio for the lowest BMI classes (P <0.001). Former smokers had similar HDL-C levels to those of non-smokers. In all BMI classes, there was a consistent positive association between tobacco use and triglyceride levels . In all tobacco use groups, waist circumference was higher than that of non-smokers, independent of sex and BMI class, except for obese male light smokers. In obese female smokers we observed the largest rise in waist circumference: from 2.2 cm in moderate smokers to 6.4 cm in heavy smokers (both P <0.001). Moderate and heavy smoking was not associated with any strong changes in fasting blood glucose level.Table P <0.001).The age-corrected odds ratios for having MetS, for men and women separately, in the three BMI classes, are depicted in Figure In the present study, performed in a large population-based cohort of almost 60,000 individuals, we investigated the relationship between smoking and the individual components of metabolic syndrome, and the association between smoking and levels of apolipoproteins and estimated lipoprotein particle size. Such a comprehensive and large-scale analysis has not been performed to date. We demonstrated that in both men and women smoking is associated with a greater prevalence of MetS, irrespective of their BMI. The largest differences between current smokers and non-smokers were observed in the levels of HDL-C and triglycerides, and, to a lesser extent, in waist circumference. While there were no consistent associations between smoking status and either blood pressure or fasting blood glucose levels, there was a dose-dependent relationship between the amount of tobacco smoked and decreased HDL-C levels and increased triglyceride levels. We also found a clear dose-dependent association between the amount of tobacco smoked and reduced ratios of HDL-C/apoA1 and LDL-C/apoB. To our knowledge, we are the first to explore these associations between smoking and levels of apolipoproteins and lipoprotein particle size in such a large cohort of individuals, with rigorously standardized physical and laboratory measurements, while taking into account both sex and BMI levels.Our analysis revealed that in both men and women the prevalence of MetS was higher in current smokers in each BMI group, than in the non-smokers within that BMI group. Several earlier small-scale studies have reported smoking to be associated with higher prevalence of MetS -27. The et al., comprising 1,164 men, reported a similar dose–response relationship with the largest effect on HDL-C and triglycerides seen in those who smoked more than 40 cigarettes per day [et al. also reported a dose–response association between the number of cigarettes per day and prevalence of MetS in a cohort of 5,033 individuals, although they did not examine the influence of the amount of tobacco smoked on the individual MetS components [With our approach we have been able to calculate precisely the effects of smoking on the lipid parameters. Our data unequivocally show that despite the fact that obese men and women have a lower mean HDL-C than non-obese, the effects of heavy smoking are similar in all three BMI groups, with a consistent 0.10 to 0.14 mmol/l lower HDL-C for smoking men, and 0.15 to 0.21 mmol/l lower HDL-C in smoking women, in all three BMI groups  [Although some studies have indicated that smoking is related to reduced insulin sensitivity and the development of insulin resistance ,40 and tin women . Such di mmol/l) .et al. found higher blood pressure in male smokers older than 45 years compared to never smokers [While it is well established that acute smoking may cause a rise in blood pressure ,45, in t smokers . We foun smokers  or for a smokers , althoug smokers .One of the new findings of our study is the association between smoking and alterations in levels of apolipoproteins and in the size of lipoprotein particles. Until now, only a limited number of studies have investigated the relationship between smoking and the levels of apoA1 and apoB, usually involving a small number of participants such as, for example, young adults ,50, middOur study has several major strengths. Considering the number of participants recruited from the general population , this is the largest study reporting these results. Our large dataset also enabled to carefully calculate effect sizes, and to perform sufficiently powered subgroup analyses, in subjects of both sexes and in those with normal body weight, overweight, and obesity, which to our knowledge has never been performed before. All participants to the LifeLines Cohort Study have been well characterized, with rigorously standardized blood pressure and anthropometric measurements. In addition, all laboratory measurements of lipids and apolipoproteins have been carried out over a period of 5 years in fresh serum samples, in the same certified laboratory, with the same equipment, and the same rigorous quality assessment and control. This unprecedented sample size also provided us with sufficient statistical power to investigate contradictory associations reported previously.There are also some limitations to our study. Firstly, since smoking status was based on self-administered questionnaires, we cannot exclude the possibility that misreporting led to some individuals being misclassified with regard to their current smoking status. Considering the large number of participants, we believe that misclassification has only very limited influence on the results obtained, and earlier studies also reported low misclassification rate of smoking status . We shouIn this very large study in individuals of western European descent, smoking was associated with an increased risk of MetS. This increased risk was observed in all BMI classes. The elevated risk of having MetS was mainly related to lower HDL cholesterol, higher triglycerides and larger waist circumference. We also found that smoking was associated with unfavorable changes in the levels of apoA1 and apoB and in estimated HDL and LDL particle size, thereby providing a new pathophysiological mechanism linking smoking to increased risk of cardiovascular disease.Apo: Apolipoprotein; BMI: Body mass index; CVD: Cardiovascular disease; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; MetS: Metabolic syndrome; TG: Triglycerides.The authors declare that they have no competing interests.SNS, JVvVO and BHRW carried out the statistical analyses and drafted the manuscript. ACMK coordinated all laboratory measurements and immunoassays. MMvdK, JMV, EJF and BHRW participated in the design of the cohort study and data collection, while JMV, HMB, SNS and MMvdK carried out the data verification and validation. RPFD and APvB participated in the data interpretation. All authors participated in drafting the manuscript, and read and approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/11/195/prepub


Each year, thousands of cases of uncomplicated malaria are imported into Europe by travellers. Atovaquone-proguanil (AP) has been one of the first-line regimens used in France for uncomplicated malaria for almost ten years. While AP’s efficacy and tolerance were evaluated in several trials, its use in “real life” conditions has never been described. This study aimed to describe outcome and tolerance after AP treatment in a large cohort of travellers returning from endemic areas.Between September 2002 and January 2007, uncomplicated malaria treated in nine French travel clinics with AP were followed for 30 days after AP initiation. Clinical and biological data were collected at admission and during the follow-up.A total of 553 patients were included. Eighty-eight percent of them were born in Africa, and 61.8% were infected in West Africa, whereas 0.5% were infected in Asia. Migrants visiting friends and relatives (VFR) constituted 77.9% of the patients, the remainder (32.1%) were backpackers. Three-hundred and sixty-four patients (66%) fulfilled follow-up at day 7 and 265 (48%) completed the study at day 30. Three patients had treatment failure. One-hundred and seventy-seven adverse drug reactions (ADR) were reported during the follow-up; 115 (77%) of them were digestive ADR. Backpackers were more likely to experiment digestive ADR compared to VFR . Twenty patients had to be switched to another regimen due to ADR.This study seems to be the largest in terms of number of imported uncomplicated malaria cases treated by AP. The high rate of reported digestive ADR is striking and should be taken into account in the follow-up of patients since it could affect their adherence to the treatment. Beside AP, artemisinin combination therapy (ACT) is now recommended as first-line regimen. A comparison of AP and ACT, in terms of efficacy and tolerance, would be useful. In 2010, the World Health Organization (WHO) estimated that 216 million cases of malaria occurred and were responsible of 650,000 deaths . In EuroAP has been licensed in France since 1997 and marketed since late 2001 and it remains the principal treatment of acute malaria. Since the National Experts Committee recommended in 2007 that AP, together with artemether-lumefantrine, be used as first-line regimen, ‘old drugs’ such as quinine or mefloquine were downgraded to second-line treatment . AtovaquPlasmodium falciparum malaria cases. It provided interesting data on the use of AP with a relatively large series (n = 253), but heterogeneity of practices, due to ‘centre effects’ between participating European centres may limit the interpretation of the study ) (Table Assessment of tolerance by patients for the 437 who answered to the questionnaire was classified as good for 304 (69.6%), satisfactory for 116 (23.8%), bad for 41 (8.4%) and very bad for 27 (5.5%). In 20 cases, a switch to another drug was reported mainly because of vomiting , confusion , headache , cutaneous eruption , and suspected resistance because of a positive smear at day 3 .P. falciparum malaria seems to be the largest series assessing the use of AP in the field of imported malaria. Patient profile  are similar to those observed in the majority of studies on imported malaria [This ‘real life condition’ prospective, observational study of 553 patients treated by AP for uncomplicated  malaria -24,26-28Not surprisingly, the rate of chemoprophylaxis and exposure prophylaxis was low. Clinical and biological presentation had no specificity but it is of interest to note that nearly one third of patients had no fever at admission, which might be misleading for non-experienced practitioners. Compared to some other studies describing non-comparative cohorts of malaria patients, follow-up, even too low, might be considered satisfactory given such a ‘real life’ design for this cohort, since outcome data are available for the majority at day 3 and since nearly half of patients were seen one month after treatment -21,26-29With regard to efficacy, if a majority of patients (95%) were fever-free at day 3, nearly a third of them were still parasitaemic confirming that AP is slow-acting ,20,30,31Even though rare under AP and comparable to other malaria treatment (1% in this study’s series), the risk of relapse has to be considered by physicians given the potential severe outcome at a time when the diagnosis of malaria may be omitted (long delay after travel in endemic area) ,21,23. GPerceived efficacy of AP was satisfying. This evaluation is not as valid as parasitological efficacy but it has not been studied in Africa before, both for curative treatment and for prophylaxis in travellers. It is considered as a significant predictor for compliance to treatment and preventative behaviours ,37.With regard to tolerance of AP, data of this study highlighted a high rate of digestive ADR, mainly at day 3, especially nausea and vomiting. Digestive ADR represented 77% of ADR reported at day 3 and 72% of the totality of ADR reported during follow-up. It seems that digestive ADR were more frequent in backpackers compared to migrants, with no particular explanation, and no comparable data were found in the literature. In 18% of cases (n = 15), vomiting was severe enough to justify a change to second-line treatment. This high occurrence of digestive ADR could be partially explained by the population enrolled in the study since black people are known to have a lower clearance rate of atovaquone compared to white people . Yet theSurprisingly, these digestive side effects are one of the most important from studies. A review of ten trials comparing Atovaquone-Proguanil (AP) with other anti-malarial drugs for uncomplicated malaria report a median rate of nausea and/or vomiting (inter quartile range) of 15.6% (5.2 – 25.0) for Atovaquone-Proguanil whereas other studies did not report this ADR ,20,30,31Nevertheless, data from this series on digestive ADR are comparable to the results of a recent cohort study showing a higher switch rate to second-line treatment in patients treated with AP, compared to others .The design of this study does not enable to guide physicians on their choice of anti-malarial drug. However, the significant risk of vomiting associated with AP needs to be taken into account, especially in patients already complaining of nausea and vomiting at the time of diagnosis. The need for fat intake with AP, as is recommended to improve absorption, may be an additional risk factor for vomiting . PrescriAs observed in the literature, this study did not reveal any liver toxicity. Moderate variations in transaminase level observed at day 3 and 7 were not significant and were possibly due to malaria parasite itself ,14,30,41A drop in haemoglobin level, as observed here, was commonly reported after initiation of treatment of acute malaria due to malaria haemolysis . The absIn 2007, French experts’ consensus recommended both AP and artemether-lumefantrine as first-line treatment for acute uncomplicated malaria . As a coWith the introduction of ACT in Europe  for uncomplicated acute malaria onset, the use of AP will probably decrease in favour of ACT, due to its prompt efficacy and good tolerance.This observational series of 553 cases, the largest to date in number of patients, describes a large experience in using AP for imported uncomplicated malaria in real life conditions. Despite a non-comparative design, it appears that its efficacy is good and comparable to other similar drugs. The study confirms that AP is a valuable treatment option, while ADR, such as vomiting and its limited absorption in some cases, may be a limitation for its use.The authors have declared that they have no competing interests.HC, PR and OB participated in the design of the study and performed the statistical analysis. PR and OB conceived of the study, and participated in its coordination. HC, JC, SM and OB contributed to the draft manuscript. OF, PB, PC, HG, PHC, NG and MB participated in the recruitment of included patients. All authors read and approved the final manuscript.


Wegener's granulomatosis (WG) is a systemic disorder characterized by necrotizing vasculitis involving the respiratory tract, and in most cases, the kidneys. The most common manifestation of WG in the kidneys is segmental necrotizing glomerulonephritis. The presence of a renal mass as a manifestation of WG is rare. We report a patient with WG in whom a CT scan revealed an infiltrating mass in the lower portion of the left kidney. After surgical exploration, we performed an open radical nephrectomy. Histopathology showed clear cell type renal cell carcinoma (RCC). RCC associated with WG has been reported in only a few cases, and in most of them, the diseases started simultaneously, suggesting common pathogenetic pathways. Long-term immunosuppressive treatment is a known risk factor in the development of malignancies, so occurrence of RCC in WG has been proposed as a side effect of cyclophosphamide treatment. Furthermore, it is important to make a differential diagnosis between RCC and pseudotumors in WG as they cannot be distinguished solely on basis of imaging findings. Due to the higher risk of urologic malignancies, more frequent checkups and screening of WG patients should be considered. Wegener's granulomatosis (WG) is a disease of unknown etiology characterized by systemic necrotizing granulomatous vasculitis, which primarily involves the upper respiratory tract and the lungs. Although renal involvement is present in only 20% of patients at time of diagnosis, it eventually occurs in approximately 80% of all patients suffering from WG. The most common manifestation of WG in the kidney is segmental necrotizing glomerulonephritis with proteinuria that often leads to rapidly progressive renal failure . The preCyclophosphamide is a mainstay therapy for WG . There iWe report a case in which renal cancer developed thirteen years after WG was diagnosed.Our patient is a 55-year-old man. His symptoms started in November 1996 with a high fever and cough. About ten days later, he developed joint, back, and chest pains, epistaxis, hemoptysis, dyspnea, and a vesicular hemorrhagic rash. He lost 15 kg in one month upon which, he was hospitalized.9/L, and platelet count of 200 × 109/L. A 24-hour urinary protein excretion was measured at 0.9 g/L with microscopic hematuria, and he had a positive serum test for antineutrophil cytoplasmic antibodies (ANCA). A chest x-ray showed multiple nodular and patchy shadows throughout both lungs and a prominent left hilum. He was diagnosed with WG and started with pulse doses of glucocorticosteroids (IV) after which cyclophosphamide (IV) was instituted, with tapering of corticosteroid dose. The symptoms soon resolved and complete remission was achieved.The patient presented with a high fever, blood pressure at 135/110 mmHg, hemoglobin at 14 g/dl, an erythrocyte sedimentation rate of 80 mm/h, white blood cell count of 7,5 × 10per os only. The patient experienced two periods of relapse, and after reinstituting therapy , went into remission. The total cumulative dose of cyclophosphamide was about 150 grams.In the second year of his ongoing treatment, because of the development of diabetes mellitus, steroid treatment was stopped, and the therapy was continued with cyclophosphamide Thirteen years later, the patient was admitted to our hospital due to pain in the left lumbar region, which began two months earlier. He is a nonsmoker; his body mass index was 26; with no exposure to occupational carcinogens, and a negative familial history for renal malignancies. A CT scan revealed an infiltrating mass, 53 mm at its widest diameter, in the lower portion of the left kidney Figure . LaboratIn 1999, Tatsis et al.  reportedImmunosuppressive therapy, primarily cyclophosphamide, and steroids have markedly improved survival and remission rates in WG patients . HoweverIn addition, in patients with WG and a renal mass, there is a differential diagnostic problem. Frigui et al.  reportedIn conclusion, we suggest that in WG patients on immunosuppressive therapy in whom the disease is in a documented remission, renal masses should be presumed to be malignant, generally RCC, but carcinoma of the renal pelvis should also be kept in mind when dealing with patients with a cyclophosphamide therapy. Definitive diagnosis can only be made by renal biopsy.Due to the higher risk of urologic malignancies, more frequent checkups and screening of WG patients should also be considered.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.WG: Wegener's granulomatosis; RCC: Renal Cell Carcinoma; ANCA: Antineutrophil Cytoplasmic Antibodies.The authors declare that they have no competing interests.UB prepared the manuscript and the literature search; CT, DD, AJ and UB did the surgery; CT and DD reviewed and edited the manuscript; VA collected the data; VCM and MC did the pathologic analysis.All authors read and approved the final manuscript.


Only one case of santorinicele without pancreas divisum pathophysiology (SWOPP) was previously reported. The purpose of the study was to determine the gross prevalence of SWOPP and santorinicele with pancreas divisum (SWPD) in community and patient populations, and investigate their clinical and radiographic features.This cross-sectional study was performed at a tertiary referral centre. The Patient group comprised 2035 consecutive patients enrolled in the study who underwent magnetic resonance cholangiopancreatography (MRCP) studies. The Community group comprised 2905 consecutive subjects who participated in our whole-body medical check-up program that routinely includes MRCP studies. SWOPP was diagnosed when a saccular dilatation of the terminal portion of the dorsal pancreatic duct was observed unaccompanied by pancreas divisum or dominant dorsal duct. The prevalence of SWOPP and SWPD, and the clinical and radiological features were assessed in each group.Five cases of SWOPP were found in the Patient group  ; there were no cases of SWOPP in the Community group  (P = 0.01). Previous history of pancreatitis (4/5) and chronic pancreatitis (3/5) was more common in patients with SWOPP than in other subjects in the Patient or Community groups (both P < 0.05). Two cases of SWOPP were accompanied by reverse-Z type meandering main pancreatic duct. Six cases of SWPD were found. These cases were asymptomatic in 4/6, had a larger santorinicele (6.9 mm) than SWOPP patients , and were not associated with pancreatitis (0/6).The second to sixth reported cases of SWOPP were presented. SWOPP is a relatively rare condition found mostly in patients suffering pancreatitis, especially chronic pancreatitis, and may be an acquired condition. Santorinicele is not always accompanied by pancreas divisum. Santorinicele is a focal cystic dilatation of the terminal portion of the dorsal pancreatic duct, just proximal to the minor papilla, and was first described in 1994 by Eisen et al. -7, and aA series of studies classified the morphology of dorsal pancreatic duct at its terminal portion into stick, branch, cudgel, spindle, and saccular types -10. SaccThree cases of santorinicele not accompanied by pancreas divisum were subsequently reported as a new entity: "santorinicele without pancreas divisum" -13; howeTo the best of our knowledge, no previous studies have closely investigated the prevalence of santorinicele without pancreas divisum pathophysiology (SWOPP), or evaluated its clinical and radiographic features. The purpose of the present study was to elucidate the clinical and radiographic features of SWOPP, including its gross prevalence in a community population and in a patient population from our hospital, based on the 1.5/3 T high-field magnetic resonance (MR) technique.Approval for the present study was obtained from the Research Ethics Committee of the University of Tokyo Hospital, Japan.The subjects were classified into two groups: a Patient group and a Community group. The Patient group comprised consecutive patients who underwent abdominal MR scans including magnetic resonance cholangiopancreatography (MRCP) between December 1 2004 and May 31 2010 in our academic tertiary care hospital. The Community group comprised consecutive subjects in a community population who responded to leaflets and Internet advertising, and participated in a whole-body medical check-up program hosted by our hospital between October 12 2006 and May 31 2010. The patients were enrolled cross-sectionally. The program included abdominal MR scans and MRCP; evaluation of smoking habits , drinking habits , and medical history; an interview regarding subjective symptoms; and a physical examination by a physician. Written informed consent was acquired prior to enrolment into the study from all subjects in both groups. It included not only agreement to enrolment into the study but also agreement to the publication of some identifying information such as age, gender, disease, family history, clinical and radiographic findings, but excluding the subject’s name and photographs of their face. In the event that a subject in the Community group was sent to our hospital for a detailed examination and found to belong to both groups, he/she was included only in the Community group.In assessing the history of subjects in the Patient group, subjects were recorded as having acute or chronic pancreatitis as of the diagnosis in January 2012 according to the latest published criteria ,15, whilIn the Patient group, MR studies were performed on 3-tesla scanners  or on 1.5-tesla scanners . Acquired sequences were heavily T2-weighted MRCP images using breath-hold two-dimensional half-Fourier fast spin echo  and respiratory-gated three-dimensional half-Fourier fast spin echo . Coronal and oblique-coronal projection images were reconstructed for MRCP images. T2-weighted, T1-weighted, and diffusion weighted images were also acquired.In the Community group, MR studies were performed on a 3-tesla scanner . Acquired sequences were heavily T2-weighted MRCP images in the coronal plane using breath-hold two-dimensional half-Fourier fast spin echo  with four coronal and oblique-coronal projection images. T2-weighted, T1-weighted, and diffusion weighted images were also acquired.All MR images were interpreted on picture archiving and communication system workstations  by two board-certified radiologists with experience in distinguishing pancreatic ductal anatomy, who were not informed of the clinical information. Discrepancies among opinions were settled by discussion.Santorinicele was defined as a focal saccular dilatation of the terminal portion of the dorsal pancreatic duct, in which the calibre changes steeply, as defined previously Figure  8-12]. -12. 8-12The radiologists were first asked to review all the radiographic records of participants for any dorsal pancreatic ductal lesions or pancreatic cystic lesions. All images of the extracted cases were then reviewed and investigated for the presence of santorinicele. When santorinicele was diagnosed, its size was measured along the axis of the dorsal pancreatic duct  and in an axis vertical to the horizontal diameter . Values obtained from the two radiologists were averaged.t-test. The level of statistical significance was set at 0.05. Family-wise error was corrected by Bonferroni’s correction for each section. All statistical computing was performed using the free software R Ver. 2.9 .Fisher’s exact test was used to compare the prevalence of SWOPP or SWPD on MRCP studies between the Patient and Community groups. Diagnosis of SWOPP or SWPD, and the Patient group were compared in terms of gender, pancreatitis, and chronic pancreatitis, also using Fisher's exact test. Diagnosis of SWOPP or SWPD, the Patient group, and the Community group were compared in terms of age, alcohol consumption, and Brinkman index, using Student's A total of 4,940 subjects were enrolled; of these, 149 subjects found to belong to both the Patient and Community groups were assigned to the Community group.Enrolled in the Patient group were 2,035 patients treated at our hospital: 964 females  and 1,071 males . A history of non-tumour induced pancreatitis and chronic pancreatitis was found in 11.5% (235/2035) and 8.50% (173/2035), respectively, of these patients.Enrolled in the Community group were 2,905 subjects who participated in the health check program hosted by our hospital: 1,151 females  and 1,754 males . Mean alcohol consumption was 29.0 g/day  and mean Brinkman index was 314 . A history of pancreatitis and chronic pancreatitis was found in 1.10% (32/2905) and 0.41% (12/2905) respectively, of these subjects.From the imaging studies of all participants, we extracted 1,193 studies that had any type of dorsal pancreatic ductal lesion or pancreatic cystic lesion. Image review of these studies revealed only five cases of SWOPP   ]. Subjects in the Patient group were older than those in the Community group . No other significant difference was detected among patients with SWOPP, the Patient group, and the Community group in terms of gender, alcohol consumption, or Brinkman index.The incidence of SWOPP was 5/2035  in the Patient group and 0/2905  in the Community group. Fisher's exact test revealed that the prevalence of SWOPP was significantly higher in the Patient group than in the Community group (P = 0.01). The incidence of pancreatitis and chronic pancreatitis was significantly higher in patients with SWOPP than in the Patient group  and in the Community group . Patients with SWOPP were older than those in the Patient group [no statistical significance after family-wise error correction . No other significant difference was detected among patients with SWPD, the Patient group, and the Community group in terms of gender, alcohol consumption, or Brinkman index.The incidence of SWPD was 5/2035  in the Patient group and 1/2905  in the Community group. No significant difference was detected regarding the prevalence of SWPD between the Patient and Community groups . No significant difference was detected regarding age between subjects with SWPD and the Patient group . Santorinicele size was significantly larger in subjects with SWPD than in those with SWOPP (P = 0.02).In the present cross-sectional study, we first determined the gross prevalence of SWOPP and SWPD in both patient and community populations, based on 1.5/3 T high-field MR studies. The results showed SWOPP to be a relatively rare condition closely associated with a history of pancreatitis. Our series appears to include the second to sixth reported cases of SWOPP.With one exception, all previously reported cases of santorinicele have been in patients with pancreas divisum, either complete or incomplete -7, or inOf the various morphological patterns reported of the dorsal pancreatic duct -10, the The incidence of SWOPP in the present study (0.25%) was the same as that of SWPD but it was low compared with the results of a previous ERCP-based study regarding saccular-type dorsal pancreatic duct (2.3%) . The reaIt is unclear whether santorinicele itself, with or without pancreas divisum, is congenital in origin or is an acquired lesion secondary to a stenosis of the dorsal duct orifice. Several studies speculated that santorinicele is a congenital anomaly ,11,12 anIn the present case series, SWOPP was not accompanied by a major morphological abnormality of the pancreatic ducts. Although there were many more cases of pancreatitis in the MRCP-based Patient group than in the Community group, a significantly high proportion of patients with SWOPP were associated with pancreatitis and chronic pancreatitis, and these patients were older than the other subjects . Although mean age was older in the Patient group than in the Community group, this finding does not appear to be in conflict with the hypothesis that SWOPP is an acquired condition that is closely related to a history of pancreatitis, especially chronic pancreatitis. Accordingly, the mechanism by which a santorinicele develops is speculated to be impeded pancreatic flow in a less patent dorsal pancreatic duct, causing the onset of pancreatitis -10; howeIn the present study, santorinicele size was larger in SWPD than in SWOPP, which indicates that ductal pressure at the terminal portion of the dorsal pancreatic duct may be higher in SWPD than in SWOPP. However, the present cases of SWPD were dominantly asymptomatic and not associated with pancreatitis. SWPD is speculated to predispose to pancreatitis , but theThere is a report of a single case of Wirsungocele , a focalMethodologically, we used MRCP as the gold standard for depicting santorinicele because this modality is reported as highly sensitive and specific (approximately 90%–100%) in investigating pancreatic ductal anatomy ,23,24. WIn clinical practice, santorinicele is more easily diagnosed with MRCP than with ERCP. The present results show that santorinicele may not be associated with pancreas divisum, and appears to be caused by impeded pancreatic flow in the dorsal pancreatic duct. Sphincterotomy or balloon dilatation may be effective in patients with intractable pancreatitis with SWOPP, as well as in those with SWPD.We presented the second to sixth reported cases of SWOPP and the first assessment of the gross prevalence of this relatively rare condition in both patient and community populations, proving that Santorinicele is not always accompanied by pancreas divisum. We also established that SWOPP is found mostly in patients suffering pancreatitis, especially chronic pancreatitis, and we consider that it is an acquired pathology.The authors declare that they have no competing interests.WG drafted the manuscript and conceived the study concept and design. HA and KH performed analysis and data interpretation. MA, MT, SK, and NO participated in critical revision of the manuscript for important intellectual content. NH, EM, TY, and KU performed acquisition of data. KK and KO gave final approval of the version to be published. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/13/62/prepub


Accurate measurement of breast tumour size determines staging and prognosis. Discrepancies amongst clinical examination (CE), ultrasonography (USG), mammography, pathological examination (PE) and magnetic resonance imaging have been reported. However, few studies have evaluated changes in breast tumour size from the operating table to the laboratory.A prospective study was designed to assess the intra-operative (IO) tumour size in 29 patients of breast cancer presenting to a tertiary care centre in Delhi and to compare it with CE, USG and PE.R2=0.877, maximum for PE). Two-way analysis of variance revealed mean difference in size to be statistically significant (p=0.000) only between CE and IO.Twenty-nine patients (mean age: 47 years), presenting with invasive duct carcinoma , were included in the study. Comparison with mean IO (4.2 cm) revealed that both USG and PE underestimated tumour size by a mean of 0.35 cm (8.4%) and 0.45 cm (10.7%), respectively, in most patients. CE tended to overestimate size by 0.82 cm (19.8%). All three modalities showed statistically significant correlation with IO (maximum Pearson’s correlation coefficient for PE=0.937, p<0.001; Formalin processing causes changes in tumour dimensions in the breast, causing reduction in tumour size. It may also have a bearing on the assessment of surgical margins in breast conservation surgery. Immediate post-operative measurement of the specimen is ideal. Protocols for specimen fixation should be standardized. Tumour size is an independent prognostic factor in breast carcinoma and is a good predictor of lymph node metastases. Change in tumour size, as a response to chemotherapy, is also an independent predictor of disease-free survival ,2. The mIt is known that there is considerable discrepancy in size after formalin processing in many cancers. Uterine, arterial, colorectal, lung and prostate have all been shown to undergo shrinkage in one or more dimensions, and even volume –7. In brThe number of studies which have attempted to quantify the extent of this size discrepancy is surprisingly low ,9,12,14 It is evident that studies addressing change in size should be organ-specific and account for tissue constitution. In this study, we intra-operatively (fresh state) measured the tumour size in patients with breast carcinoma and, considering it as the actual size, compared it to CE, USG and PE. We also attempted to predict the actual size from other measurements, using statistical formulae.A prospective study was carried out at the departments of surgery and pathology at the University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India from December 2006 to March 2008. Twenty-nine patients with a palpable breast lump diagnosed to be cancer, and planned for surgery, were enrolled for the study. Patients without a definite palpable breast lump, and those with inflammatory carcinoma, were excluded.A detailed history was obtained regarding patients’ complaints and history of known risk factors such as family history of breast or ovarian cancer, previous breast disease, radiation exposure, reproductive details and drug therapy.Physical examination, chest x-ray, and USG of the breast for tumour size were carried out on all patients. The latter was done by an experienced radiologist to minimize operator variation. For patients with locally advanced disease, imaging for metastases in the form of a bone scan and USG of the abdomen was also performed.The accuracy in measurement was given maximum importance, and all the patients were seen by the same team (surgeon and radiologist) to avoid inter-observer variation.Clinically, the breast lump diameter was measured in two dimensions with Vernier’s calipers, and tumour size was taken as the maximum diameter.A high-resolution linear array ultrasonic transducer with a frequency 7.5 MHz was used to assess the breasts mainly for tumour size, and for associated findings such as satellite nodules. Here, the measurements were taken in three dimensions, and the maximum diameter was recorded as tumour size.The assessment of the patient was completed as close to the proposed operation as feasible (2–3 days maximum), to avoid changes in the observations.After completing the proposed operation , the specimen was examined by the same surgeon who had performed the clinical examination. The specimen was sliced with the help of a scalpel, by cutting longitudinally from the posterior aspect into slices approximately 2 cm thick. Maximum tumour diameter in three dimensions was measured to the nearest millimeter, and labelled as tumour size. To avoid problems in reporting due to the slicing affecting the deep-resected margin, tissue from deep within the tumour specimen was excised and labelled separately for histopathological examination.The surgical specimen was fixed in formalin (for 14–20 hours) after intra-operative recording of tumour size, and sent for histological examination. The pathologist also recorded the size in three dimensions.Follow-up advice to patients was in accordance with the accepted protocol for breast carcinoma.The maximum diameters measured by the different methods were compared, and the difference between individual data and the mean difference was calculated. Using two-way analysis of variance, taking size as a dependent variable, and the measurement method and subject as independent factors, post-hoc pairwise comparison was done using Bonferroni adjustment for calculating significant value of the mean and the difference of means.R2 was derived from differences between the line of best fit and the line of equality.Pearson’s method was used to calculate correlation between maximum sizes measured by all four methods. Plotting a graph, and identifying the line of best fit by linear regression obtained correlation between intra-operative, clinical, ultrasonographic and pathological size. Significance value Using stepwise multiple regressions, taking the intra-operative measurement as dependent, and clinical, ultrasonographic and pathological measurements as independent predictors, an estimation of the intra-operative measurement was achieved using the other three methods.A total of 29 patients were included in the study. The patients had a mean age of 47 years (range of 31–70 years). Most patients were 31–50 years of age. All patients had a lump in one breast. Three patients complained of associated pain and two of bloody nipple discharge. Only one patient had a history of associated risk factors, that is mastectomy for contralateral breast cancer two decades previously. Seventeen (58.6%) patients had a tumour located in the upper outer quadrant of the breast, while two had a large tumour occupying all four quadrants.The stage-wise distribution  of patients is shown in (1)The mean diameter on clinical measurement was 4.98 cm and on intra-operative measurement was 4.16 cm. Hence, clinical examination tended to overestimate the tumour size by 19.76% (mean 0.82 cm). In 24 patients (82.75%), tumour size was overestimated by clinical examination, and in only five patients it was of the same value as intra-operative.(2)The mean maximum diameter (tumour size) by USG was 3.81 cm, while intra-operative measurement was 4.16 cm. The mean difference was 0.35 cm, and an underestimation by USG of 8.38%. Only in five patients did USG overestimate the size of the tumour.(3)Pathological measurement tended to underestimate the tumour size. In seven specimens (24.14%), pathological measurement was the same value as intra-operative, but in 22 (75.86%), it underestimated the size (range 0–2.5 cm). The mean pathological size was 3.71 cm, as compared to 4.16 cm intra-operatively .Using Pearson’s correlation co-efficient, pathological measurement was found to have maximum correlation with intra-operative measurement . Clinical measurement and USG also showed good correlation R2 was derived from differences between the line of best fit and the line of equality. This also showed that pathological measurement had maximum correlation with intra-operative size . It was seen that the mean difference in size was statistically significant (p=0.000) only for comparison between intra-operative and clinical measurement.Using stepwise multiple regression taking intra-operative measurement as dependent, and clinical, USG and pathological measurement as independent predictors, the following equations were derived:Hence, by using the clinical and pathological tumour size, we can predict the intra-operative size.The demographic profile of our patients is similar to other Indian data –17. MostAll the modalities used in our study have proven to be as accurate as suggested in the literature. Clinical examination was compared with pathological examination as early in 1983, and some ‘adjustment’ was attempted for skin and fat thickness, as it tends to result in overestimating the size . CE has et al have shown that loss of margins due to fixation can be substantial enough to influence re-excision decisions. They have thus recommended suspension of the specimen during transport, as well as stressing the need for more guidelines for specimen handling, to minimize these errors [et al also states that overnight fixation does not change the gross tumour size, as long as microscopic measurements are not considered for comparison [Despite the importance of tumour size in staging, management, choice of operation and prognosis, the exact state of the specimen to be measured has not been standardized. Formalin processing has been shown to alter tumour dimensions in many solid organ cancers, including the breast –7,12–14.e errors . From oumparison . There iFormalin fixation of tissue specimens occurs in two phases. During the first phase, the fixative penetrates the tissue by diffusion and accumulates to a sufficient concentration. In the second phase, formalin exhibits a gelling action and chemically binds to protein amino groups, eventually leading to extensive cross-links between proteins or between proteins and nucleic acids ,26. AlthIn two other similar studies carried out in breast carcinoma ,14, all Estimation of the accurate tumour size by deriving formulae from other modalities of tumour size estimation  has been attempted by a few workers previously . The equThe tumour-size measurement is affected by factors such as specimen handling, delay in tumour fixation, duration of formalin fixation. Keeping in mind the great importance of tumour size in the management of breast cancer, the protocols used to measure size should be standardized to minimize chances of error in measurements and to bring uniformity in data analysis. Current data suggests that immediate fixation and 6–8 hours of formalin immersion does not affect the tumour size measurement. Larger studies are required to validate this conclusion.


The aim of the present study was to identify the long-term major adverse cardiovascular events (MACE) in adult congenital heart disease (ConHD) patients in Taiwan.From the National Health Insurance Research Database (1997-2010), adult patients (≥18 years) with ConHD were identified and compared to non-ConHD control patients. The primary end point was the incidence of MACE. Cox proportional hazards models were used to compute hazard ratios as estimates for multivariate adjusted relative risks with or without adjusting for age and sex.A total of 3,267 adult patients with ConHD were identified between 2000 and 2003 with a median follow-up of 11 years till December 31, 2010. The five most common types of ConHD were atrial septal defects, ventricular septal defects, patent ductus arteriosus, tetralogy of Fallot, and pulmonary stenosis. Overall, the incidence of MACE was 4.0-fold higher in the ConHD group compared with the controls. After adjustment for age and gender, the patients with ConHD had an increased risk of heart failure, malignant dysrhythmia, acute coronary syndrome, and stroke. The adult ConHD patients had a decreased life-long risk of MACE if they received surgical correction, especially in the patients with atrial septal defects.After a median of 11 years of follow-up, the Taiwanese patients with ConHD were at an increased risk of life-long cardiovascular MACE, including heart failure, stroke, acute coronary syndrome, and malignant dysrhythmia. Surgical correction may help to decrease long-term MACE in ConHD patients, especially those with ASD. Congenital heart disease (ConHD) is the most common congenital disorder in newborns and can remain a complication throughout life . The preMost reports on adult patients with ConHD have been on Western ,10 rathehttp://nhird.nhri.org.tw/date_01.html) from 1997-2010 in Taiwan. Currently, the National Health Insurance program covers more than 99% of the population of Taiwan [This is a nationwide population-based retrospective cohort study using the claims database of the National Health Insurance Research Database (NHIRD) . During 2000-2003, 3,267 adult patients (aged ≥18 years) with ConHD (the exposed cohort) were identified from the HV database and followed up till December 31, 2010. The patients with a first MACE before ConHD was diagnosed, and the patients without age and gender information were excluded  database, (http://nhird.nhri.org.tw/date_01.html). All non-ConHD subjects were matched with the study cohort for age, sex, and residential area. Details were described in the right of the flow chart  without ConHD (non-ConHD), who were not in the Registry of Catastrophic Illness Patients and not diagnosed with a previous MACE at baseline. This control group was randomly selected from the Longitudinal Health Insurance Database (LHID), a subset of the NHIRD containing all original claims data of one million randomly sampled insured patients in 2000 .The primary outcome of this study was newly diagnosed MACE during the study period. Newly diagnosed cases of MACE were identified as those with 3 or more visits to outpatient care clinics within one year or those hospitalized with a diagnosis of MACE  [χ2 tests. The person-time for each participant was calculated from January 1, 2000 or the date of confirmed ConHD during 2000-2003 to the date of any type of MACE, death, insurance discontinuation, or December 31, 2010, whichever came first. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for incident MACE, adjusting for age and sex. The assumption of proportional hazards was checked by including the interaction between covariates and the logarithm of time in the model. If variables other than the primary variables of interest did not satisfy the proportional hazards assumption, we included the time-interaction terms for these variables in the model. The results of the analysis in the models with and without the time-interaction terms were essentially the same; therefore, we did not include the time-interaction terms in the models presented here. Age and sex adjusted survival curves were generated from the Cox proportional hazards models. A p value less than 0.05 was considered to be statistically significant. Statistical analyses were performed using SAS software .Group characteristics at baseline were compared using The characteristics of the study population are shown in Table p < 0.0001) compared with those without ConHD , VSD , PDA (n = 314), TOF (n = 232), and PS (n = 85) . The risk of developing MD was significantly higher in the subjects with ConHD than in those without ConHD . The adjusted HR for ACS was 2.9 times  higher for the subjects with ConHD than for those without ConHD. The risk of developing stroke was 2.2 times  higher for the subjects with ConHD than for those without ConHD.To evaluate the risks of various incident cases of MACE, we analyzed different MACE outcomes in separate models Table . The patp < 0.0001) compared with those without ConHD patients (Table p < 0.0001), ASD  and PDA  have higher MACE risk than those without ConHD and the significance persisted even after Bonferroni correction.In the ConHD cohort, those with cyanotic ConHD, especially TOF, were associated with a significantly increased risk of MACE  (Table p < 0.0001) (Table In the ConHD patients, the adjusted HR for incident MACE in those with a history of surgery versus those with no history of surgery was 0.5 (95% CI, 0.4-0.6; The results of this long-term population study showed that the adult ConHD patients had a much higher risk of MACE. The prevalence of ConHD in live-births was similar to those previously reported , and theIn the current study, heart failure, malignant dysrhythmia, stroke, and acute coronary syndrome were the most common types of MACE in the ConHD group Table . When adHowever, the high risk of acute coronary syndrome in the adult ConHD patients in the current study is different from the previous reports. Pillutla et al reported a high rate of myocardial infarction-related mortality in non-cyanotic adult congenital heart disease in the US after 2000, and concluded that this might be due to the natural process of aging . The curMalignant dysrhythmia was thought to be the most important and common MACE , howeverAmong different types of ConHD, the incidence of MACE was the highest in cyanotic ConHD patients, followed up by PDA, ASD and VSD as KM curve shown at Figure We further separated ConHD patients into short-term and long-term follow up to demonstrate that the incidence of MACE decreased with longer follow up time. Another interesting finding as table In summary, the current study is the first to confirm the increased long-term morbidity observed in adults with ConHD in a large scale Asian-based population, and the benefit of surgical correction in decreasing the risk of MACE in those patients. These findings emphasize the necessity of lifetime medical expertise as part of regular follow-up for adults with ConHD.Because this is a population-based study from database, there are some limitations. First, the environmental and risk factors such as aging, smoking, obesity, and metabolic syndrome were difficult to identify from the database and could not be adjusted in the analysis. Second, although the echocardiography data for application of HV are essential, the exact detailed laboratory or echocardiography information was inaccessible. Therefore, this study reported the results from clinically diagnosed ConHD patients without the severity of the disease. The may imply underestimation of the effects of severe ConHD on MACE. However, the cyanotic ConHD did show the highest MACE and mortality in this study as previously discussed. In addition, surgical conditions including perioperative risk, medical compliance and detailed surgical procedures were difficult to elucidate based on ICD-coded record system. A prospective study about the surgical benefit under different surgical conditions should be designed in the coming future.After a median of 11 years of follow-up, the Taiwanese patients with adult congenital heart disease were at an increased risk of life-long cardiovascular MACE, including heart failure, stroke, acute coronary syndrome, and malignant dysrhythmia. Surgical correction may help to decrease long-term MACE in ConHD patients, especially those with ASD.The authors declared that they have no competing interests.YSL designed the study and prepared all the data, acquisition of data, analysis and writing the draft. PHL prepared all the data, acquisition of data, analysis and writing the statistical part of the draft. LSW participated in the data collection, analysis and interpretation of data and revision. YMC participated in the discussion, analysis and interpretation of data and revision. CJC initiated the study and supervised the acquisition of data and statistical analysis, helped the final approval of the version to be published and wrapped up the manuscript. PHC Initiated the study and supervised the acquisition of data, helped the final approval of the version to be published and wrapped up the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/14/38/prepub


Background: Liver dysfunction during on-pump coronary artery bypass graft surgery (CABG) is a rare complication but is associated with significant morbidity and mortality. The ability to identify high-risk patients may be helpful in planning appropriate management strategies. We aimed to evaluate the factors influencing liver function tests during on-pump CABG.Methods: In 146 patients scheduled for on-pump CABG, the liver function test was done preoperatively and on the first postoperative day. Some preoperative and intraoperative risk factors were checked and then the postoperative liver function tests were compared with the preoperative ones. Probable relationships between these changes and the preoperative and intraoperative risk factors were studied.Results: A medical history of diabetes had a significant relationship with the changes in direct bilirubin. Preoperative central venous pressure had a significant relationship with the changes in aspartate aminotransferase and alanine aminotransferase. Use of intra-aortic balloon pump and duration of aortic cross-clamp were significantly related to the changes in the liver function tests except for alanine aminotransferase and alkaline phosphatase. Conclusion: It seems that the techniques for the reduction of cardiopulmonary bypass and aortic cross-clamp duration may be useful to protect liver function. We recommend that a larger population of patients be studied to confirm these findings. Dilutional anemia and hemodynamic changes can affect tissue oxygenation, and most studies state that a minimum hematocrit level of 22% is necessary for the on-pump technique.2In coronary artery bypass graft surgery (CABG), various changes take place in the different organs of the body because of the effect of bypass pumps and hemodilution.3 During cardiopulmonary bypass (CPB), the possibility of liver damage increases owing to the-non pulsatile perfusion, low-flow state, free radicals formation, and increased levels of catecholamines.4 Some studies have reported that CPB usually induces mild hepatocellular damage, whereas off-pump coronary bypass decreases the possibility of this damage.5 However, reports on CPB are conflicting because hypothermia decreases the oxygen demand of the splanchnic organs and, thus, hepatocellular oxygenation is preserved better during hypothermic CPB.6 Comparison between pulsatile and non-pulsatile flows during CPB shows no significant difference between the two flows during CPB.7 Moreover, comparison between CABG with or without CPB demonstrates that the liver metabolic function is not changed by the type of coronary bypass surgery but that hepatic ischemia is detected after cardiac surgery with CPB, which is usually marked with an increase in alanine aminotransferase (ALT) enzyme levels.8Suitable perfusion and tissue oxygenation is considerably effective in the function of organs before, during, and after surgery.Given the inconsistency in the studies on the effects of CPB on the liver function test post on-pump CABG, we aimed to evaluate the impact of CPB and other factors that may aggravate changes on the liver function test after on-pump cardiac surgery. In this quasi-experimental clinical trial, which was done during 2011, after obtaining approval from the Ethics Committee and written informed consent from the patients, 146 out of 190 patients who referred to hospitals affiliated to Shiraz University of Medical Sciences, southern Iran, for elective CABG were recruited. The sample size was calculated to be 142 patients considering α of 0.05, power of 80%, and standard deviation (SD) of 9 . Patients who had simultaneous cardiac valvular surgery, those with hemolytic disorders, and those with abnormal liver function tests prior to surgery or those with a history of fatty liver or chronic liver disease were excluded from the study.The patients’ data including age, sex, Body Surface Area, hematocrit level, direct and indirect bilirubin levels, hepatic enzymes , serum creatinine, ejection fraction, history of cardiovascular and cerebral diseases, and history of diabetes mellitus were recorded in a specific form.Following anesthesia induction using Midazolam, Sufentanil, Na-Thiopental, and Pancuronium, Morphine was administered for the patients. After inserting the central venous catheter in place, the initial central venous pressure (CVP) was recorded. Oxygen and Isoflurane were used for the maintenance of anesthesia.2 and a temperature of at least 32°C was used. Anesthesia was maintained using the α-stat method for arterial blood gas management, and the mean arterial blood pressure was kept at 60-70 mm Hg. Upon necessity, the patients’ blood pressure was maintained using inotrope and vasopressors. Moreover, in order to correct the hematocrit level, blood transfusion was done for the patients if needed.A CPB pump with a flow of 2.4-2.6 lit/min/mAt the end of surgery, the patients’ minimum hematocrit level, number of infused blood packs, use of intra-aortic balloon pump, CPB time, aortic cross-clamp time, and use of inotrope and vasopressors until the first postoperative day were recorded. After the transfer of the patients to the Intensive Care Unit (ICU), data regarding serum bilirubin (direct and indirect), ALT, AST, and ALP for the first postoperative day were also recorded. t test, analysis of variance (ANOVA), and the Pearson correlation coefficient were employed as appropriated and multiple regression test was used for adjustment. A P<0.05 was considered statistically significant. The data were analyzed using SPSS software (version 16). In order to determine the normality of the data, the Kolmogorov-Smirnov test was utilized. The paired Eighty-six (58.9%) patients were men, 41 (28.1%) patients had a history of myocardial infarction, and 53 (36.3%) patients had a history of diabetes mellitus. Intra-aortic balloon pumps were not used for 132 (90.4%) patients. The mean±SD of direct and indirect bilirubin changes, ALP, ALT, and AST was 0.137±0.45, 0.378±1.19, -45.12±8.2, 11.15±2.88, and 41.46 7.56, respectively. Except for ALP, all the other liver function test indices had a significant increase after surgery . CompariThere were no significant differences between the changes in the liver function tests and age, Body Surface Area, hematocrit, and lowest hematocrit level of the patients during surgery (the Pearson correlation coefficient test). The creatinine level showed a reverse significant correlation with the mean indirect bilirubin changes (P<0.05). However, it did not have any correlation with the mean changes in the other hepatic enzymes (P>0.05). The ejection fraction had a significant reverse correlation with the mean ALP changes (P<0.05), and it did not have a significant correlation with the other liver function tests . The CVP had a direct and significant relationship with the mean ALT and AST changes (P<0.05). Moreover, CPB time had a direct and significant relationship with the mean direct and indirect bilirubin and AST (P<0.05), whereas it had no significant correlation with the changes in the ALT and ALP levels. The aortic cross-clamp time only showed a direct significant relationship with AST . In this study, all the patients received inotrope and vasopressors until the first postoperative day. None of the patients had a history of cerebral vascular disease.For all the recent advances in the techniques and modes of anesthesia in on-pump cardiac surgery, liver complications still remain one of the most severe postoperative consequences of cardiac surgery. 2 we found no significant relationship between the changes in the liver function tests and age, sex, and Body Surface Area.Although it is believed that a lower hemoglobin level in women, small stature, and age-related atherosclerosis can affect the perfusion of visceral organs,9-13 In our study, the lowest hematocrit level was not below 22%; consequently, we found no significant relationship between the hematocrit level before surgery, lowest hematocrit level on pump, and changes in the liver function tests.During on-pump cardiac surgery, even with mild hypothermia, the basal metabolic rate is decreased. Hypothermia helps the individual to tolerate low hematocrit because of hemodilution. On the other hand, the drop in hematocrit levels and the resulting reduction in perfusion can damage visceral organs, especially when they are compromised by an underlying disease. A large body of research states that with a drop in hematocrit levels to below 17%, the patient will have serious complications; and if the hematocrit level drops below 14%, the patient might be at risk of death.14 stated that a history of myocardial infarction, revascularization, and ejection fraction below 40% were the independent factors affecting postoperative gastrointestinal complications. Moreover, the authors found that a history of renal failure was effective in the occurrence of gastrointestinal complications. Also, Raman et al.15 reported that a history of diabetes mellitus and heart failure could cause severe liver ischemia after cardiac surgeries. In our study, a history of diabetes had a significant relationship with direct bilirubin changes, and not with the other liver function tests. Also, myocardial infarction and preoperative creatinine levels did not have a significant relationship with any of the liver function tests, while the ejection fraction had a reverse significant relationship with the changes in the ALP levels and the CVP pressure had a direct and significant relationship with the changes in the liver enzymes.Mc Sweeny et al.The results of the present study are not in agreement with that of in some previous studies. Conflicting results can also be found between the previous investigations; this is because different studies employ different markers for detecting hepatocellular injury such as alcohol dehydrogenase (AD) and glutathione S-transferase (GST). It is worthy of note that we used conventional transaminases, which are, albeit a lesser indicator of hepatic damage, more practical than the others.16 In our study, inotrope and vasopressors were infused for all the patients until the first postoperative day. Therefore, we could not assess their effect on the changes in the liver function tests.Holmes showed that using inotrope and vasopressors could increase visceral vascular resistance and cause ischemia by vascular contracture. For instance, while infusion of epinephrine could increase cardiac output, it would reduce visceral perfusion.8 In our study, only AST had a considerably significant increase in the patients for whom intra-aortic balloon pumps were used. Another study showed that inadequate venous drainage caused liver congestion and increased postoperative liver damage. Venous drainage during CPB depends on multiple factors.17 However, during CPB, the amount of the pump flow directly correlates with the amount of systemic venous return. In our study, the pump flow was maintained at 2.4-2.6 lit/min/m2, so venous drainage during our study was acceptable and did not damage the liver function.Some researchers have reported that the use of intra-aortic balloon pumps could reduce tissue perfusion and cause gastrointestinal complications, especially liver complications.18 found that prolong pump time would affect visceral vascular and hepatocellular perfusion. In our study, the CPB time had a direct and significant relationship with the changes in the direct and indirect bilirubin and AST levels. Nevertheless, the aortic cross-clamp time only had a direct and significant relationship with the AST changes, which could indicate the skillfulness of the surgeon in minimizing the bypass time to reduce postoperative complications.The effects of pump time and aortic cross-clamp time on visceral perfusion have also been studied. Murphy et al.It seems that the techniques for the reduction of CBP and aortic cross-clamp duration may be useful to protect the liver function. We recommend that future studies be conducted on a larger population of patients and with a single surgeon so as to achieve more comprehensive results.


The demand for interdisciplinary research is increasing in the new millennium to help us understand complex problems and find solutions by integrating the knowledge from different disciplines. The present review is an excellent example of this and shows how unique combination of physics, chemistry, and biological techniques can be used for the evaluation of Indian medicinal herbs used for treating diabetes mellitus. Laser-induced breakdown spectroscopy (LIBS) is a sensitive optical technique that is widely used for its simplicity and versatility. This review presents the most recent application of LIBS for detection of glycemic elements in medicinal plants. The characteristics of matrices, object analysis, use of laser system, and analytical performances with respect to Indian herbs are discussed. The World Health Organization estimates that about 80% of the world's population relies on herbal medicines for primary healthcare , 2. KnowOne important analytical technique that has led to advances in natural product research is laser induced breakdown spectroscopy (LIBS). In this paper, we review the applications of this technique and then review its use for the evaluation of Indian medicinal plants used for treating diabetes mellitus. Specifically, we review what these glycemic elements are and how LIBS has been used to detect these elements in plants known to have hypoglycemic property.A number of plant species have hypoglycemic property , 11. DesThe LIBS technique is used for qualitative and quantitative analysis of trace elements. It was used for the first time in 2008 to study the presence of certain trace elements in medicinal plants with hypoglycemic effects . This teInitially, liquid analysis with LIBS was not popular because of problems such as sloshing, splashing, and focal length changes with a high repetition rate laser. Apart from this, high local density within the liquid caused intrinsic complexity with LIBS analysis; the spectral transition in comparison to that for a rarefied gas, considerably broadens when the high collision rate within the plasma is confined in a liquid. If attributes like minimal sample preparation and high detection sensitivity are resolved, then LIBS offers great potential for detection of elements in liquids. Consequently, various attempts were made by several researchers to overcome the problems encountered for liquid samples –15.in situ and real time techniques have a range of applications in the analysis of small particles that range from submicrometer to several micrometers in diameter. Such techniques are useful in atmospheric sciences, process monitoring and control, and effluent waste stream monitoring. The LIBS technique was used to detect chromium in aerosols using a constant-output aerosol generator called atomizer [In today's world, atomizer . In multatomizer . LIBS has been used for direct and rapid determination of various types of trace metals. For analyzing the various trace elements, such as Mg, Cu, Cr, Si, and Ca, in rock samples, a time-resolved LIBS (TRELIBS) technique was used by Song et al. . The anain situ probe [2) showing the feasibility and scope of the use of LIBS in space exploration [With the increased research awareness, LIBS has also been used for environmental monitoring, specifically for online and remote analysis of potential hazards. The United States Environmental Protection Agency (EPA) encourages facilities to evaluate the use of real-time emissions monitoring technology in industry. Theriault et al. used LIBS for screening heavy-metal-contaminated soils using an tu probe . The detloration . HoweverR2 > 0.92) were obtained for Cr, Cu, Mn, Ni, and Fe, which appeared in concentration range of 200 ppm but were actually 10% of 200 ppm, as compared to the normalized atomic emission intensities of these elements in the laboratory result. The detection limits for these and other elements were extrapolated to be around 300 ppm. Fabre et al. used LIBS in geological materials for the determination of lithium in melt inclusions, quartz, and associated fluid inclusions and then compared the results (obtained with LIBS) with the result of electron microprobe technique. The results obtained with LIBS were in good agreement with bulk and microprobe data obtained for the same minerals [LIBS was adapted in mining and coal industries for both exploration as well as ore body imaging; it is employed by using an optical fiber bundle with wide acceptance angle, placed at a distance to find out the elemental content of the mineral core drill sample. LIBS was also used in the study of archaeological objects and for conservation and restoration of cultural heritage, though the main focus has been on laser artwork cleaning. Mineral assaying applications were performed using TRELIBS as reported by Bolger . They usminerals .In recent years, LIBS has received much attention with applications to solid and liquid analysis of plants materials –30. Due 2 coatings were achieved. The surface analyses of photonic-grade silicon were also tested using LIBS technique [2 was analyzed with a lateral resolution of 70 mm and depth resolution of about 0.16 mm. Two-dimensional (2D) and three-dimensional (3D) distribution maps of carbon contamination on silicon were presented. The use of LIBS for quantitatively mapping the multielement distribution on polish rock and for copper in printed circuits was proposed by Yoon et al. and Kim et al. [In the field of surface analysis, including composition mapping and in-depth profile analysis of advanced materials, the most advanced LIBS techniques have been used. Major progress at the nanometric range has been achieved for depth-resolved measurement. Detailed spatial information by imaging mode of LIBS has been achieved by point-to-point mapping using a spherical lens focusing system, when a multidimensional detector is used. Romero and Laserna used multichannel LIBS to generate selective chemical images for Ag, Ti, and C from silicon photovoltaic cells . Both suechnique . A totalm et al. , 37.LIBS application for the online multielement analyses of glass melts in a vitrification process of high-level liquid waste (HLLW) was investigated by Yun et al. . Twelve β-cells of pancreas or due to improper utilization of insulin  due to insensitiveness of cell receptors to insulin [Diabetes mellitus, hereafter referred to as diabetes, is a heterogeneous disorder characterized by excess blood glucose due to improper metabolism of proteins, fats, and carbohydrates. Diabetes is characterized by elevated fasting blood glucose (FBG) and postprandial glucose (PPG) levels. The body is unable to utilize available blood sugar (glucose), either due to unavailability of insulin caused by inactivation of  insulin .The World Health Organization (WHO) has listed diabetes as one of the major killers of our time. About 225 million people worldwide are estimated to be suffering from diabetes. This number may probably double by the year 2030. It is the 7th leading cause of death even in a developed country like the US . India hβ-cells of the islets of Langerhans in the pancreas. The α-cells of islets of Langerhans secrete glucagon, a hormone with action nearly opposite of insulin. The role of insulin is to stimulate the GLUT-4 glucose transporter. GLUT-4 is the most important of the glucose transporter molecules, and its insertion into the muscles and adipose cell membranes serves to facilitate glucose delivery into these cells. This is the only mechanism by which the glucose can be delivered to fat, muscle, and also liver cells , it occurs when the Formerly known as noninsulin-dependent diabetes mellitus (NIDDM), typical type 2 diabetes is rarely found as an isolated abnormality. Obesity, hypertension, dyslipidemia, and hyperurinemia appear to cluster in the same individuals. Insulin resistance may be the underlying cause of this type of metabolic syndrome. Typical dyslipidemia associated with type 2 diabetes is hypertriglyceridemia and hypocholesterolemia, –47. The The term “type 3 diabetes” reflects the fact that Alzheimer's disease (AD) represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 and type 2 diabetes mellitus. The characteristic molecular and biochemical abnormalities associated with AD include cell loss, increased activation of prodeath genes and signaling pathways, impaired carbohydrate metabolism, chronic oxidative stress, DNA damage, and so forth. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus and obesity to AD pathogenesis . HoweverSeveral Indian plants and their glycemic elements have been discussed in the literature.−1 [C. dactylon indicate that its extracts consist of elements like Mg, C, and Ca in the spectral range 200–500 nm. Commonly known as “Dhoob” in India, is a weed, and is regarded to possess antidiabetic properties. Aqueous and ethanolic extracts of whole plant were found to have hypoglycemic and hypolipidemic effects in STZ-induced diabetic rats at a dose of 500 mg kg−1 , 56. Rec−1 , 25. ResBecause the intensity of a spectral line of a particular element present is directly proportional to its concentration, the proportion of the concentration of these elements could be evaluated by taking the ratio of intensity of these elements and the intensity of a reference line. In the aforesaid study, C III (229.4 nm) is the reference as carbon (C) being an essential constituent of trace elements present in plants, is abundant. C III (229.4 nm) line is interference-free line and, hence, fulfills the requirement to be chosen as a reference line. The intensity ratio of Mg/C and Ca/C has been calculated and tabulated in E. officinalis has been reported to have potent antimicrobial, antioxidant, hepatoprotective, antitumor, and hypolipidemic properties [E. officinalis seeds has antidiabetic and antioxidant activities [E. officinalis fruit extract was taken in different spectral ranges at optimized experimental conditions. It revealed the presence of Mg, Na, Cl, Ca, H, O, C, and N elements in the spectral range of λ 200–900 nm. According to the Boltzmann distribution law, intensity is directly related to concentration [Commonly known as “Amla” in Hindi, grows in India as well as tropical and subtropical regions of the world. The fruit of operties , 58. Thetivities , 60. Thentration , therefontration , 55–60.Ficus bengalensis as compared to other elements present.Commonly known as “Indian Banyan Tree or Bur,” is distributed throughout India. A glycoside called bengalenoside was isolated from the bark and showed more potent hypoglycemic action compared to the crude ethanolic bark extract, and the activity being was half that of the synthetic drug tolbutamide . Oral adM. oleifera are lopped for fodder [M. oleifera fruit extract was taken at optimized experimental conditions. It revealed the presence of Mg, Ca, H, O, C, and N elements in the spectral range of 200 nm to 400 nm. The proportion of the concentration of these elements could be evaluated by taking the ratio of intensity of these elements with intensity of reference lines .Commonly known as Drumstick tree, is indigenous to Northwest India. Most parts of this tree possess antimicrobial activity . The trer fodder  and haver fodder , 70. Ethr fodder , 72. Ther fodder . The LIBM. charantia powder was found to have antidiabetic activity [M. charantia fruit powder was recorded to identify its glycemic trace elements that may be responsible for diabetes management in biological systems. The LIBS results point out that dried fruit pellet of M. charantia consists of elements like Na, K, Mg, Ca, Fe and Al in the spectral range of 200 nm–500 nm. The concentrations of these elements were determined by calibration-free (CF)-LIBS method. This approach requires extensive data processing and, hence, a data processing algorithm was developed [Commonly known as bitter gourd (melon) or Karela, is widely planted in tropical areas and is usually consumed as a vegetable. Bitter gourd has also been frequently used as a medicinal herb in Asia, Africa, and South America because of its antidiabetic, anthelmintic, abortifacient, antibacterial, antiviral, and chemopreventive functions , 75. In activity . LIBS speveloped  to quanteveloped . 1, B2, and B6, and free sugars  have been reported in this fruit [P. guajava fruit has been discovered as a new source of antioxidants and is reported to have hypoglycemic effect [Is a semideciduous tropical tree commonly known as “Amrood” in Hindi and is widely grown throughout India for its fruit. A high percentage of vitamin C, carotene, vitamins Bis fruit . The P. c effect  on bloodc effect , and thec effect . Trichosanthes dioica, have shown hypocholesterolemic, hypotriglyceridemic, and hypophospholipedemic effects [It is a dioecious perennial herbaceous vegetable. It is commonly known as “Parval” in Hindi and is widely grown throughout India. Its fruits are a rich source of vitamin C and minerals . Normal animals fed with a diet consisting of shade dried fruits of  effects . Normal  effects . Direct  effects  and albi effects . Effect  effects . Aqueous effects , 85–88.W. coagulans, has cardiovascular effect [W. coagulans fruits has shown to exert hepatoprotective, anti-inflammatory and antidiabetic effects [W. coagulans fruits increases the glucose utilization in isolated rat hemidiaphragm cells [Is commonly known as Indian cheese maker. A steroidal lactone, withanolide , isolater effect . Alcoholr effect . The hot effects –93. The gm cells .C. cajan leaves have hyperglycemic activity. LIBS spectra of C. cajan clearly reveal that the extract consists of elements like Mg, C, and Ca in the spectral range 200–500 nm. The intensity ratios of Mg/C and Ca/C have been calculated and found that these ratios for C. cajan are lower in comparison to the above-mentioned plant extracts known to have antidiabetic activity  will be on developing on-site and doing remote analysis of elements, improving precision in measurement, developing accurate calibration procedures and detection limits.