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BACKGROUND AND AIMS Liver stiffness measurements (LSMs) by 2-dimensional-shear-wave elastography (LSM2D-SWE) are now widely used in hepatology. However, relevant information for primary biliary cholangitis (PBC) is scant. We compare LSM2D-SWE with liver biopsy (LB) in a cohort of PBC patients in Greece. METHODS Data of 68 LBs from 53 PBC patients were retrospectively analyzed and fibrosis stage was compared to LSM2D-SWE. Forty-six patients (86.8%) were females and at the time of LBx median (IQR) age was 62.6 (53.2-72.1). Demographic, UDCA treatment, histological and B-mode ultrasound data were tested for their influence on LSM2D-SWE estimates. RESULTS Liver fibrosis stages F0-F4 were found in 4, 19, 19, 16 and 10 cases, respectively. Across stages F0-F4, the LSM2D-SWE was 5.6 (5.1-6.1), 7.0 (5.8-7.7), 9.1 (7.3-11.5), 10.8 (9.9-12.2) and 14.5 (11.9-25.7) kPa, respectively, with highly significant difference (p

Purpose We investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes ( BRCA1, BRCA2, PALB2, and ATM) in consecutive patients with pancreatic adenocarcinoma. Methods One hundred fifty patients with French-Canadian (FC) ancestry were evaluated for founder mutations, and 114 patients were subsequently assessed by full gene sequencing and multiplex ligation-dependent probe amplification for nonfounder mutations. Two hundred thirty-six patients unselected for ancestry were also assessed for mutations by full gene sequencing. Results The FC founder mutation prevalence among the 150 patients was 5.3% (95% CI, 2.6% to 10.3%), and the nonfounder mutation prevalence across the four genes among the 114 patients tested was 2.6% (95% CI, 0.6% to 7.8%). In the case series unselected for ancestry, 10.0% (95% CI, 2.7% to 26.4%) of patients reporting Ashkenazi Jewish (AJ) ancestry carried an AJ founder mutation, with no nonfounder mutations identified. The mutation prevalence among patients without FC/AJ ancestry was 4.9% (95% CI, 2.6% to 8.8%). Mutations were more frequent in patients diagnosed at ≤ 50 years of age ( P = .03) and in patients with either two or more first- or second-degree relatives with pancreas, breast, ovarian or prostate cancer, or one such relative and a second primary of one of these cancer types ( P < .001). BRCA1, BRCA2, and PALB2 carriers with late-stage (III or IV) disease had an overall survival advantage ( P = .049), particularly if treated with platinum-based chemotherapies ( P = .030). Conclusion Considering these results, we recommend reflex founder mutation testing of patients with FC/AJ ancestry and full gene sequencing of patients who are ≤ 50 years or meet the identified family history criteria. Reflex testing of all incident patients for these four genes may become justified as full gene sequencing costs decline.

// Markus Wallner 1, 2, * , Mounir Khafaga 1, * , Ewald Kolesnik 1 , Aris Vafiadis 1 , Gerold Schwantzer 3 , Deborah M. Eaton 2 , Pero Curcic 4 , Martin Kostenberger 5 , Igor Knez 4 , Peter P. Rainer 1 , Martin Pichler 6 , Burkert Pieske 1, 7, 8 and Dirk Von Lewinski 1 1 Division of Cardiology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria 2 Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, 19140 PA, United States of America 3 Institute for Medical Informatics, Statistics, and Documentation, Medical University of Graz, 8036 Graz, Austria 4 Division of Cardiac Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria 5 Department of Pediatric Cardiology, Medical University of Graz, 8036 Graz, Austria 6 Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria 7 Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charite University Medicine, Berlin, 13353 Berlin, Germany 8 Department of Internal Medicine and Cardiology, German Heart Center, Berlin, 13353 Berlin, Germany * These authors contributed equally to this work Correspondence to: Ewald Kolesnik, email: ewald.kolesnik@medunigraz.at Keywords: prostate cancer, hormone therapy, cardiac disease models, heart failure, istaroxime Received: March 06, 2017 Accepted: April 14, 2017 Published: April 30, 2017 ABSTRACT The current gold standard for prostate cancer treatment is androgen deprivation therapy and antiandrogenic agents. However, adverse cardiovascular events including heart failure can limit therapeutic use. Istaroxime, which combines Na + -K + -ATPase (NKA) inhibition with sarco/endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) stimulation, has recently shown promising anti-neoplastic effects in prostate cancer (PC) models and may also improve cardiac function. Considering the promising anticancer effects of istaroxime, we aimed to assess its functional effects on human myocardium. Results: Istaroxime and strophanthidin elicited dose-dependent positive inotropic effects with a decline in developed force at supraphysiological concentrations in human atrial, nonfailing, and failing ventricular (ToF) myocardium. Diastolic force and RT50% did not change after exposure to both drugs. The maximal developed force in our in-vitro model of heart failure (ToF) was significantly higher after istaroxime administration. Such a difference did not occur in atrial or nonfailing ventricular trabeculae and was not applicable to the diastolic force. Materials and Methods: Human atrial and ventricular trabeculae were isolated from nonfailing hearts and hearts of infants with tetralogy of Fallot (ToF), which were used as an in-vitro model of heart failure. The samples were electrically stimulated and treated with increasing concentrations of istaroxime and strophanthidin (10 nM–1 μM). Systolic and diastolic force development and relaxation parameters (RT50%) were analyzed. Conclusions: Combined NKA inhibition/SERCA2a stimulation increases contractility in atrial, nonfailing, and failing myocardium. Considering that heart failure is a potential side effect of current PC treatments, especially in elderly patients, istaroxime might combine beneficial cardiac and anti-cancer properties.

Background. Decoy-receptor 3 (DcR3) exerts antiapoptotic and immunomodulatory function and is overexpressed in neoplastic and inflammatory conditions. Serum DcR3 (sDcR3) levels during the chronic hepatitis/cirrhosis/hepatocellular carcinoma (HCC) sequence have not been explored.Objective. To assess the levels and significance of sDcR3 protein in various stages of chronic liver disease.Methods. We compared sDcR3 levels between healthy controls and patients with chronic viral hepatitis (CVH), decompensated cirrhosis (DC), and HCC. Correlations between sDcR3 levels and various patient- and disease-related factors were analyzed.Results. sDcR3 levels were significantly higher in patients with CVH than in controls (P<0.01). sDcR3 levels were elevated in DC and HCC, being significantly higher compared not only to controls (P<0.001for both) but to CVH patients as well (P<0.001for both). In addition, DcR3 protein was detected in large quantities in the ascitic fluid of cirrhotics. In patients with CVH, sDcR3 significantly correlated to fibrosis severity, as estimated by Ishak score (P=0.019) or by liver stiffness measured with elastography (Spearmanr=0.698,P<0.001). In cirrhotic patients, significant positive correlations were observed between sDcR3 levels and markers of severity of hepatic impairment, including MELD score (r=0.653,P<0.001).Conclusions. Circulating levels of DcR3 are elevated during chronic liver disease and correlate with severity of liver damage. sDcR3 may serve as marker for liver fibrosis severity and progression to end-stage liver disease.

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first-line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg-negative CHB patients treated with entecavir. HBeAg-negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0-4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir-treated HBeAg-negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.

Left ventricular diastolic dysfunction (LVDD) constitutes the prominent characteristic of cirrhotic cardiomyopathy, but its relevance on the clinical course of cirrhotic patients has not been clearly defined. The aim of the study was to evaluate the relationship of LVDD with the severity and etiology of liver disease and to investigate whether it affects the outcome of cirrhotic patients. Cardiac function of 45 cirrhotics was studied by a tissue Doppler imaging echocardiography. Diagnosis of LVDD was made according to the latest guidelines of the American Society of Echocardiography. All patients were followed up for a period of 2 years. Death or liver transplantation was the endpoint of the study. LVDD was found in 17 (38 %) of 45 patients. Its presence was not found to be associated with the etiology and stage of cirrhosis, but its severity was directly correlated with the Child-Pugh score. At the end of follow-up, 14 patients had died; 9 had LVDD (9/17, 53 %) and 5 had not (5/28, 18 %). Patients who died at the beginning of observation period had a higher Child-Pugh and MELD score, higher BNP, lower albumin and more prolonged QTc. On Kaplan-Meier analysis, patients with LVDD had statistically significantly worse prognosis compared to those without (p = 0.013, log rank: 5.495). Low albumin values (p = 0.003) and presence of LVDD (p = 0.017) were independent predictive factors of mortality. LVDD is a common complication of cirrhosis. As its development seems to be related to a worse prognosis, patients with LVDD must be under a strict follow-up.

Hepatitis D virus (HDV) has decreased in Europe, but recent reports indicate a rising trend. We report the epidemiological changes, clinical progress, and effect of treatment on the natural course of HDV infection in Greece during the last 13 years.Prospective data were extracted from the HepNet.Greece Cohort-Study.Since 1997, 4673 chronic HBV (CHB) cases (4527 adults, 146 children) have been followed prospectively. Two thousand one hundred thirty-seven patients were tested for anti-HDV [101 (4.7%) positive]. Anti-HDV testing in Greece decreased significantly (57.0% before 2003, 35.3% thereafter; p0.001). Anti-HDV prevalence among HBsAg-positives was 4.2%; lower in native Greeks (2.8%) than in immigrants (7.5%) or in children (15.3%; p0.001). Within 2.3 years of follow-up, HDV occurred in 11/2047 HBsAg-positive patients (2.2 new delta-infected adults and 8.7 children per 1000 HBsAg-positive annually). HDV-positive compared to CHB adults were younger (p=0.035) and had more active and advanced disease at baseline, as indicated by laboratory indices and the higher prevalence of cirrhosis at younger age. During a 4.2-year median observation, significantly more anti-HDV-positive than CHB adults developed a liver-related first event (20.0% vs. 8.5%, p Log-rank=0.014).Treatment was received by 46/90 (51.1%) patients, 40 of them interferon-based. In multivariable analysis, interferon significantly decreased disease progression in HDV-positive patients [HR=0.14 (95% CI: 0.02-0.86; p=0.033)].In Greece, HDV serology is currently tested in only one-third of HBsAg-positive patients. HDV prevalence is lower in native Greeks compared to immigrants, who may contribute50% of the HDV infection burden in Greece. Data show that HDV infection is a rapidly progressive disease, but interferon-based treatment may alter its course.

Background. HCV infection and transfusional iron overload in Thalassemic patients may result in liver disease. HCV treatment in Thalassemia has raised safety concerns. Aim. Estimate effectiveness and tolerability of interferon-based therapy in HCV-infected Thalassemic patients. Material and methods. Over a 12-year period, consecutive patients with β Thalassemia major (TM) and chronic hepatitis C received treatment. Liver biopsy, HCV-RNA and genotyping were performed beforehand. Sustained virological response (SVR) was defined as negative HCV-RNA 6 months post-treatment. Forty eight patients (26 M-22 F, mean age 39.8) were enrolled. Twenty nine patients were treated with conventional interferon alpha (IFNa) for 48 weeks (group A). Nineteen patients (10 naive-9 previously IFNa experienced) received pegylated interferon (PEGIFN) (group B). Results. HCV-1 was found in 44%, HCV-2 in 14%, HCV-3 in 23% and HCV-4 in 19%. Group A: ten patients (38.5%) achieved SVR, 2 (7.5%) relapsed and 17 (54%) were non responders. Group B: five (28%) achieved SVR, 8 (44%) relapsed and 6 (28%) never responded. High HCV-RNA levels, genotype 1 and advanced liver fibrosis were independently associated with no response. Four patients (3 treated with IFNα, 1 with PEG-IFN) had to discontinue treatment due to complications. Conclusions. The response rate of IFN monotherapy in multi-transfused, HCV-infected Thalassemic patients is not inferior to that in nonmulti-transfused patients. IFNa administration is well-tolerated and should be recommended as initial treatment schedule in this setting.

Background and Aim Cirrhotic patients are predisposed to intestinal bacterial overgrowth with translocation of bacterial products which may deteriorate liver hemodynamics. Having shown that short-term administration of rifaximin improves liver hemodynamics in decompensated cirrhosis, we conducted this study to investigate the effect of intestinal decontamination with rifaximin on the long-term prognosis of patients with alcohol-related decompensated cirrhosis (Child-Pugh > 7) and ascites. Methods Patients who had received rifaximin and showed improved liver hemodynamics were enrolled in the current study and continued to receive rifaximin (1200 mg/day). Each patient was matched by age, sex, and Child-Pugh grade to two controls and followed up for up to 5 years, death or liver transplantation. Survival and risk of developing portal hypertension-related complications were compared between rifaximin group and controls. Results Twenty three patients fulfilled the inclusion criteria and matched with 46 controls. Patients who received rifaximin had a significant lower risk of developing variceal bleeding (35% vs 59.5%, P = 0.011), hepatic encephalopathy (31.5% vs 47%, P = 0.034), spontaneous bacterial peritonitis (4.5% vs 46%, P = 0.027), and hepatorenal syndrome (4.5% vs 51%, P = 0.037) than controls. Five-year cumulative probability of survival was significantly higher in patients receiving rifaximin than in controls (61% vs 13.5%, P = 0.012). In the multivariate analysis, rifaximin administration was independently associated with lower risk of developing variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, and higher survival. Conclusions In patients with alcohol-related decompensated cirrhosis, long-term rifaximin administration is associated with reduced risk of developing complications of portal hypertension and improved survival.

Background Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. Objectives The aim of the study was to estimate population event rates for NSAID-associated ALFT Methods This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). Results In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1–2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2–3.9) for ibuprofen, 1.9 (95 % CI 0.8–3.7) for nimesulide, 1.6 (95 % CI 0.6–3.4) for diclofenac and 1.6 (95 % CI 0.3–4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6–4.1) without overdoses and 7.8 (95 % CI 6.8–9.0) including overdoses. Conclusions ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure. Electronic supplementary material The online version of this article (doi:10.1007/s40264-012-0013-7) contains supplementary material, which is available to authorized users.

Barrett’s esophagus (BE) is a major complication of gastroesophageal reflux disease due to its neoplastic potential. The length of the metaplastic epithelium has been associated with cancer risk. Angiogenesis, inflammation, and increased cell proliferation are early events in the malignant sequence. Vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) and Ki-67 are indirect markers of these complex mechanisms. To examine the expression of VEGF, COX-2 and Ki-67 in BE and investigate whether there is an association to Barrett’s length. Immunohistochemistry for VEGF, COX-2, and Ki-67 was performed in well-characterized Barrett’s samples, evaluated using a qualitative scale and compared between long (LSBE) and short (SSBE) segments. The study population consisted of 98 patients (78 men). LSBE and SSBE was diagnosed in 33 (33.7%) and 65 (66.3%) cases, respectively. VEGF was expressed in vascular endothelium of all Barrett’s specimens. COX-2 and Ki-67 expression in metaplastic epithelia was strong in 81.6 and 61.2% of the samples, respectively. Ki-67 expression was significantly stronger in LSBE (p = 0.035), whereas VEGF expression was significantly increased in SSBE (p = 0.031). COX-2 expression was not associated with Barrett’s length. VEGF, COX-2, and Ki-67 were overexpressed in the majority of Barrett’s samples. The length was inversely associated with VEGF expression and directly associated with Ki-67 expression.

Decoy receptor-3 (DcR3) is a member of the TNF receptor superfamily of proteins, which has been implicated in anti-apoptotic and anti-inflammatory pathways, via binding to TL1A, LIGHT and Fas-L. The role of the TL1A/DcR3 ligand/receptor pair in ulcerative colitis (UC) has not been studied. We investigated the systemic (peripheral blood) and local (large intestine) expression of DcR3 and TL1A in 64 patients with UC and 56 healthy controls. DcR3 serum concentrations were highly elevated in patients with active UC (P

INTRODUCTION: Data on small bowel abnormalities in patients with portal hypertension (PHT) are limited. Bleeding from the gastrointestinal tract and anemia are common complications in these patients. Capsule endoscopy (CE) was used to evaluate small bowel (SB) pathology in patients with PHT and anemia, and possible associations with various parameters were examined.METHODS: Thirty-five patients with PHT referred for CE investigation of the SB for anemia were prospectively enrolled in the study, as well as 70 age- and sex-matched control patients with anemia, normal liver function and no evidence of PHT who underwent CE.RESULTS: Findings compatible with portal hypertensive enteropathy (PHE) were detected in 65.7% of the patients and in 15.7% of the controls (χ2=26.641, P=0.000). Abnormalities in PHT patients included varices in 25.7%, diffuse changes of mucosa with inflammatory-like appearance in 42.9%, and angiodysplasias and/or spider angiomas in 22.9% of cases. The presence of PHE was significantly associated only with the presence of severe portal hypertensive gastropathy, while the presence of SB varices alone was significantly associated with the presence of severe portal hypertensive gastropathy, larger esophageal varices and the presence of colonic varices.CONCLUSIONS: Varices, diffuse changes of mucosa with inflammatory-like appearance, and angiodysplasias and/or spider angiomas are detected more often in patients with PHT than in controls, and probably constitute the endoscopic characteristics of PHE. CE of the SB added a significant number of likely important findings to those detected by conventional endoscopic techniques for the clinical management of patients with PHT and anemia.

Background: In the last decade, the diagnostic approach of Gastrointestinal Stromal Tumors (GIST) has drastically changed with the utilization of tissue-specific biomarkers, such as c-Kit. However, a serum biomarker aiding in differential GIST diagnosis prior to surgery would provide added benefit in the daily clinical practice. Thus, the aim of the study was to investigate whether detection of c-Kit protein in the serum could be used as a reliable diagnostic biomarker. Methods: Twenty-seven patients with histologically confirmed GIST (16 men; age 41-80 years), 27 healthy controls (14 men; age 45-76 years) and 24 patients with submucosal tumors other than GIST (10 men; age 25-85 years) were enrolled in the study. Detection of serum c-Kit protein in blood samples of all patients prior to any treatment-related intervention and of healthy participants was accomplished using flow cytometry. The sensitivity and specificity of the assay were estimated. Results: Of the 27 patients with GIST, 25 were serum c-Kit positive. In the control group of 27 healthy participants, all except one were serum c-Kit negative, while among the 24 patients with tumors either than GIST, 22 were serum c-Kit negative and 2 were positive. Based on these results, the sensitivity of the assay was 92.6%, while the specificity was 96.3% when compared with the healthy volunteers and 91.7% in comparison with the non-GIST group. Conclusion: c-Kit protein detection with flow cytometry could represent a reliable sensitive and specific serum bioassay for differential GIST diagnosis.

Summary. The epidemic of hepatitis C virus (HCV) infection is a major public health issue. We conducted a comprehensive analysis to estimate future HCV-related morbidity and mortality, using a model which is the first to take into account currently available treatments. We reconstructed the incident infections per year in the past that progressed to chronic hepatitis C (CHC) in Greece. Then, the natural history of the disease was simulated in subcohorts of newly infected subjects in the presence or absence of treatment using yearly estimates of the number of treated patients obtained from national databases. Annual estimates of the incidence and prevalence of CHC by fibrosis stage, hepatocellular carcinoma (HCC) and mortality were obtained up to 2030. The current proportion of naive CHC patients receiving treatment in Greece is 1.2% per year. Treatment of 1.2–10% of naive CHC patients per year would reduce the cumulative number of incident cirrhosis and HCC cases from 2002 to 2030 by 10.8–39.4% and 12.8–39.8%, respectively and decrease the number of prevalent cirrhosis and HCC cases in 2030 by approximately 17–48% compared with the number estimated under the assumption of no treatment. Approximately 17 cirrhosis cases or six HCC cases or 10 premature deaths would be prevented for every 100 treated patients. However, the prevalent cirrhotic/HCC cases because of HCV and HCV-related deaths would not plateau until 2030. Despite the introduction of effective treatment, HCV-related morbidity and mortality will likely increase during the next 20–30 years in Greece. Intensive primary prevention efforts coupled with increased access to the currently available treatments are necessary to control the chronic consequences of HCV epidemic.

Summary. In this study, a comprehensive methodology for modelling the hepatitis C virus (HCV) epidemic is proposed to predict the future disease burden and assess whether the recent decline in the incidence of HCV may affect the future occurrence of cirrhosis and hepatocellular carcinoma (HCC) cases. Using the prevalence of HCV, the distribution of chronic hepatitis C (CHC) patients within the various transmission groups and their infection-onset times, it was possible to reconstruct the incident infections per year in the past that progressed to CHC in Greece. The natural history of the disease was simulated in subcohorts of newly infected subjects using transition probabilities derived either empirically between fibrosis stages 0–4 or from literature review. Annual estimates of the incidence and prevalence of CHC by fibrosis stage, HCC and mortality in Greece were obtained up to 2030. HCV incidence peaked in the late 1980s at five new infections/10 000 person-years. Under the assumption of 20–100% decline in HCV incidence after 1990, the cumulative number of incident cirrhosis and HCC cases from 2002–2030 was projected to be lower by 9.6–48.2% and 5.9–29.5%, respectively, than that estimated under the assumption of no decline. However, the prevalent cirrhotic/HCC cases and HCV-related deaths are predicted to decline in the next 30 years only under the assumption of complete elimination of new HCV infections after 1990. Despite the progress in the reduction of HCV transmission, primary prevention does not seem adequate to reverse the rise in the incidence of cirrhosis and HCC.

Summary. A randomized trial was conducted to assess the efficacy of interferon-alpha (IFN) daily in combination with ribavirin in 301 naive patients with chronic hepatitis C (CHC). Patients were randomized to receive ribavirin 1.2 g daily (QD) for 48 weeks with either IFN 5 MU (thrice weekly) TIW for 8 weeks followed by IFN 3 MU TIW for 40 weeks (IFN TIW, n = 154) or IFN 5 MU QD for 8 weeks followed by IFN 3 MU QD for 16 weeks followed by IFN 3 MU TIW for 24 weeks (IFN QD, n = 147). Treatment discontinuation rates, because of adverse events, were similar in the two arms (14.9% in IFN TIW and 14.3% in IFN QD, P = 0.87). The proportion of patients with sustained virological response (SVR) was 27.9% for patients treated TIW and 38.8% for those treated QD (P = 0.046). According to logistic regression analysis, patients in the IFN QD arm had 1.7 times higher probability of achieving SVR, than those receiving IFN TIW (P = 0.038). Low baseline viral load (P = 0.017) and genotype non-1 (P = 0.036) were associated with higher SVR rates. Combination of IFN/ribavirin for 48 weeks is more effective when IFN is administered daily for the first 24 weeks in naive patients with CHC.

Fifty-seven patients with chronic hepatitis B, hepatitis B virus (HBV) e antigen (HBeAg) and HBV DNA positivity, and aminotransferase elevation despite a previous course of any type of adequate interferon alfa (IFN-α) therapy were included in a multicenter prospective randomized controlled trial. The objective of the study was to compare a second course of IFN-α therapy (9 million units [MU] of IFN-α-2a, Roferon-A, thrice weekly for 6 months) versus no therapy in terms of loss of HBV DNA and HBeAg. At the end of the study, a sustained clearance of HBV DNA and HBeAg was observed in 9 of the 27 (33.3%) patients who had received retreatment with IFN-α compared with 3/30 (10%) patients who spontaneously cleared these markers in the untreated control group (χ2 = 4.66, P = .031; odds ratio: 4.5, 95%; confidence interval: 1.1-18.9). None of the responders lost HBsAg. Patients retreated with IFN-α were more likely to have biochemical remission in association with HBV clearance (5/27, 18.5%) compared with untreated patients (1/30, 3.3%; Fisher's exact test P = .09). Histological improvement in the liver necroinflammatory activity was observed among sustained responders to IFN-α retreatment, consisting of regression of the portal and periportal inflammation and of the piecemeal necrosis; there was no change in the degree of liver fibrosis. Side effects were similar to those previously reported during IFN-α treatment; these were mild and reversible on IFN-α discontinuation. None of the baseline features were associated with response by Cox's regression analysis. In summary, viremic patients with chronic HBeAg-positive hepatitis may experience disease remission following retreatment with IFN-α. Thus, retreatment with IFN-α may be considered a therapeutic option

Genetic studies have identified a number of loci demonstrating linkage to type 1 diabetes. One of the largest single contributors to genetic susceptibility, after the major histocompatability complex, is the IDDM2 locus, which maps to a nontranscribed variable number of tandem repeats (VNTR) minisatellite upstream of the insulin (INS) and insulin-like growth factor 2 (IGF2) genes. In a progression from population to functional studies, recent reports have shown that VNTR susceptibility alleles (class I) have different transcriptional effects on INS than protective VNTR alleles (class III) in thymus and pancreas, two tissues important in the pathogenesis of the disease. Similar VNTR transcriptional effects on IGF2 have also been proposed as a mechanism by which the IDDM2 locus confers susceptibility in addition to, or instead of, effects on INS. We evaluated this hypothesis by comparing IGF2 expression levels from chromosomes with the protective class III alleles to those with class I alleles in tissues relevant to type 1 diabetes pathogenesis. In thymus, class III alleles were associated with an IGF2 mRNA level of 4.7 +/- 0.9 (mean +/- SE, arbitrary units, n = 12) compared with 4.7 +/- 1.3 for class I alleles (n = 17). The same absence of a significant difference was found in pancreas, where class III alleles were associated with a level of 28.4 +/- 4.2 (n = 7) and class I alleles with a level of 29.5 +/- 5.2 (n = 6). There was a significant correlation between fetal age and IGF2 in both tissues, but fetal ages were not different in the genotype groups compared. We therefore did not detect any significant difference in IGF2 mRNA levels associated with the protective class of VNTR alleles as compared with the predisposing class. This is evidence against the hypotheses that have suggested IGF2 is a mediator of IDDM2-encoded susceptibility and corroborates previous studies suggesting insulin is the gene involved.

Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) is due to autoimmune destruction of pancreatic beta-cells. Genetic susceptibility to IDDM is encoded by several loci, one of which (IDDM2) maps to a variable number of tandem repeats (VNTR) minisatellite, upstream of the insulin gene (INS). The short class I VNTR alleles (26-63 repeats) predispose to IDDM, while class III alleles (140-210 repeats) have a dominant protective effect. We have reported that, in human adult and fetal pancreas in vivo, class III alleles are associated with marginally lower INS mRNA levels than class I, suggesting transcriptional effects of the VNTR. These may be related to type 1 diabetes pathogenesis, as insulin is the only known beta-cell specific IDDM autoantigen. In search of a more plausible mechanism for the dominant effect of class III alleles, we analysed expression of insulin in human fetal thymus, a critical site for tolerance induction to self proteins. Insulin was detected in all thymus tissues examined and class III VNTR alleles were associated with 2- to 3-fold higher INS mRNA levels than class I. We therefore propose higher levels of thymic INS expression, facilitating immune tolerance induction, as a mechanism for the dominant protective effect of class III alleles.

Nocturnal reflux has been associated with severe complications of gastro-oesophageal reflux disease and a poorer quality of life. Hiatal hernia predisposes to increased oesophageal acid exposure, but the effect on night reflux symptoms has never been investigated. The aim of the study was to investigate if hiatal hernia is associated with more frequent and severe night reflux symptoms.A total of 215 consecutive patients (110 male, mean age 52.6 ± 14.7 years) answered a detailed questionnaire on frequency and severity of specific day and night reflux symptoms. Subsequently, all patients underwent upper endoscopy and were categorized in two groups based on the endoscopic presence of hiatal hernia.Patients with hiatal hernia were more likely to have nocturnal symptoms compared to those without hiatal hernia (78.6 vs. 51.8%, p = 0.0001); 59.2% of patients with hiatal hernia reported heartburn and 60.2% regurgitation compared to 43.8 and 39.3% of those without hiatal hernia, respectively (p = 0.033 and p = 0.003). The proportions of patients with day heartburn or regurgitation were not significantly different between the two groups. Night heartburn and regurgitation were graded as significantly more severe by patients with hiatal hernia (4.9 ± 4.2 vs. 3.2 ± 3.7, p = 0.002, and 3.8 ± 4.2 vs. 2.2 ± 3.5, p = 0.001, respectively). Patients with hiatal hernia had more frequent weekly night heartburn and regurgitation compared to those without hiatal hernia (p = 0.004 and p = 0.008, respectively).More patients with hiatal hernia reported nocturnal reflux symptoms compared to those without hiatal hernia. Furthermore, nocturnal reflux symptoms were significantly more frequent and graded as significantly more severe in patients with presence of hiatal hernia rather than in those without hiatal hernia.

The cardiac dysfunction presented in cirrhotic patients is already known as cirrhotic cardiomyopathy. The pathogenesis of this entity is not fully understood.The aim of this study was to evaluate the frequency and characteristics of cirrhotic cardiomyopathy and to investigate the possible role of bacterial endotoxemia on its aggravation.Forty-five cirrhotics were studied by a tissue Doppler imaging echocardiography at rest and after stress. The diagnosis of left ventricular diastolic dysfunction was based on the latest guidelines of the American Society of Echocardiography, whereas its severity was defined by the E/e'av ratio. Endotoxemia was estimated by measuring the serum levels of lipopolysaccharide-binding protein (LBP) and cytokines.None of the patients had systolic dysfunction, but 17/45 (37.8 %) had a diastolic one. Patients with grade II diastolic dysfunction had significantly longer QTc (p = 0.049), larger left atrium volume (p = 0.013), higher Brain Natriuretic Peptide levels (p = 0.007) and higher LBP levels (p = 0.02), compared to those with normal cardiac function, without differences in the systemic hemodynamics and the cytokines' levels. Moreover, the severity of diastolic dysfunction as reflected by the E/e'av. was significantly correlated with the LBP levels (p = 0.002). On the multivariate analysis, the LBP was independently associated with the presence of diastolic dysfunction.Cirrhosis is commonly complicated by cardiac dysfunction. Patients with severe cirrhotic cardiomyopathy have higher LBP levels, which are significantly correlated with the degree of diastolic dysfunction. Our findings support a potential role of bacterial endotoxemia on the aggravation of cardiomyopathy in cirrhotic patients.

IntroductionWe evaluated the effect of Helicobacter pylori (HP) eradication on p53, cyclin D1 expression, and cell proliferation in gastric mucosa.Materials and MethodsWe assessed p53, cyclin D1, and ki67 immunoexpression in gastric mucosa from 31 HP chronic gastritis patients and 12 controls. Reassessment was performed 6 months after successful HP eradication.ResultsSuccessful eradication resulted in significant decrease of p53 (1.53 ± 0.16 vs 0.83 ± 0.19, P = 0.01) and ki67 (9.84 ± 0.96 vs 4.77 ± 0.27, P < 0.001) staining in the antrum. Similarly, p53 immunoreactivity significantly decreased in the corpus (1.27 ± 0.20 vs 0.46 ± 0.15, P = 0.02), while there was a trend for decreased corpus cyclin D1 and ki67 expression (0.17 ± 0.07 vs 0.0, P = 0.08 and 8.71 ± 1.24 vs 5.85 ± 0.54, P = 0.09, respectively). Importantly, after successful HP eradication, the immunoreactivity of the studied parameters was similar to that of controls.ConclusionSuccessful HP infection eradication restores p53, cyclin D1, and ki67 immunoreactivity in the gastric mucosa to the level of controls.

The contact of the gastric refluxate with the lower esophagus results in an inflammatory-mediated tissue damage. The role of inflammation both in the development and in the advance of Barrett's esophagus (BE) has not been elucidated. The aim of this study was to assess the inflammatory infiltration in metaplastic Barrett's epithelium and to explore the association of microscopic inflammation to healed esophagitis and Barrett's length.Inflammatory infiltration was qualitatively evaluated in well-characterized Barrett's specimens. Esophagitis was healed prior to histological sampling. Univariate comparative analysis was performed based on BE length.Ninety-eight patients (78 male, mean age 58.3 ± 13.3 yrs) were retrospectively studied. Thirty-three cases with long segment BE (LSBE) (33.7%) were spotted. Inflammatory infiltration was mild, moderate, and severe in 35 (35.7%), 54 (55.1%), and 9 (9.1%) specimens, respectively. The samples with moderate/severe inflammatory infiltration were obtained from patients who had more frequently been diagnosed with esophagitis (p = 0.025). Hiatal hernia (p = 0.001), esophagitis (p = 0.019), and previous use of anti-secretory drugs (p = 0.005) were more common in LSBE.Inflammatory infiltration of Barrett's epithelium was largely moderate despite preceding healing of erosions with PPIs. Previous diagnosis of esophagitis correlated to the degree of inflammation. No association of inflammation to Barrett's length was established.

To evaluate the risk and predictors of hepatocellular carcinoma (HCC) in HBeAg-negative chronic hepatitis B patients of the large HEPNET.Greece cohort study who received long-term oral antivirals starting with lamivudine monotherapy.Retrospective analysis of HCC incidence in HBeAg-negative chronic hepatitis B patients from a retrospective-prospective cohort who were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy for ≥12 months.A nationwide network of liver centres.818 patients were included: 517 with chronic hepatitis B only; 160 with compensated cirrhosis; 56 with decompensated cirrhosis; 85 with unclassified disease severity.All patients were treated with nucleos(t)ide analogue(s) starting with lamivudine monotherapy.Development of HCC.During a median follow-up of 4.7 years, HCC developed in 49 (6.0%) patients. The 5-year cumulative incidence of HCC was higher in patients with cirrhosis than in those with chronic hepatitis B only (11.5% vs 3.2%, respectively; p0.001). HCC developed in 0.7%, 6.7% and 11.7% of patients50, 50-60 and60 years old, respectively (p0.001). Virological on-therapy remission did not significantly affect the incidence of HCC in all patients or those with cirrhosis, but it showed a trend for lower HCC incidence in patients with chronic hepatitis B only (p=0.076). In multivariate analysis, age, gender and cirrhosis were independently associated with HCC risk regardless of virological remission.Long-term therapy with nucleos(t)ide analogue(s) starting with lamivudine monotherapy does not eliminate HCC risk in HBeAg-negative chronic hepatitis B. The risk of HCC is particularly high in patients with cirrhosis, who should remain under HCC surveillance even during effective therapy. Older age and male gender remain independent risk factors for HCC, while virological on-therapy remission does not seem to significantly reduce the overall incidence of HCC.

Blood pressure (BP)-related diseases, specifically, stroke, coronary heart disease, heart failure, and kidney disease, are leading causes of morbidity and mortality in the United States and throughout the world. In the United States, coronary heart disease and stroke are the leading causes of mortality, whereas heart failure is the leading cause of hospitalizations.1 Concurrently, the prevalence of chronic kidney disease remains high and is escalating.2,3 The direct and indirect costs of these conditions are staggering, over $400 billion just for cardiovascular disease (CVD) in 2009.1,4 The human consequences are likewise enormous. The relation between BP and adverse health outcomes is direct and progressive with no evidence of a threshold, that is, the risk of CVD, stroke, and end-stage kidney disease increases progressively throughout the range of usual BP starting at a level of ≈115/75 mm Hg.5,–,7 Overall, elevated BP is the second leading modifiable cause of death, accounting for an estimated 395 000 preventable deaths in the United States in 2005.8 Worldwide, elevated BP accounts for 54% of stroke and 47% of coronary heart disease events; importantly, about half of these events occur in persons without hypertension.9 The 2020 goal of the American Heart Association (AHA) is to improve the cardiovascular heath of all Americans by 20% while continuing to reduce deaths from CVD and stroke by 20%.4 Two of the key metrics for ideal cardiovascular health are a BP of

To determine the associations between leptin and ghrelin concentrations and sustained virological response (SVR) in chronic hepatitis C patients with steatosis.We retrospectively assessed 56 patients infected with hepatitis C virus (HCV) genotype-1 and 40 with HCV genotype-3. Patients with decompensated cirrhosis, and those with other causes of chronic liver disease, were excluded. Serum HCV-RNA concentrations were measured before the initiation of treatment; at weeks 12 (for genotype 1 patients), 24 and 48 during treatment; and 24 wk after the end of treatment. Genotype was determined using INNO-LIPA HCV assays, and serum leptin and ghrelin concentrations were measured using enzyme-linked immunosorbent assay. Biopsy specimens were scored according to the Ishak system and steatosis was graded as mild, moderate, or severe, according to the Brunt classification.Overall, SVR was positively related to the presence of genotype-3, to biopsy-determined lower histological stage of liver disease, and lower grade of steatosis. Patients ≥ 40 years old tended to be less responsive to therapy. In genotype-1 infected patients, SVR was associated with a lower grade of liver steatosis, milder fibrosis, and an absence of insulin resistance. Genotype-1 infected patients who did not achieve SVR had significantly higher leptin concentrations at baseline, with significant increases as the severity of steatosis worsened, whereas those who achieved SVR had higher ghrelin concentrations. In genotype-3 infected patients, SVR was associated only with fibrosis stage and lower homeostasis model assessment insulin resistance at baseline, but not with the degree of steatosis or leptin concentrations. Genotype-3 infected patients who achieved SVR showed significant decreases in ghrelin concentration at end of treatment. Baseline ghrelin concentrations were elevated in responders of both genotypes who had moderate and severe steatosis.Increased serum leptin before treatment may predict non-SVR, especially in HCV genotype-1 infected patients, whereas increased ghrelin may predict SVR in genotype-1.

Interferon (IFN-alpha)-based regimens have been used with varying success in the treatment of chronic hepatitis C (CHC) for over two decades. The effect of such treatments on the natural course of CHC has been evaluated in small clinical trials with conflicting results.To investigate the natural course of IFNalpha-based-treated and untreated patients with CHC by analysing data from the HEPNET.GREECE study.We retrospectively analysed 1738 patients from 25 Greek Centres (median age 40.1; males 57.6%; cirrhosis 9.2%), 734 untreated and 993 treated with IFNalpha-based regimens [44.7% sustained viral response (SVR)], followed-up for median 25.2 and 46.8 months, respectively.During follow-up, 48 patients developed liver decompensation and 24 HCC. Older age was significantly related to disease progression (HR = 2.6 per 10 years of increasing age). Stratified by baseline cirrhosis, Cox analysis showed that patients with SVR, but not without SVR, had significantly lower hazard for events compared with nontreated patients (HR = 0.16; P0.001), whereas the detrimental effect of older age remained highly significant. Separate group analysis demonstrated that in cirrhosis, the beneficial effect of treatment was evident even without SVR. Treatment effect interacted significantly with age, indicating that older patients, mainly noncirrhotic, gained the most benefit.IFNalpha-based treatment does alter the natural course of CHC. A protective effect is mostly present in patients with SVR, but older patients, at higher risk of events, gain the greatest benefit. In established cirrhosis, treatment carries a protective effect even among those without SVR.

Adiponectin possesses anti-inflammatory, insulin-sensitizing and anti-atherosclerotic properties. The aim of this study was to assess the levels of serum adiponectin in patients with chronic viral hepatitis C and B and correlate them with parameters exploring insulin resistance and indices of chronic liver disease. Seventy-two patients with chronic hepatitis C virus (HCV) infection and 73 patients with chronic hepatitis B virus (HBV) infection, matched for age and sex, were studied. All individuals were examined for serum concentrations of adiponectin, insulin, C-peptide and homeostasis model assessment for insulin resistance (HOMA-IR). Viral parameters and liver histology were also evaluated. Serum adiponectin levels were significantly higher in HCV compared with HBV-infected patients. Correlation analysis in the whole group demonstrated that serum adiponectin was positively correlated with aspartate aminotransferase, alkaline phosphatase, globulins, high-density lipoprotein cholesterol and staging score, while it was negatively correlated with body mass index, insulin, C-peptide and HOMA-IR. Logistic regression analysis identified type of infection (HCV vs HBV), alcohol consumption more than 25 g daily, serum total globulin and low C-peptide as significant predictive variables associated with high adiponectin levels. Higher levels of serum adiponectin in HCV compared with HBV patients could have a role in the slower disease progression of chronic HCV infection. In addition, alcohol intake more than 25 g daily seems to be a significant predictor for hyperadiponectinaemia in patients with chronic viral hepatitis C or B. Finally, in this study, a clear positive association between adiponectin and hepatic necroinflammation or staging score was not found.

Purpose The autoregulatory control of retrobulbar blood flow in response to postural challenge was investigated in normal-tension glaucoma (NTG) patients in comparison with primary open-angle glaucoma (POAG) patients and healthy volunteers. Design Prospective cohort study. Participants and Controls Twenty POAG patients, 20 NTG patients, and 20 control subjects. Methods Peak systolic velocity (PSV), end diastolic velocity (EDV), and resistivity index (RI) in the short posterior ciliary artery (SPCA), central retinal artery (CRA) and ophthalmic artery (OA) were recorded after a change from sitting upright to a supine body position using color Doppler imaging. Main Outcome Measures Peak systolic velocity, EDV, and RI. Results Ten minutes after postural change to a supine position, blood flow velocities in the SPCA remained unchanged in controls, whereas a significant increase of PSV and EDV was found in both glaucoma groups. The RI in the SPCA was significantly lowered in the NTG group. Recordings for the OA and CRA showed a significant increase in EDV and significant decrease in RI in all 3 groups; a significant increase in PSV in the CRA was detected only in the NTG group. Conclusions The unaltered flow velocities in the SPCA of healthy controls may indicate tight autoregulatory control, whereas the flow velocities in the CRA and OA appeared to follow alterations in hydrostatic pressure. In contrast, NTG and POAG patients demonstrated an insufficient compensatory response to postural change, leading to accelerated flow in the SPCA. This compromised autoregulatory control could represent another contributing factor in the pathogenesis of glaucoma.

SUMMARY. A randomized trial was conducted to assess the efficacy of daily (QD) or thrice weekly (TIW) administration of interferon-a (IFN) in high doses in combination with ribavirin (1.0‐1.2 g/day) in patients with chronic hepatitis C (CHC) who were nonresponders to previous IFN monotherapy. Interferon was administered as 10 MU IFN (QD or TIW) for 4 weeks, followed by 5 MU IFN (QD or TIW) for 20 weeks, and then by 3 MU IFN (QD or TIW) for 24 weeks. Sustained virological response (SVR) was evaluated in 142 patients who received at least one dose of medication. Onefourth of the patients achieved SVR, 26% of those treated with IFN QD and 25% of those treated with IFN TIW (P ¼ 0.85). For genotype 1 patients, SVR rates were 32.4 and 15.8% for IFN QD and IFN TIW, respectively, whereas for genotype non-1 patients the corresponding SVR rates were 20.6 and 36.4%, respectively (test of homogeneity: P ¼ 0.031). This finding was further confirmed by multivariate logistic regression analysis where a statistically significant interaction (P ¼ 0.012) was found between treatment and HCV genotype indicating that the IFN QD regimen was superior to IFN TIW among genotype 1 patients whereas, among genotype non-1 patients, the two treatments were similar (odds ratio of SVR in IFN QD vs IFN TIW: 3.33 among genotype 1 patients, 95% CI: 1.00‐ 11.14). In conclusion, re-treatment of patients not responding to previous IFN monotherapy with a combination of high daily dose of IFN with ribavirin may be beneficial for genotype 1 infected patients.

In an attempt to investigate the significance of lipid peroxidation in the pathogenesis of gastritis associated with or without Helicobacter pylori infection, malonodialdehyde (MDA) levels were measured by the thiobarbiturate assay in the gastric juice of 101 patients undergoing upper GI endoscopy and correlated with histopathological findings. Elevated MDA levels were found in all patients with gastritis compared with controls. MDA levels were significantly correlated with the extent of the mucosal inflammation and with disease activity in patients with reactive gastritis. In patients with H. pylori associated gastritis MDA levels were not correlated with disease activity but rather with the degree of atrophy. In this case, MDA levels were equal or even less than in patients with reactive gastritis. MDA levels were not affected by the history of consumption of PPIs, of H(2)-blockers or of NSAIDs over the last month before the endoscopy. It is concluded that lipid peroxidation is a mechanism involved in the pathogenesis of gastritis associated or not to H. pylori infection.

Background To evaluate changes in H pylori infection prevalence in Greece during a ten-year period, and to examine its antigenic profile. Methods Three groups of patients were studied. Group O-87: Banked serum samples of 200 consecutive adult outpatients, from the Hepato-Gastroenterology clinic of a teaching hospital at Athens, collected in 1987. Group O-97: Serum samples of 201 similarly selected outpatients from the same Unit, collected in 1997. Group BD-97: Serum samples of 120 consecutive blood donors from the same hospital, collected in 1997. H pylori IgG antibody seroprevalence was studied by a quantitative ELISA. Antigenic profile was studied by western-blot IgG assay, in 62 IgG positive patients of O-97 and BD-97. Results were analyzed by conventional statistics and multivariate regression analysis. Results The H pylori seroprevalence increased with age in the three tested groups. In O-97, seroprevalence did not differ from that, in BD-97. On the contrary, there was a significant decrease in seropositivity between O-87 and O-97 (59.5% vs 49.2%, p = 0.039). Multiple regression analysis showed that age over 35 years (OR:3.45, 95% CI:1.59–7.49, p = 0.002) and year of patients' selection – that is 1987 or 1997 – (OR:1.73, 95% CI:1.14–2.65 for 1987, p = 0.010), were independent risk factors of H pylori infection. The seroprevalence of CagA+ and VacA+ strains was 77.4% and 58.5%, respectively, and type I(CagA+/VacA+) strains were significantly more common than type II(CagA-/VacA-) strains (59.7% vs 22.6%, p < 0.001). Conclusions During a ten-year period, we found a significant decrease of H pylori infection in Greece and our data support the birth cohort phenomenon as an explanation for the age-dependent increase of H pylori infection. The prevalence of CagA and/or VacA positive strains is relatively high, in a country with low incidence of gastric cancer.

Type 1 diabetes results from autoimmune destruction of the insulin-producing pancreatic β cells. The insulin gene (INS) is also expressed in human thymus, an ectopic expression site likely involved in immune tolerance. The IDDM2 diabetes susceptibility locus maps to a minisatellite composed of a variable number of tandem repeats situated 0.5 kb upstream of INS. Chromosomes carrying the protective long INS variable number of tandem repeats alleles (class III) produce higher levels of thymic INS mRNA than those with the predisposing, short class I alleles. However, complete silencing of thymic INS transcripts from the class III chromosome was found in a small proportion of heterozygous human thymus samples. We hypothesized that the specific class III alleles found on these chromosomes silence rather than enhance thymic insulin expression. To test the prediction that these alleles are predisposing, we developed a DNA fingerprinting method for detecting two putative “silencing” alleles found in two thymus samples (S1, S2). In a set of 287 diabetic children and their parents we found 13 alleles matching the fingerprint of the S1 or S2 alleles. Of 18 possible transmissions, 12 of the S1–S2 alleles were transmitted to the diabetic offspring, a frequency of 0.67, significantly higher than the 0.38 seen in the remaining 142 class III alleles; P = 0.025. This confirms our prediction and represents an additional level of correlation between thymic insulin and diabetes susceptibility, which supports a thymic enhancer effect of the INS variable number of tandem repeats as the mechanism of IDDM2 and refines the contribution of IDDM2 genotyping to diabetes risk assessment.

To evaluate the clinicopathological features of chronic hepatitis C, 170 liver biopsies were studied and histological grade and stage (degree of fibrosis) of hepatitis were correlated with epidemiological features and characteristic histological findings.Normal liver was found in 3 (1.8%), minimal chronic hepatitis in 40 (23.5%), mild chronic hepatitis in 104 (61.2%) and moderate chronic hepatitis in 23 (13.5%) cases. Cirrhosis was observed in 24 (14.1%) patients and was more frequently encountered among patients more than 40 years old (34.4% vs 2.8%, p10(-6) and rarely among intravenous drug users in comparison with post-transfusion and sporadic cases (3% vs 25% and 20% respectively, p0.005). Minimal chronic hepatitis was more frequently observed among patients 40 years old or younger (30.3% vs 11.5%, p0.01)), while moderate chronic hepatitis was significantly more common in older age groups (24.6% vs 7.3%, p0.005). Multiple regression analysis revealed that only age was statistically related to histological grade and stage of hepatitis (p10(-5). The frequency of the histological features more likely seen in chronic hepatitis C, including steatosis (57.6%), lymphoid follicles and/or aggregates (F/A) (47.1%) and bile duct lesions (22.9%), increased with hepatitis grade and the latter two features were more often encountered in moderate chronic hepatitis (p0.005); in addition, both lesions statistically coexisted (p0.005). No correlation was found between histological findings and possible source of infection.More than half of the chronic hepatitis C patients presented mild histological lesions. Age was proven to be the only independent epidemiological factor related to histological grade and stage of hepatitis. Lymphoid F/A and bile duct damage are important diagnostic findings associated with hepatitis activity.

Introduction The aim of the study is to define whether the measurement of c-Kit protein serum levels can be used as a biomarker of response to treatment or disease progression in patients with GIST. Methods In a period of one year, we monitored 9 patients with GIST (6 men, 3 women), age from 46 to 77 years old (mean age 61). They had all been under endoscopic, imaging and histological follow up. Serum detection of c-Kit protein was determined by flow cytometry, performed with MILLIPLEX MAP Total c-Kit MAPmates pair, in conjunction with the MILLIPLEX MAP Cell Signaling Buffer and Detection Kit (Merck Millipore, USA), to detect the presence of total c-kit in cell lysates, using the Luminex IS100 System (Luminex corp, USA). Cut-off levels were determined according to the manufacturer's instructions. Results First of all, it is important to notice that four patients (3 men, 1 woman), had negative value of serum c-Kit three months after surgery, that turned into positive at the time of tumor relapse. A reduction in the titre of c-Kit protein in serum (from positive to negative values), was recorded in three patients (2 men, 1 woman), three months after surgery. One of them, presented with negative value of c-Kit before surgery that turned into positive when tumor relapsed. Moreover, one patient with GIST had a negative value of c-Kit protein in serum, both before and after surgery. Finally, another patient was recorded with positive c-kit in serum before surgery, that turned into negative three months after, and was rendered again positive at the time of tumor relapse. Serum c-Kit levels turned into negative when imatinib mesylate was administrated and finally became positive when relapse was clinically suspected. Conclusion Similarly to epithelial tumor markers, measurement of serum c-Kit levels in patients with GIST, seems to be a reliable and easy to perform serum biomarker for the clinical monitoring of these patients. Nevertheless, further well-organized, large studies and clinical trials are required in order to establish its use in everyday clinical practice.

Introduction The diagnostic approaches for GIST have rapidly evolved in the last few years. Nowadays, a serum biomarker for their diagnosis is not available, even though a biomarker which would possess both high sensitivity and specificity would be of a great value and obvious necessity. The aim of this study was to investigate whether the measurement of c-Kit protein serum levels consists a reliable diagnostic biomarker in patients with GIST. Methods Serum detection of c-Kit protein was determined by flow cytometry, performed with MILLIPLEX MAP Total c-Kit MAP mates pair in conjunction with the MILLIPLEX MAP Cell Signaling Buffer and Detection Kit (Merck Millipore co.,USA), to detect the presence of total c-Kit in cell lysates using the Luminex IS100 System (Luminex corp.). Cut-off levels for positive and negative values were calculated according to the manufacturer's instructions. Results The serum levels of c-Kit protein were assessed in 22 patients with histologically confirmed GIST (13 men, 9 women, age from 41 to 80 years old, mean age 61) and 22 healthy controls. GIST were located as follow: 15 in stomach, 3 in duodenum, 3 in jejunum and one in the ileum. From all 22 patients with GIST, 20 had positive values of c-Kit protein in serum, whereas negative results were recorded in the remaining 2. In the control group of 22 patients, only negative values were recorded. Based on these results, sensitivity and specificity was 91% and 95%, respectively, whereas positive (PPV) and negative predictive value (NPV) of the method were 95% and 92%, respectively. Conclusion Similarly to the serum markers of epithelial tumors, c-Kit protein could be a reliable and easy to perform serum biomarker with high specificity and sensitivity in the diagnosis of GIST.

G A A b st ra ct s for HE-related, and all-cause hospitalizations were 0.21 and 0.45 with long term rifaximin use; both rates were significantly lower (p

Introduction The risk of acute liver failure (ALF) related to NSAIDs is still discussed and the European Medicines Agency requested a study investigating this. University Bordeaux Segalen conducted the study independently. Aim To estimate the incidence rates of ALF leading to registration for liver transplantation (LT) in patients exposed to NSAIDs. Method Multinational, multicentre, case-population study performed in France, Greece, Ireland, Italy, the Netherlands, Portugal, and the UK retrospectively evaluating a 3-year period (2005–2007) in adults. Data of ALF cases were sought through liver transplant registries and hospital records. Demographic and clinical data were collected for all ALF cases and drug use information was collected for the exposure window of 30 days prior to index date (ID, initial symptoms of liver disease). For ALF cases exposed to NSAIDs (ATC code M01A), rate per million treatment-years (tt-yrs) was calculated using sales data from IMS. Poisson CIs (95% CI) were estimated. Results In the seven participating countries, 62 LT centres were identified and contacted, five were excluded (four paediatric, one oncology), and 50 actively contributed data before database lock. Among the 8824 patients identified from LT lists for the period 2005–2007, 500 were cases of ALF: 197 with identified clinical cause, 21 with incomplete or unavailable medical files, and 241 drug-exposed without identified clinical cause. Among the latter, 34 were exposed to at least one NSAID, 123 exposed to other drugs, and 84 were acute drug intoxications. Mean age of NSAID-exposed ALF cases was 43.8 years, 24 were female. Event rates per million treatment-years were 4.4 (95% CI 3.0 to 6.1) for all NSAIDs pooled, 5.6 (2.4 to 11.1) for nimesulide (8 cases), 5.8 (2.8 to 10.6) for ibuprofen (10 cases), 4.5 (1.5 to 10.4) for diclofenac (5 cases), and 4.7 (1.0 to 13.6) for ketoprofen (3 cases). 71 of the 157 non-intoxication cases had been exposed to paracetamol (9.8 per million treatment-years, 95% CI 7.7 to 12.4), and 83 of the 84 intoxications. Conclusion In seven countries over 3 years only 34 NSAID-exposed ALF cases leading to registration for LT were identified with no differences in incidence rates per million tt-yrs among the most used NSAIDs. Non-overdose paracetamol-associated liver failure was twice more common.

AIM: To investigate the significance of ileocolonoscopy with histology in the evaluation of post-transplantation persistent diarrhea (PD). METHODS: We retrospectively reviewed all records of renal transplant patients with PD, over a 3-year period. All patients were referred for ileocolonoscopy with biopsy, following a negative initial diagnostic work up. Clinical and epidemiological data were compared between cases with infectious or drug-induced diarrhea. RESULTS: We identified 30 episodes of PD in 23 renal transplant patients (1-3 cases per patient). There were 16 male patients and the mean age at the time of PD was 51.4 years. The average time from transplantation to a PD episode was 62.3 ± 53.2 mo (range 1-199 mo). Ileocolonoscopy detected mucosal abnormalities in 19 cases, whereas the intestinal mucosa appeared normal in 11 cases. Histological examination achieved a specific diagnosis in 19/30 cases (63.3%). In nine out of 11 cases (82%) with normal endoscopic appearance of the mucosa, histological examination of blinded biopsies provided a specific diagnosis. The etiology of PD was infectious in 11 cases (36.6%), drug-related in 10 (33.3%), of other causes in three (10%), and of unknown origin in six cases (20%). Infectious diarrhea occurred in significantly longer intervals from transplantation compared to drug-related PD (85.5 ± 47.6 mo vs 40.5 ± 44.8 mo, P < 0.05). Accordingly, PD due to drug-toxicity was rarely seen after the first year post-transplantation. Clinical improvement followed therapeutic intervention in 90% of cases. Modification of immunosuppressive regimen was avoided in 57% of patients. CONCLUSION: Early ileocolonoscopy with biopsies from both affected and normal mucosa is an important adjunctive tool for the etiological diagnosis of PD in renal transplant patients.

1. The biliary maximum secretory rate (SRmax.) of glycoursodeoxycholate in the bile fistula anaesthetized rat was about five times that of unconjugated ursodeoxycholate. 2. Likewise, the biliary SRmax. of tauro-7-ketolithocholate was more than three times that of unconjugated 7-ketolithocholate. The SRmax. of 7-ketolithocholate infused with taurine (to avoid depletion of the taurine pool) was still significantly lower than that of exogenous tauro-7-ketolithocholate. 3. These data support the hypothesis that, for bile acids that are poorly water soluble, the maximal biliary secretion rate is dependent on conjugating capacity, which is the limiting step in the overall transport from plasma into bile.

It has been reported that biliary secretion is the limiting step in the hepatic transport of bile acids by the hepatocyte from plasma to canalicular bile. The aim of the present study was to examine the role of conjugation in the transport process using ursodeoxycholate (UDCA) and tauroursodeoxycholate (TUDCA), two bile acid with low liver toxicity. Rats were given constant intravenous infusions of cholate (C), taurocholate (TC), UDCA, or TUDCA at progressively increasing rates. The biliary maximum secretory rate (SRm), in nmol . min-1 . 100 g body wt-1, for TC (1,835.2 +/- 135.5, mean +/- SE) was not significantly different from that of C (1,749.4 +/- 85.6). In contrast, the SRm for TUDCA (5,909.4 +/- 304.4) was approximately sevenfold that of UDCA (802.1 +/- 134.2), the difference being statistically significant (P less than 0.001). The SRm of UDCA in the presence of a taurine infusion (1,367 +/- 84.4) was higher than that of UDCA infused alone but still much lower than that of TUDCA. Phenobarbital sodium pretreatment did not increase SRm of UDCA alone or in the presence of a taurine infusion. These results suggest that in the rat 1) conjugation is the rate-limiting step in the overall transport of UDCA (and perhaps other bile acids) by the liver, and 2) the conjugation process itself is limiting, rather than the availability of taurine. They support the view that, although not mandatory for secretion into bile, conjugation of bile acids confers a biological advantage, possibly by increasing the solubility of the bile acid.