Murat Törüner

Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat

BACKGROUND & AIMS A reduction in nitric oxide (NO) has been implicated as a cause of intrahepatic vasoconstriction in cirrhosis, but the regulatory mechanisms remain undefined. The aim of this study was to examine a contributory role for caveolin-1, a putative negative regulator of endothelial NO synthase, in mediating deficient intrahepatic NO production in the intact cirrhotic liver. METHODS Cirrhosis was induced by carbon tetrachloride inhalation. Flow regulation of NO production and perfusion pressure was examined in the perfused rat liver. Protein expression of endothelial NO synthase (eNOS), caveolin, and calmodulin was examined by Western blotting and immunohistochemistry. NOS activity and NO production were assessed by citrulline generation and chemiluminescence, respectively. Protein-protein interactions were examined using whole tissue protein immunoprecipitation. RESULTS In response to incremental increases in flow, cirrhotic animals produced significantly less NO(x) than control animals. NOS activity was significantly reduced in liver tissue from cirrhotic animals compared with control animals in the presence of similar eNOS protein levels. Deficient eNOS activity was associated with a severalfold increase in binding of eNOS with caveolin. Protein levels of caveolin-1 were markedly increased in the cirrhotic liver. CONCLUSIONS These studies provide evidence that enhanced expression and interaction of caveolin with eNOS contribute to impaired NO production, reduced NOS activity, and vasoconstriction in the intact cirrhotic liver.

Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies.

Summary.  Although hepatitis B virus (HBV) reactivation in HBV carriers undergoing immunosuppressive therapy is clearly documented, the role of antiviral prophylaxis in such individuals is still controversial. The aim of this study was to determine the efficacy of lamivudine prophylaxis in HBV carriers with haemato/oncological malignancies, who receive chemotherapy. Eighteen HBV carriers with malignancy, who were candidates for chemotherapy, were enrolled. Eight subjects (three with leukaemia, four with lymphoma and one with multiple myeloma) were enrolled for prophylactic lamivudine therapy. The remaining 10 patients (six with leukaemia, three with lymphoma and one with breast cancer) were not treated with lamivudine and were used as a control. Lamivudine was administered beginning on the same day as the chemotherapy and was maintained for a year after chemotherapy was discontinued. No HBV‐related mortality was observed in either group. In the lamivudine‐treated group, none of the subjects had clinical, biochemical or serological evidence of HBV reactivation during the time they were receiving chemotherapy and after their chemotherapy was discontinued. In contrast, five of the 10 HBV carriers not receiving lamivudine therapy experienced a reactivation of HBV infection. This reactivation of HBV was observed during the chemotherapy in four with one individual experiencing a HBV activation 12 months after chemotherapy was discontinued. No lamivudine‐related major adverse effects were observed. Hence prophylactic lamivudine treatment in HBV carriers with haemato/oncological malignancy receiving chemotherapy prevents chemotherapy‐induced HBV reactivation.

Colorectal cancer in inflammatory bowel disease: Results of the 3rd ECCO pathogenesis scientific workshop (I)

Epidemiological studies demonstrate an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). A detailed literature review was conducted on epidemiology, risk factors, pathophysiology, chemoprevention and outcomes of colorectal cancer (CRC) in IBD as part of the 3rd ECCO scientific pathogenesis workshop.

NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene polymorphisms in Turkish patients with inflammatory bowel disease

PurposeThe genetic susceptibility of people with certain NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene variants to inflammatory bowel disease is still under investigation. The aim of this study was to investigate polymorphisms in the NOD2/CARD15 (R702W, G908R, and 3020insC), NOD1/CARD4 (E266K, D372N), and ICAM-1 (G241R, K469E) genes, which are known to be associated with inflammation, in Turkish patients with inflammatory bowel disease and healthy control groups.MethodsThe genotypes of 70 patients with endoscopically and histopathologically diagnosed Crohns disease (38 men, 32 women; mean age, 38.8 ± 1.3), 120 patients with ulcerative colitis (67 men, 53 women; mean age, 41.7 ± 1.3) and 106 healthy control subjects (37 men, 69 women; mean age, 35.7 ± 1.4), who stated that they had never had any prior bowel disease history, were compared. A polymerase chain reaction-restriction fragment length polymorphism analysis was performed for two variants of the ICAM-1 gene, the three main variants of the NOD2/CARD15 gene, and the E266K variant of the NOD1/CARD4 gene, and DNA sequencing was used for the D372N polymorphism of the NOD1/CARD4 gene.ResultsIn this study, the three previously described Crohns disease-predisposing variants of the NOD2/CARD15 gene and the polymorphisms examined in the NOD1/CARD4 and ICAM-1 genes were not found to be associated with ulcerative colitis or Crohns disease.ConclusionsThese findings suggest that the polymorphisms observed in the NOD2/CARD15, NOD1/CARD4, and ICAM-1 genes are not genetic susceptibility factors for Crohns disease or ulcerative colitis in Turkey.

Barrett's esophagus: Prevalence and its relationship with dyspeptic symptoms

Background and Aim:  Barretts metaplasia is a premalign condition which plays a pivotal role in the development of esophageal adenocarcinoma. It is considered a complication of chronic gastroesophageal reflux disease. Although esophageal adenocarcinoma is an uncommon cancer, its incidence is rapidly increasing. The aims of the present study were to determine the prevalence of Barretts metaplasia in outpatients referred for gastroscopy for upper gastrointestinal symptoms, and to clarify the relationship between Barretts metaplasia and upper gastrointestinal symptoms.

NF-κB Signaling

Abstract:  The transcription factor, nuclear factor‐κB (NF‐κB), is a dominant regulator of the expression of hundreds of genes, many of which play important roles in the regulation of inflammation and programmed cell death (apoptosis). Since the discovery of NF‐κB in the mid 1980s, this transcription factor has been the subject of intense investigation. Excess or inappropriate activation of NF‐κB has been observed in human inflammatory bowel disease and in a host of other inflammatory diseases and type of cancer. Functional studies in animals have shed light on the role of NF‐κB in broader pathophysiological contexts. From such studies, it has become quite clear that NF‐κB plays unique and distinct functions in different cell types. Because of the importance of NF‐κB in signaling inflammation, and in inhibiting programmed cell death, many pharmaceutical companies are developing small‐molecule inhibitors of this pathway. In this article, we evaluate the relative pros and cons of blocking NF‐κB as a therapeutic approach for inflammatory bowel disease. On the basis of the results of studies in animals that have primarily used genetic approaches to inhibit NF‐κB activity, we suggest that there are certain niche indications for blocking NF‐κB in inflammatory bowel disease that offer particular promise.

Lamivudine vs lamivudine and interferon combination treatment of HBeAg(−) chronic hepatitis B

Summary.  To determine whether combination treatment of HBeAg(−) chronic hepatitis B is beneficial we studied 78 patients with HBeAg(−), HBV DNA‐positive chronic hepatitis B who were randomized to lamivudine, 100 mg, qd, for 12 months or lamivudine–interferon (9 MU, t.i.w.) in combination. In the combination arm, 2 months of lamivudine treatment preceded 10 months of combination treatment. Biochemical, virologic and histologic responses were assessed at the end of treatment, after six and a median 27 months of drug‐free follow‐up (short‐ and long‐term follow‐up, respectively). Virologic response was defined as undetectable HBV DNA with a hybridization assay and biochemical response as normal alanine aminotransferase (ALT). Change in HBV DNA was also assessed by real‐time polymerase chain reaction (PCR). Presence of YMDD mutants at the end of treatment was investigated with a line probe assay. Both treatment regimes led to a median 2 log decline in HBV DNA levels. Virologic end of treatment responses were 90 and 92% with mono‐ and combination treatment, respectively. Corresponding virologic responses at short‐ and long‐term follow‐up were 59 and 54%, and 27 and 25%, respectively. Patients having a baseline HBV DNA value ≥200 pg/mL were more likely to relapse within 6 months off therapy than those patients with a baseline HBV DNA level <200 pg/mL (P = 0.041). YMDD mutants were observed in 53% of patients receiving lamivudine compared with 24% of patients receiving the combination regime (P = 0.017). In conclusion, efficay of combination treatment is similar to lamivudine monotherapy. However, combination treatment decreases the development of YMDD mutant strains compared with lamivudine monotherapy.

Cytokine gene polymorphisms in Turkish patients with inflammatory bowel disease

Objective. Crohns disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the bowel, the causes of which are not fully known. Ethnic differences in disease prevalence, familial aggregation of the disease and studies of twins provide the most important evidence to suggest that genetic factors play a role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to examine the allelic polymorphisms that can determine the immune response levels in tumor necrosis factor alpha (TNFα), interleukin-1β (IL-1B), interleukin-1 receptor antagonist ( IL-1RN) and interleukin-10 (IL-10) genes and to investigate their roles in the inflammatory pathway in IBD. Material and methods. The study included 120 patients with UC and 70 patients with CD who were diagnosed either endoscopically or histopathologically. The control group comprised 105 healthy individuals who stated that they had never had any bowel disease during their life span. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method for polymorphisms in the TNFα gene at positions −308 and −238, the IL-10 gene at positions −1082 and −627, the IL-1B gene at −511 regions and the variable number of tandem repeat (VNTR) method for polymorphism in the intron 2 of the IL-1RN gene were performed. The results were analyzed on agarose gel electrophoresis. Results. No significant differences were found in the allele and genotype frequencies of the polymorphisms in the IL-1B, IL10, TNFα and IL-1RN genes between the patients with UC and CD and controls. Conclusions. The results suggest that these polymorphisms were not important risk factors in the susceptibility to IBD in Turkish patients.

The characteristics and clinical outcome of drug-induced liver injury: a single-center experience.

Background and Goals The aim of this cohort study was to determine the characteristics and clinical outcome of 170 patients with drug-induced liver injury (DILI) in a single center. Study Between January 2001 and June 2007, a total of 170 individuals who were diagnosed with DILI were retrospectively analyzed. The median follow-up period was 110.0 days. Results During the study period, a total of 5471 new patients were assessed for liver test abnormalities. Of those, 170 patients (3.1%) fulfilled the criteria of DILI. A total of 83 different drugs were considered to be related to the hepatotoxicity; a single drug was suspected in 57.6% of individuals. The median interval between the suspicious drug intake and DILI recognition was 15.0 days. Hepatocellular pattern was observed in 50.0% of patients with a mean alanine aminotransferase level of 952.2±907.0 U/L. The main causative group of drugs was antibiotics. Sixty-two patients required hospitalization; acute liver failure developed in 14 (8.2%), chronicity was observed in 19 (11.2%), and 7 died (4.1%). Overall, complete recovery occurred in 82% of patients. The presence of jaundice on admission and shorter interval period between drug intake and DILI recognition were identified as risk factors for the development of acute liver failure. Conclusions DILI is an important cause of liver test abnormalities in outpatient clinics, and antibiotics represent the most common drug group. Overall, complete recovery after the withdrawal of the suspicious drug occurred in the majority of patients, but DILI may progress to acute liver failure, chronicity, and death.

CASE REPORT: Remission of Severe Aplastic Anemia Associated with Hepatitis B Virus Infection After Viral Clearance: Potential Role of Lamivudine

Although viral hepatitis infection is known to be associated with aplastic anemia, a causal link between viral hepatitis and aplastic anemia has not been convincingly demonstrated. A case of hepatitis B-associated severe aplastic anemia is described which only partially responded to conventional immunosuppressive treatment but went into complete clinical remission after clearance of the hepatitis B virus. Disappearance of the hepatitis B virus occurred during lamivudine treatment and coincided with immune activation secondary to discontinuation of immunosuppressive therapy. This case was somewhat atypical in that a history of acute hepatitis preceding the aplastic anemia was absent. The observation made in this case report supports a cause-effect relationship between hepatitis B virus infection and aplastic anemia.