Sequence variability at the internal ribosome entry site of the HCV genome in relation to therapy outcome

Different types of interferon are widely used to treat hepatitis C virus (HCV) infection. Results obtained in vitro suggest that interferon inhibits internal ribosome entry site (IRES)-mediated translation of the HCV genome. To elucidate the possible effect of the nucleotide sequence of IRES on therapy outcome, we compared HCV isolates from patients with sustained response and non-response to interferon/ribavirin combination therapy. In 56 analyzed HCV isolates, nucleotide changes appeared strictly in the stem-loop IIIb region, the stem part from 243 nt to 248 nt, and the polypyrimidine-II region. The natural sequence variability of IRES in isolates of genotype 3a was significantly higher than in isolates of genotype 1b (p < 0.05). The average number of nucleotide changes in genotype 3a correlated with response to therapy (p < 0.05).Interferonska terapija se danas najčešće koristi u lečenju infekcije virusom hepatitisa tipa C (HCV). In vitro rezultati su pokazali da interferoninhibira translaciju kod ovog virusa preko interakcije sa delom genoma koji učestvuje u inicijaciji translacije tzv. 'unutrašnje ribozomalno ulazno mesto' (IRES). U ovom radu smo ispitivali nukleotidne izmene u IRES-u kod izolata HCV-a dobijenih iz seruma osoba koje su primale kombinovanu terapiju interferon/ribavirin. U analiziranoj grupi od 56 HCV izolata, nukleotidne izmene su utvrđene u: IIIb petlji, regiji između 243 nt i 248 nt i polipirimidin-II regiji. Utvrđena varijabilnost IRES-a kod izolata genotipa 3a značajno je veća u poređenju sa izolatima genotipa 1b (p < 0.05). Prosečan broj nukleotidnih izmena kod izolata genotipa 3a je u korelaciji sa odgovorom na primenjenu terapiju (p < 0.05).Projekat ministarstva br. 143010 i 14301

Sequence variability at the internal ribosome entry site of the HCV genome in relation to therapy outcome

Different types of interferon are widely used to treat hepatitis C virus (HCV) infection. Results obtained in vitro suggest that interferon inhibits internal ribosome entry site (IRES)-mediated translation of the HCV genome. To elucidate the possible effect of the nucleotide sequence of IRES on therapy outcome, we compared HCV isolates from patients with sustained response and non-response to interferon/ribavirin combination therapy. In 56 analyzed HCV isolates, nucleotide changes appeared strictly in the stem-loop IIIb region, the stem part from 243 nt to 248 nt, and the polypyrimidine-II region. The natural sequence variability of IRES in isolates of genotype 3a was significantly higher than in isolates of genotype 1b (p < 0.05). The average number of nucleotide changes in genotype 3a correlated with response to therapy (p < 0.05).Interferonska terapija se danas najčešće koristi u lečenju infekcije virusom hepatitisa tipa C (HCV). In vitro rezultati su pokazali da interferoninhibira translaciju kod ovog virusa preko interakcije sa delom genoma koji učestvuje u inicijaciji translacije tzv. 'unutrašnje ribozomalno ulazno mesto' (IRES). U ovom radu smo ispitivali nukleotidne izmene u IRES-u kod izolata HCV-a dobijenih iz seruma osoba koje su primale kombinovanu terapiju interferon/ribavirin. U analiziranoj grupi od 56 HCV izolata, nukleotidne izmene su utvrđene u: IIIb petlji, regiji između 243 nt i 248 nt i polipirimidin-II regiji. Utvrđena varijabilnost IRES-a kod izolata genotipa 3a značajno je veća u poređenju sa izolatima genotipa 1b (p < 0.05). Prosečan broj nukleotidnih izmena kod izolata genotipa 3a je u korelaciji sa odgovorom na primenjenu terapiju (p < 0.05).Projekat ministarstva br. 143010 i 14301

Xenobiotics-induced hepatotoxicity and an influence of HLA typisation

Introduction: The increased reporting of cases of drug-induced liver injuries, reflects the growing number of new agents introduced into clinical practice in the last decades. It should be added to the modernization of industries, and new chemicals which it applied. Drug-induced liver injuries make up a persisting and challenging problem for physicians, health agencies and pharmaceutical firms. Research objectives: The aim of the study is the determination of the most common causes of drug-induced liver injury in our surroundings. We compared the importance of hepatotoxic action of drugs in relation to other noxa in human environment. We determinated the importance of the body sensitivity on the acting agents. We also examined the importance of different drugs in the development of hepatotoxicity, regardless the dose. Materials and methods: We analyzed 52 patients with a diagnosis of hepa-totoxic liver injury (medical history, detailed clinical evaluation of patients, histopathological analysis of the liver, abdominal ultra sound, laboratory determination of standard liver function tests) and followed up for 12 months. In the period from 01.04. 2005 to 01.04.2009, in these patients of the Institute of Gastroenterology and Hepatology, Clinical Center of Serbia in Belgrade, we monitored liver functional tests and morphological findings. We used biological markers relevant for the differential diagnosis, monitoring of disease progression and response to therapy. The results of the patients with hepatotoxic liver injury were compared with the values of the findings of the 52 patients in the control group, with the diagnosis of chronic viral hepatitis, hospitalized in the same institution during the same time. Results: The causes of toxic liver damage in our study were following agents, classified into groups: Industrial toxins (8 patients), Food and beverages (9 pts), Antirheumatics and analgesics (6 pts), Antiarrhythmic drugs (4 pts) Antilipemic (4 pts), Antibiotics (4 pts), Vitamins (3 pts), Antihypertensive drugs (3 pts), Antiplatelet drugs (2 pts), Anticonvulsants (2 pts), Drugs for osteoporosis (2 pts), Antihipertireoidni drugs (1 pt), Oral antidiabetic agents (1 pt), Oral contraceptives (1 pt), Glucocorticoids (1 pt) and Antidepressants (1 pt). We got the results of HLA typing for 29 patients of the 52 patients with hepatotoxic liver injury and for 22 patients of 52 patients with chronic viral hepatitis. Conclusion: The paper points to hepatotoxicity, which is not rare in our population. Structure of xenobiotics causing liver toxicity in our environment is mainly industrial toxins, as well as food and beverages, more than drugs. It would be necessary to examine what are the ingredients of food causing hepatotoxicity. It would be very important to cover the wider population with HLA typing, in order to create a database with the frequency of certain HLA haplotypes in our population for the identification of patients at risk for developing hepatotoxicity

Distal splenorenal shunt with partial spleen resection

Introduction: Hypersplenism is a common complication of portal hypertension. Cytopenia in hypersplenism is predominantly caused by splenomegaly. Distal splenorenal shunt (Warren) with partial spleen resection is an original surgical technique that regulates cytopenia by reduction of the enlarged spleen. Objective. The aim of our study was to present the advantages of distal splenorenal shunt (Warren) with partial spleen resection comparing morbidity and mortality in a group of patients treated by distal splenorenal shunt with partial spleen resection with a group of patients treated only by a distal splenorenal shunt. Method. From 1995 to 2003, 41 patients with portal hypertension were surgically treated due to hypersplenism and oesophageal varices. The first group consisted of 20 patients (11 male, mean age 42.3 years) who were treated by distal splenorenal shunt with partial spleen resection. The second group consisted of 21 patients (13 male, mean age 49.4 years) that were treated by distal splenorenal shunt only. All patients underwent endoscopy and assessment of oesophageal varices. The size of the spleen was evaluated by ultrasound, CT or by scintigraphy. Angiography was performed in all patients. The platelet and white blood cell count and haemoglobin level were registered. Postoperatively, we noted blood transfusion, complications and total hospital stay. Follow-up period was 12 months, with first checkup after one month. Results In the first group, only one patient had splenomegaly postoperatively (5%), while in the second group there were 13 patients with splenomegaly (68%). Before surgery, the mean platelet count in the first group was 51.6±18.3x109/l, to 118.6±25.4x109/l postoperatively. The mean platelet count in the second group was 67.6±22.8x109/l, to 87.8±32.1x109/l postoperatively. Concerning postoperative splenomegaly, statistically significant difference was noted between the first and the second group (p&lt;0.05). Comparing the postoperative platelet count between the first and second group, we found that there was a very significant statistical difference, too (p&lt;0.01). Conclusion. Distal splenorenal shunt (Warren) with partial spleen resection is a very reliable surgical technique in treatment of hypersplenism and decompression of oesophageal varices caused by portal hypertension and has advantage in treatment of hypersplenism over the distal splenorenal shunt method.

Sepsis as a cause of intrahepatic cholestasis

Introduction. The causes of intrahepatic cholestasis include cholestatic viral hepatitis, primary biliary cirrhosis, benign recurrent cholestasis, primary sclerosing cholangitis and sepsis. During sepsis, proinflammatory cytokines and nitric oxide cause cholestasis by impairing hepatocellular and ductal bile formation. Case Outline. We report a 48-year-old woman who was admitted to hospital due to malaise, jaundice, fever and pain in the neck. Physical examination revealed jaundice, tachycardia (pulse rate was 120/min), hypotension 90/60 mm Hg. Laboratory findings showed normocytic normochromic anaemia, inflammatory syndrome and abnormal liver function tests indicating cholestasis and hepatocellular necrosis. Abdominal ultrasonography detected hepatosplenomegaly. Chest computed tomography showed bronchopneumonic infiltrates. Percutaneous liver biopsy was performed using a Menghini needle of 1.4 mm. Pathohystological analysis of the liver tissue confirmed reactive, intrahepatic cholestasis. Blood cultures isolated Staphylococcus aureus. After the diagnosis was established the treatment with broad-spectrum antibiotics was carried out, resulting in the improvement of general condition of the patient, regression of inflammatory syndrome, disappearance of cholestasis and regression of pulmonary infiltrates. Abdominal ultrasonography after antibiotic treatment did not show hepatosplenomegaly. Conclusion. Concerning patients with cholestasis of uncertain origin, we should always think of sepsis as a possible cause in order to start antibiotic treatment in time

Sequence variability at the internal ribosome entry site of the HCV genome in relation to therapy outcome

Different types of interferon are widely used to treat hepatitis C virus (HCV) infection. Results obtained in vitro suggest that interferon inhibits internal ribosome entry site (IRES)-mediated translation of the HCV genome. To elucidate the possible effect of the nucleotide sequence of IRES on therapy outcome, we compared HCV isolates from patients with sustained response and non-response to interferon/ribavirin combination therapy. In 56 analyzed HCV isolates, nucleotide changes appeared strictly in the stem-loop IIIb region, the stem part from 243 nt to 248 nt, and the polypyrimidine-II region. The natural sequence variability of IRES in isolates of genotype 3a was significantly higher than in isolates of genotype 1b (p &lt; 0.05). The average number of nucleotide changes in genotype 3a correlated with response to therapy (p &lt; 0.05)

Sequence Variability At the Internal Ribosome Entry Site of the Hcv Genome in Relation to Therapy Outcome

Different types of interferon are widely used to treat hepatitis C virus (HCV) infection. Results obtained in vitro suggest that interferon inhibits internal ribosome entry site (IRES)-mediated translation of the HCV genome. To elucidate the possible effect of the nucleotide sequence of IRES on therapy outcome, we compared HCV isolates from patients with sustained response and non-response to interferon/ribavirin combination therapy. In 56 analyzed HCV isolates, nucleotide changes appeared strictly in the stem-loop IIIb region, the stem part from 243 nt to 248 nt, and the polypyrimidine-II region. The natural sequence variability of IRES in isolates of genotype 3a was significantly higher than in isolates of genotype 1b (p LT 0.05). The average number of nucleotide changes in genotype 3a correlated with response to therapy (p LT 0.05)

Oxidative stress in rat liver during acute cadmium and ethanol intoxication

The aim of our study was to investigate the effects of binge drinking on prooxidant/antioxidant system in rat liver in acute cadmium (Cd) intoxication. In experiment male Wistar rats were used and divided into following groups: 1. control, 2. ethanol-treated group, in five subsequent doses of 2 g/kg administered by orogastric tube, 3. Cd-treated group in a single dose of 2.5 mg/kg intraperitoneally, 4. group that received Cd 12 hours after the last dose of ethanol. Blood and liver samples were collected for determination of oxidative stress parameters, 24 hours after treatment. When administered in combination, ethanol and Cd induced a more pronounced increase in serum and liver malondialdehyde level than either of these substances alone (p&lt;0.01). Liver manganese superoxide dismutase (MnSOD) activity was increased both in ethanol and Cd-treated group (p&lt;0.01), while liver copper/zinc superoxide dismutase (Cu/ZnSOD) activity was elevated in Cd group only. However, when administered in combination, ethanol and Cd induced a more pronounced decrease in liver MnSOD and Cu/ZnSOD activity 24 hours after treatment (p&lt;0.01). Based on our study, it can be concluded that ethanol may act sinergistically with Cd in inducing lipid peroxidation and reduction in liver SOD activity

Rimonabant Improves Oxidative/Nitrosative Stress in Mice with Nonalcoholic Fatty Liver Disease

The present study deals with the effects of rimonabant on oxidative/nitrosative stress in high diet- (HFD-) induced experimental nonalcoholic fatty liver disease (NAFLD). Male mice C57BL/6 were divided into the following groups: control group fed with control diet for 20 weeks (C; n=6); group fed with HFD for 20 weeks (HF; n=6); group fed with standard diet and treated with rimonabant after 18 weeks (R; n=9); group fed with HFD and treated with rimonabant after 18 weeks (HFR; n=10). Daily dose of rimonabant (10 mg/kg) was administered to HFR and R group by oral gavage for two weeks. Treatment induced a decrease in hepatic malondialdehyde concentration in HFR group compared to HF group (P<0.01). The concentration of nitrites + nitrates in liver was decreased in HFR group compared to HF group (P<0.01). Liver content of reduced glutathione was higher in HFR group compared to HF group (P<0.01). Total liver superoxide dismutase activity in HFR group was decreased in comparison with HF group (P<0.01). It was found that rimonabant may influence hepatic iron, zinc, copper, and manganese status. Our study indicates potential usefulness of cannabinoid receptor type 1 blockade in the treatment of HFD-induced NAFLD

Ultrasound measurement of visceral fat in patients with primary biliary cirrhosis

Background/Aim. Primary biliary cirrhosis (PBC) is a progressive, chronic liver disease with elevated serum lipids, but it is unclear whether hyperlipidemia in PBC patients is associated with atherosclerosis. Metabolic syndrome promotes development of atherosclerotic cardiovascular disease related to abdominal type obesity and insulin resistance. The aim of our study was to assess abdominal adiposity in patients with PBC. Methods. The study included 40 patients with PBC and 50 healthy controls. Age, sex and anthropometric measurements (weight, height, body mass index and waist circumference) were registered for all patients and controls. We used ultrasonography to measure subcutaneous (SF) and visceral fat (VF) diameter, subcutaneous area (SA) and visceral area (VA), as well as perirenal fat diameter (PF). Results. Values of SF, VF and PF thicknesses in PBC patients were 19.23 ± 5.85 mm, 10.92 ± 3.63 mm, and 7.03 ± 1.82 mm, respectively. In controls these measurements were 22.73 ± 6.70 mm, 16.84 ± 5.51 mm and 10.50 ± 2.70 mm respectively. In PBC patients SA and VA were calculated to 983.64 ± 322.68 mm2 and 403.64 ± 166.97 mm2 and in controls 1124.89 ± 366.01 mm2 and 720.57 ± 272.50 mm2 respectrively. Significant difference was found for VF, VA and RF values. Conclusions. Considering that the amount of visceral fat plays an important role in development of metabolic syndrome and cardiovascular diseases, we concluded that the lower amount of visceral fat in PBC patients could be related to lower incidence of cardiovascular events, despite hyperlipidemia