Kendo Kiyosawa

Detection of antibodies to a putative hepatitis G virus envelope protein

BACKGROUND A flavivirus designated hepatitis G virus (HGV) has been isolated from the serum of patients with non-A-E hepatitis. Hitherto, the presence of HGV RNA in serum has been detected with the reverse transcription-polymerase chain reaction (RT-PCR) amplification method. We have now developed an immunoassay for antibodies against an HGV protein. METHODS Recombinant HGV envelope protein E2 was used as antigen in an ELISA. 80 blood donors, 99 intravenous-drug users, and 11 patients with acute post-transfusion hepatitis were tested for antibodies to E2. The HGV-RNA status was assessed by RT-PCR. FINDINGS Anti-E2 seroprevalence was 9% among the blood donors and 41% among the drug users; HGV-RNA prevalence was 2.5% and 38%, respectively. Whereas anti-E2 prevalence increased with the duration of drug use, HGV-RNA prevalence declined in parallel. In each group, the presence of anti-E2 and HGV RNA was almost mutually exclusive: none of the blood donors and only 4% of the drug users were positive for both markers at the same time. Of the 11 post-transfusion patients--who were all HGV-RNA positive and anti-E2 negative at the onset of disease--four developed antibodies to E2 during the following year, and two of the four subsequently became HGV-RNA negative. INTERPRETATION We conclude that a humoral immune response to E2 is associated with loss of detectable HGV viraemia. Thus, E2-specific antibodies might serve as a useful marker for diagnosing recovery from HGV infections. The immunoassay we describe should facilitate investigation of suspected infections and may be helpful in the elucidation of the clinical significance of HGV.

Hepatitis C in Hospital Employees with Needlestick Injuries

Hepatitis virus infection has been a problem among hospital employees. Hepatitis B virus (HBV) infection is now controlled by hospital safety practices limiting exposure to blood and other body flu...

Operative morbidity of living liver donors in Japan

BACKGROUND Deaths of living liver donors have been reported in western countries, whereas the morbidity and mortality of such donors in Japan, one of the leading countries for living liver transplantation, have not been reported in detail. We aimed to review the operative morbidity and mortality of such donors in Japan. METHODS 1853 donors of 1852 living liver transplants done in 46 liver transplant centres, and registered in the database of the Japanese Liver Transplantation Society, were assessed for eight donor-related factors of morbidity and mortality. Data for 1841 donors were analysed. FINDINGS No perioperative mortality was recorded since inception of the liver transplantation programme in Japan from Nov 13, 1989, to April 11, 2002. 244 postoperative complications were reported in 228 (12%) donors. The frequency of complications was significantly higher in donors of the right liver lobe than in those involving the lateral segment, and left lobe graft (p<0.0001, and p<0.0001, respectively). Postoperative hospital stay was significantly longer in donors of the right lobe (mean 19.7 [SD 13.0]) than in those of the lateral segment (14.2 [7.6]), left lobe (14.0 [6.5]), and left lobe and caudate lobe (16.3 [12.1]). Re-operation related to donor hepatectomy was done in 23 donors. INTERPRETATION By contrast with western countries, no perioperative mortality was recorded in living liver donors in Japan. However, a proportion of these donors developed serious complications. This morbidity should be reduced to maintain zero mortality in living liver donors.

Highly Purified Eicosapentaenoic Acid Treatment Improves Nonalcoholic Steatohepatitis

Recent studies have demonstrated that n-3 polyunsaturated fatty acids ameliorate nonalcoholic fatty liver disease. Although eicosapentaenoic acid (EPA), one of the major components of n-3 polyunsaturated fatty acids, is widely used as an antilipidemic agent, its single efficacy for nonalcoholic steatohepatitis (NASH) remains unclear. As such, we aimed to evaluate the efficacy and safety of EPA on 23 biopsy-proven NASH patients in a pilot trial. Highly purified EPA (2700 mg/d) was administered for 12 months and efficacy was assessed by biochemical parameters and liver histology. All patients completed the treatment with no adverse events, indicating acceptable tolerance to the treatment. After 12 months, serum alanine aminotransferase levels were significantly improved (from 79±36 to 50±20 U/L), and serum free fatty acids, plasma soluble tumor necrosis factor receptor 1 and 2 levels, and serum ferritin and thioredoxin levels, which may reflect hepatic oxidative stress, were significantly decreased. Body weight, blood glucose, insulin, and adiponectin concentrations remained unchanged. Seven of the 23 patients consented to undergo posttreatment liver biopsy, which showed improvement of hepatic steatosis and fibrosis, hepatocyte ballooning, and lobular inflammation in 6 patients. In conclusion, EPA treatment seems to be safe and efficacious for patients with NASH, largely due to its anti-inflammatory and antioxidative properties. To confirm these results, appropriately powered, controlled trials are needed.

Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells.

Pancreatic adenocarcinoma is an aggressive human malignancy and is characterized by resistance to apoptosis. Recently, NADPH oxidase (Nox) 4-mediated generation of intracellular reactive oxygen species (ROS) was proposed to confer antiapoptotic activity and thus a growth advantage to pancreatic cancer cells. The signaling mechanism by which Nox4 transmits cell survival signals remains unclear. Here, we show that both a flavoprotein inhibitor, diphenylene iodonium (DPI), and small interfering RNAs designed to target Nox4 mRNA (siNox4RNAs) inhibited superoxide production in PANC-1 pancreatic cancer cells, and depletion of ROS by DPI or siNox4RNAs induced apoptosis. Parallely, DPI treatment and siNox4RNA transfection blocked activation of the cell survival kinase AKT by attenuating phosphorylation of AKT. Furthermore, AKT phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) on Ser-83 was reduced by DPI and siNox4RNAs. When ASK1Ser83Ala (an AKT phosphorylation-defective ASK1 mutant) was introduced into PANC-1 cells, this mutant alone induced apoptosis. But, addition of DPI or co-transfection of siNox4RNA had no additive effect, indicating that the mutant can substitute for these reagents in apoptosis induction. Taken together, these findings suggest that ROS generated by Nox4, at least in part, transmit cell survival signals through the AKT–ASK1 pathway in pancreatic cancer cells and their depletion leads to apoptosis.

PPARα activation is essential for HCV core protein–induced hepatic steatosis and hepatocellular carcinoma in mice

Transgenic mice expressing HCV core protein develop hepatic steatosis and hepatocellular carcinoma (HCC), but the mechanism underlying this process remains unclear. Because PPARalpha is a central regulator of triglyceride homeostasis and mediates hepatocarcinogenesis in rodents, we determined whether PPARalpha contributes to HCV core protein-induced diseases. We generated PPARalpha-homozygous, -heterozygous, and -null mice with liver-specific transgenic expression of the core protein gene (Ppara(+/+):HCVcpTg, Ppara(+/-):HCVcpTg, and Ppara(-/-):HCVcpTg mice. Severe steatosis was unexpectedly observed only in Ppara(+/+):HCVcpTg mice, which resulted from enhanced fatty acid uptake and decreased mitochondrial beta-oxidation due to breakdown of mitochondrial outer membranes. Interestingly, HCC developed in approximately 35% of 24-month-old Ppara(+/+):HCVcpTg mice, but tumors were not observed in the other genotypes. These phenomena were found to be closely associated with sustained PPARalpha activation. In Ppara(+/-):HCVcpTg mice, PPARalpha activation and the related changes did not occur despite the presence of a functional Ppara allele. However, long-term treatment of these mice with clofibrate, a PPARalpha activator, induced HCC with mitochondrial abnormalities and hepatic steatosis. Thus, our results indicate that persistent activation of PPARalpha is essential for the pathogenesis of hepatic steatosis and HCC induced by HCV infection.

Present status of autoimmune hepatitis in Japan - correlating the characteristics with international criteria in an area with a high rate of HCV infection

BACKGROUND/AIMS A nationwide survey of autoimmune hepatitis (AIH) was carried out in Japan. METHODS Four hundred and ninety-six patients were enrolled by questionnaires sent to 101 hospitals with hepatology specialists. RESULTS The clinical features of Japanese AIH were as follows: most patients were middle-aged women; serum autoantibodies, especially antinuclear antibody, were frequently positive, serum IgG level was high, and HLA-DR4 was the major HLA allotype. Liver-kidney microsomal type 1 antibody was positive in nine of 79 patients tested. Eight of these antibody positive patients were also positive for antinuclear antibody and five for anti-smooth muscle antibody. Ninety-two percent of the patients showed piecemeal necrosis and 60% bridging necrosis; plasma cell infiltration in the portal areas was observed in 50% of the patients. Only 12.3% were diagnosed as having liver cirrhosis. A favorable effect of corticosteroid, normalization of serum transaminases, was observed in 89% of 317 patients, who were treated with an initial dose of over 30 mg/day. Sixty-two patients were positive for hepatitis C virus (HCV) markers. In these patients, however, only one patient was liver-kidney microsomal type 1 antibody positive. Corticosteroid was effective in 30 (81%) of 37 HCV-marker-positive patients treated with this agent. Thus the efficacy of corticosteroid did not differ from that in AIH patients without HCV infection (90%). Similarly, interferon treatment was used in 20 patients, all of whom were positive for HCV-RNA, and resulted in 50% efficacy as determined by normalization of the serum transaminase level 6 months after treatment. The International Diagnostic Scoring System for the diagnosis of AIH worked well in these patients, except for HCV-infected individuals, that is, approximately 10% of the total of AIH patients.

Transmission of hepatitis C in an isolated area in Japan : community-acquired infection

Abstract Background/Aims: The spread of hepatitis C virus (HCV) infection not due to drug needle sharing or transfusion is largely unknown in communities. A search for risk factors for HCV infection in an endemic area might elucidate inapparent modes of transmission. Methods: We conducted screening for hepatitis virus markers and parenteral exposures to blood among 435 inhabitants in an isolated area known for its endemicity for non-A, non-B hepatitis and in a nonendemic area with 1542 inhabitants. Results: The prevalence of hepatitis B surface antigen was the same in both areas. The prevalence of antibody to HCV verified by the recombinant immunoblot assay was 32.4% in the highly endemic area and 2.3% in the nonendemic area ( P Conclusions: Folk remedies such as acupuncture and cutting of the skin using nonsterilized knives should be considered as possible routes of HCV transmission not associated with blood transfusion or sharing of drug paraphernalia.

Characteristic pancreatic duct appearance in autoimmune chronic pancreatitis: A case report and review of the Japanese literature

We report a case demonstrating the progressive narrowing of the pancreatic duct, which is presumed to be characteristic of autoimmune pancreatitis, and we review the 37 cases of chronic pancreatitis in which autoimmunity was suggested as an etiological factor in the Japanese literature. A 55-year-old man presented with abdominal discomfort, jaundice, and diffuse swelling of the pancreas on ultrasonography. Serial endoscopic retrograde pancreatography demonstrated the progression of an irregular narrowing of the main pancreatic duct forming diffusely over the course of 2 months. Because the patient had hyperglobulinemia and tested positive for autoantibodies, he was diagnosed as a case of autoimmune chronic pancreatitis. Steroid therapy was carried out with excellent success.

Acquisition versus Loss of Helicobacter pylori Infection in Japan: Results from an 8-Year Birth Cohort Study

Studies of the pattern of change in the epidemiology of Helicobacter pylori infection are scarce. A longitudinal cohort study consisted of 644 children and adults, and two independent cross-sectional surveys were conducted in rural Japan between 1986 and 1994. The anti-H. pylori IgG seroconversion rates were 1.1% and 1% per year for children and adults, respectively. The seroreversion rate per year was 1.8% for children and 1.5% for adults. The cohort study was confirmed by the two cross-sectional studies. H. pylori prevalence fell in all age groups in both children (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.2-1.0, P = .05) and adults (OR = 0.4, 95% CI = 0.3-0.6, P = .001). The rate of loss of H. pylori infection was greater than the acquisition. Data regarding acquisition and loss of H. pylori infection are critical to understanding the epidemiology of the infection and to developing treatment and vaccination strategies.