Biomedical subjects
Publications and source records attributed to M Omata.
Hepatitis precedes hepatocellular carcinoma, especially in Type C virus infection. Considering the high risk of developing HCC, we have to check patients with C-viral hepatitis carefully for the possible presence of HCC.
OBJECTIVE: To explore the mechanisms for augmented neutral endopeptidase inhibitor-induced natriuresis in deoxycorticosterone acetate (DOCA)-salt rats. METHODS: We examined effects of a neutral endopeptidase-inhibitor, candoxatril, on plasma and urinary brain natriuretic peptide (BNP) levels, the influence of a specific atrial natriuretic peptide (ANP) receptor antagonist, HS-142-1, on the response to candoxatril, and the renal neutral endopeptidase activity in DOCA-salt rats. RESULTS: Candoxatril decreased blood pressure and increased urinary sodium excretion, both of which were greater in DOCA-salt rats than in normotensive control rats. These effects were associated with a significant rise in the plasma BNP level and the plasma ANP level in DOCA-salt rats. Urinary ANP excretion also increased, but urinary BNP excretion was not changed by candoxatril. Pretreatment with a specific ANP receptor antagonist (HS-142-1) diminished the effect of candoxatril on urinary sodium excretion, blood pressure and urinary cyclic GMP excretion. Urinary neutral endopeptidase-like activity was greater in DOCA-salt rats than in control rats. Northern blot analysis revealed that the ratio of renal neutral endopeptidase messenger RNA (mRNA) to beta-actin mRNA was comparable between the two groups. CONCLUSIONS: The neutral endopeptide inhibitor exerted its hypotensive and natriuretic effects mainly via the potentiation of the endogenous natriuretic peptides, including BNP. The augmented response of DOCA-salt rats also seems to be mediated by both the downregulation of clearance receptors and an increase in renal neutral endopeptidase activity.
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To determine the risk of death at an early stage of fulminant viral hepatitis, we created severity indexes drawn from clinical data on the day of development of encephalopathy in 128 patients with fulminant hepatitis B and 103 with fulminant hepatitis non-A, non-B. In fulminant hepatitis B, the risk score was 2.75 x BL + 2.75 x BR + 2.7 x AG + 2.3 x WB + 1.67 x CD + 1.56 x AL - 0.098 x PR - 0.88, where BL is 1 if total bilirubin is higher than 20 mg/dl, BR is 1 if the ratio of total to direct bilirubin exceeds 2.2, AG is 1 if age is above 40 yr, WB is 1 if white blood cell count is less than 4,000 cells/mm3 or more than 18,000 cells/mm3, CD is 1 if a hazardous disease coexists and AL is 1 if ALT is less than 100 times the upper limit of normal (otherwise all are 0), and PR is prothrombin time (percentage of normal value). Using a cutoff score of 0, we found the positive predictive value, negative predictive value and predictive accuracy to be 0.90, 0.86 and 0.89, respectively. Sensitivity and specificity were 0.94 and 0.77, respectively. In fulminant non-A, non-B hepatitis, the risk score was 2.66 x BR + 2.25 x BL + 2.24 x DI + 2.05 x AL +/- 1.38 x AG + 0.00021 x WB - 6.33.(ABSTRACT TRUNCATED AT 250 WORDS)
In an attempt to clarify the mechanisms of neutrophil-accumulation in the liver of alcoholics, release of KC/gro protein (intercrine cytokine family) from hepatocytes in the chronically ethanol fed rats was examined. Chemotactic activity for rat neutrophils was demonstrated in the culture supernatant of hepatocytes isolated from the ethanol fed rats, which was then inhibited in the presence of antibody against rat KC/gro protein. Immunoblot analysis revealed that the peptide reacted with antiserum against KC/gro protein was demonstrated at a molecular weight of 20-23kDa, and an amount of KC/gro protein released from the hepatocytes of the chronically ethanol fed rats was increased, as compared with that of the control rats.
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BACKGROUND: p53 gene mutations at codon 249 have been reported in hepatocellular carcinoma (HCC) from China and South Africa, a phenomenon shown to be closely associated with food contamination by aflatoxin. There have been few reports, however, in regard to p53 gene mutations in HCC from other geographic areas. METHODS: The authors analyzed 20 HCC from Japan for alteration of the p53 gene by restriction fragment length polymorphisms and for nucleic acid mutations by polymerase chain reaction with direct sequencing. RESULTS: Alterations associated with the p53 gene were found in 6 of 20 HCC (30%). Allelic loss of chromosome 17p occurred in 5 of 14 informative (heterozygous) cases (36%). Mutations in the p53 gene were detected in three cases (15%), at codons 176 (exon 5), 236 (exon 7), and 294 (exon 8). These cases were different from the HCC cases from China and South Africa, where point mutations in the p53 gene were reported at the same codon 249 in half of the cases and where aflatoxin food contamination and hepatitis B virus infection are recognized risk factors of HCC. No p53 gene alterations were found in smaller HCC (< 3 cm) or at earlier stages. CONCLUSIONS: In Japan, p53 gene alterations seem to be a late event in the progression of hepatocarcinogenesis, which is often associated with persistent infection by the hepatitis C or B virus, but not usually with exposure to aflatoxin.
Pancreatic adenocarcinomas are known to have a high incidence of K-ras gene mutations. Differential diagnosis of pancreatic cancer and chronic pancreatitis sometimes presents a clinical dilemma. We recently developed a highly sensitive and specific polymerase chain reaction capable of detecting 3-30 copies of mutant K-ras genes harboring codon 12 single base changes in the presence of 300,000 normal copies. Mutant ras genes were detected in DNA purified from pancreatic juice from all 6 cases of pancreatic adenocarcinoma and 1 case of intraductal papillary neoplasms of the pancreas. In 2 of 6 other cases with pancreatic adenocarcinoma, circulating metastatic cells were detected in DNA purified from peripheral blood. Activated ras genes were not found in pancreatic juice of three control cases (chronic pancreatitis and choledocholithiasis) or in the peripheral blood of two patients with insulinomas. Notable conclusions of this study are that there can be significant levels of shed tumor cells in peripheral blood and an even higher number in pancreatic juice. In addition, two different K-ras mutations were found in some patients.
To elucidate the physiological role of C-type natriuretic peptide (CNP) as a local mediator, we examined the production of CNP in the rat kidney. The content of CNP in the kidney was 0.47 +/- 0.02 [SE] fmol/mg wet weight and the major molecular form of CNP was CNP-53. An established cell line from the rat kidney, NRK-52E cell, secreted CNP at a rate of 9.15 +/- 0.96 fmol/24 hr/mg protein. Furthermore, CNP mRNA was detected in the rat kidney and NRK-52E cell utilizing reverse transcription-polymerase chain reaction (RT-PCR). On the other hand, ANP in the rat kidney (2.56 +/- 0.19 fmol/mg wet weight) had the molecular form of alpha-ANP, but ANP mRNA was not detected by RT-PCR. No BNP immunoreactivity was found in the rat kidney, although BNP mRNA was detected by RT-PCR. These results indicate that only CNP among the natriuretic peptides is produced in significant amounts in the rat kidney under normal physiological conditions and that renal parenchymal cells may produce CNP.
The presence of hepatitis C virus RNA was examined in the sera of 32 patients with acute non-A, non-B hepatitis. Hepatitis C virus RNA was extracted from serum, reverse transcribed to cDNA and amplified by two rounds of polymerase chain reaction. Hepatitis C virus RNA was detected in all patients who developed anti-C100-3 as well as 79% who did not. These data suggest that hepatitis C virus accounts for most cases of acute non-A, non-B hepatitis whether anti-C100-3-positive or not. In addition, hepatitis C virus RNA was detected in the earliest serum samples, 9 +/- 11 weeks before anti-C100-3, and thus may be valuable as a diagnostic marker for acute hepatitis C.
Hepatocyte Growth Factor (HGF) was originally identified as hepatotrophic factor for liver regeneration. More recently, HGF was revealed to stimulate proliferation of various epithelial cells. At present study, we have investigated the mitogenic effect of HGF on gastric epithelial cells in the primary culture system. HGF remarkably stimulated proliferation of these cells dose dependently and synergistically with EGF and insulin. Mitogenic action of HGF might be mediated not by intracellular Ca2+ but by tyrosine kinase pathway. Conditioned medium of cultured fibroblast-like cells showed proliferative effects on cultured gastric epithelial cells in a similar way as exogenous HGF. These results suggest that HGF might be involved in the repair process of gastric mucosa.
To elucidate the temporal relationship between liver damage and mutation(s) in hepatitis B virus core gene, serial sera from a progressive liver disease patient and an asymptomatic carrier were studied. By direct sequencing, missense mutations in the core gene were only found in serum from the progressive liver disease patient during the period with frequent exacerbation. Using methods of cloning and sequencing, missense mutations were also found in clones derived from the progressive liver disease patient at a relatively early phase, but strains with a missense mutation from earlier sera did not exist in sera of a later period. Furthermore, there was a tendency of concentrating missense mutations in clones derived from the progressive liver disease patient. These data suggested that missense mutations in the core gene that occurred at an earlier phase might evoke an immune response to eliminate mutated virus and that concentrating missense mutations during a phase of exacerbation might be a result of adaptive mutation.
Putative hepatitis C virus core sequence was amplified from a serum sample positive for anti-C-100-3 and expressed in Escherichia coli. Approximately 62 kDa fusion protein with maltose binding protein containing 20 kDa hepatitis C core protein was obtained. The antibody to this protein was detected in 53 of 54 (98%) sera from hepatitis C virus ribonucleic acid-positive patients including 40 sera positive for anti-C-100-3 and 13 sera negative for anti-C-100-3. The antibody was also detected in all of 12 patients with acute hepatitis C showing the earlier detectability of the antibody than anti-C-100-3. Thus, the protein expressed from the amplified hepatitis C core sequence by the polymerase chain reaction would be useful for the diagnosis of hepatitis C.
Individuals with chronic hepatitis B virus (HBV) infection are generally divided into asymptomatic healthy carriers and patients with chronic liver disease. Several studies have suggested that the core antigen (HBcAg) could be an immunological target of cytotoxic T lymphocytes (CTL). To investigate the possible pressure site from CTL, the entire core region of HBV DNA was sequenced in 30 subjects (10 asymptomatic healthy carriers and 20 patients with chronic liver disease). No significant changes in the nucleotide sequence and deduced amino acid residue were noted in the 10 healthy carriers. In contrast, a cluster of changes in small segment of 18 amino acids (codon 84 to 101 from the start of the core gene) was found in 15 of the 20 chronic liver disease patients. All these 15 patients had advanced liver diseases (chronic active hepatitis and cirrhosis), whereas only mild liver disease (chronic persistent hepatitis) was found in the 5 patients without mutation. These data suggest that this region with clustering mutations may play an important role in the pathogenesis of B viral liver disease, and the mutations in the region may be related to progressive liver disease.
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Putative hepatitis C virus E2 protein was applied for detection of anti-E2 antibody in patients with type C hepatitis. The Putative E2 sequence was expressed in E. coli and approximately 38 KDa hepatitis C E2 protein fused with 42 KDa maltose binding protein was obtained. The HCV E2 antibody was detected in 2 of 7 acute hepatitis cases, in 8 of 12 chronic persistent hepatitis, in 17 of 25 chronic active hepatitis, and in 2 of 4 cirrhosis. It was not detected in 10 normal subjects. Anti-E2 antibody became undetectable after successful interferon treatment in patients with type C hepatitis. The High detection rate of E2 antibody in chronic hepatitis C and disappearance of the antibody after the interferon treatment indicate that the E2 antibody is related to viral replication and is unlikely to be a neutralizing antibody.
Since November 1989, the Japan Red Cross has been screening blood donors for hepatitis C virus antibody (anti-HCV) with 1st generation assay and high-titer antibody to hepatitis B virus core antigen (HBcAb). To clarify the effectiveness of the new screening tests for the prevention of post-transfusion hepatitis, the incidence of post-transfusion hepatitis after the introduction of new tests (December 1989 to September 1990) was compared with the incidence before the in introduction (January 1982 to December 1987). The incidence of "definite" post-transfusion hepatitis was 10.3% (205/1991) with a mean transfusion volume of 10.2 units before the screening, and 3.9% (11/282) with a mean transfusion volume of 14.6 units after the introduction of the new screening tests. Statistical analysis revealed a significant decrease of post-transfusion non-A, non-B hepatitis after the introduction of new tests (chi 2 = 10.9, P < 0.01). The incidence of "probable" post-transfusion hepatitis was 12.4% (246/1991) and 11.7% (33/282) respectively. No significant change was observed between the rates of "probable" post-transfusion hepatitis before and after the introduction of the new tests. It was concluded that anti-HCV and high-titer anti-HBc screening of volunteer blood donors could contribute to the prevention of the post-transfusion non-A, non-B hepatitis in Japan.
To assess the effects of interferon treatment on chronic hepatitis C, histological changes long after treatment were compared with normalization of aminotransferases and seroconversion of hepatitis C virus RNA. Twenty one histologically proven chronic hepatitis C patients received alpha-interferon, 3 million units 3 times weekly for 12 months. Hepatitis C virus RNA was detected by reverse transcription/polymerase chain reaction method. Follow-up liver biopsies were performed 3 to 5 years after treatment. Fourteen of 21 (67%) patients showed normal aminotransferases for 3 to 5 years after treatment. HCV RNA seroconversion was observed in 12 of these patients. These responders showed improvement in histological activity indices and in histological findings. Two patients improved from chronic active hepatitis 2a to nonspecific changes, 1 from chronic active hepatitis 2a to portal fibrosis, 1 from chronic active hepatitis 2a to chronic persistent hepatitis and 1 from chronic active hepatitis 2b to chronic persistent hepatitis. Histological improvement of the liver correlated well with normalization of aminotransferases and seroconversion of hepatitis C virus RNA. These data indicate that complete histological resolution of chronic hepatitis C can be achieved by elimination of the virus with interferon treatment.