摘要:

AbstractNonbile salt cholephiles and bile salts are two classes of organic anions that are efficiently taken up and excreted by the liver. Recent evidence suggests that a microtubular system–dependent, colchicine‐sensitive transcellular pathway may transport both classes of these ligands. The relationship of this pathway to flux rates, however, remains unclear. Some structural evidence suggests an important role for a Golgi‐associated vesicular system. Monensin, like colchicine, is a perturbing agent that is believed to target primarily Golgi and related organelles. The effects of a minimal effective dose of both colchicine (0.06 mg to 0.12 mg/100 gm body wt) and monensin (0.6 mg/100 gm body wt) were examined in the isolated perfused rat liver in a single‐pass mode. The nonbile salt cholephile, phenol red, was studied at two doses: 1 nmol and 5 μmol. Sodium taurocholate was studied at three doses: 2 nmol, 1 μmol and 5 μmol. Colchicine affected the transcellular transport for both classes of organic anions equally. Partially inhibitory effects on both anions occurred only at high ligand flux rates. In contrast, monensin greatly impaired the transport of nonbile salt cholephiles but had no influence on transcellular bile salt flux. We conclude that the monensin effect appears to define a distinct transcellular transport pathway for each of the two classes of organic anions. (HEPATOLOGY 19

ISSN:0270-9139    

DOI:10.1002/hep.1840140102

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractIt has been proposed that a microtubule‐dependent transport of vesicles derived from the Golgi apparatus may play a role in biliary secretion of bile salts and other cholephilic anions. To test this hypothesis, we examined the influence of colchicine and vinblastine, two microtubule inhibitors, on diethylmaleate‐induced bile flow and on the biliary secretion of diethylmaleate, an organic anion whose glutathione conjugates may be secreted into bile through the Golgi apparatus and Golgi‐derived vesicles. Rats were pretreated with colchicine or vinblastine, and diethylmaleate was injected intraperitoneally at doses of 28 to 400 μmol/100 gm body wt. Basal bile flow was unaffected by colchicine or vinblastine. In contrast, diethylmaleate‐induced bile flow and the secretion into bile of diethylmaleate conjugates (estimated by the cation‐anion gap in bile) were significantly lower in colchicine‐treated and vinblastine‐treated animals than in controls. Diethylmaleate‐induced bile flow was reduced in proportion to diethylmaleate conjugate secretion. A linear relationship was seen between bile flow and biliary output of diethylmaleate conjugates: this relationship was similar in colchicine‐treated or vinblastine‐treated animals and in controls. At electron microscopy, diethylmaleate had induced distension of the Golgi saccules of the hepatocytes.In conclusion, colchicine and vinblastine inhibited the secretion into bile of diethylmaleate conjugates and diethylmaleate‐induced bile flow. These results support the view that microtubule‐dependent transport of Golgi‐derived vesicles is involved in the biliary secretion of diethylmaleate and, perhaps, other cholephilic organic anions.

ISSN:0270-9139    

DOI:10.1002/hep.1840140103

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractThe woodchuck was selected to study the efficacy of liver‐targeted antiviral drugs on hepadnavirus replication. Nineteen woodchucks chronically infected with woodchuck hepatitis virus were treated with adenine arabinoside monophosphate or acyclovir monophosphate, either free or conjugated with the liver‐targeting molecule lactosaminated human serum albumin.Circulating woodchuck hepatitis virus DNA levels remained unchanged in untreated animals and in those receiving the carrier lactosaminated human serum albumin alone; in contrast, they were consistently lower after 5 days of treatment with the antiviral drugs. Free and conjugated adenine arabinoside monophosphate were active at doses of 10 and 0.75 mg/kg, respectively, and free and coupled ACVMP were active at doses of 20 and 2.6 mg/kg, respectively.These results indicate that the dosages of adenine arabinoside monophosphate and acyclovir monophosphate required to inhibit hepadnavirus growth can be sharply reduced by coupling the drugs to lactosaminated human serum albumin. (HEPATOLOGY 1991;14:16

ISSN:0270-9139    

DOI:10.1002/hep.1840140104

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractSeparation of 7–8 S and 19 S forms of serum IgM antibodies to the hepatitis delta virus by rate‐zonal centrifugation was carried out on serum from 24 patients with hepatitis delta virus infection: 4 patients with acute, self‐limited hepatitis; 5 patients with hepatitis delta virus superinfection progressing to chronicity; and 15 patients with chronic hepatitis delta virus.The high molecular weight IgM form (19 S) was predominantly detected in acute hepatitis delta virus cases, whereas the low molecular weight (7 S) form was found in chronic hepatitis delta virus cases. The serological profile of these two forms of IgM antibody to hepatitis delta virus was investigated in serial samples from five patients with acute hepatitis delta virus superinfection that evolved to chronic hepatitis delta virus. We found that, in the acute stage of the disease, the 19 S form was predominant, whereas 6 mo later a predominance of 7–8 S IgM was observed. These results suggest that IgM antibody to hepatitis delta virus antibody forms are different in acute and chronic hepatitis delta virus infection and that their detection only helps in differentiating an acute infection from a chronic infection but not a hepatitis delta virus—hepatitis B virus.‐HBV coinfection from hepatitis delta virus superinfection in the acute stage of the disease. (HEPATOLOGY 199

ISSN:0270-9139    

DOI:10.1002/hep.1840140105

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractFormalin‐fixed, paraffin‐embedded specimens from 110 cases of chronic hepatitis and 108 cases of cirrhosis were stained for HBxAg by the avidin‐biotin complex technique using specific antisera made against full‐length HBxAg polypeptide or derived synthetic peptides. These tissues were also stained for the HBsAg and HBcAg by the peroxidase—anti‐peroxidase method. Among patients with chronic hepatitis, 86% were HBsAg positive in liver cells, 60% were surface antigen positive and 32% were core antigen positive. Among patients with cirrhosis, 97% were HBsAg positive in liver cells, 72% were surface antigen positive and 17% were positive for core antigen. Staining specificity was demonstrated, in part, by using preimmune sera in the place of primary antibody, by blocking of the primary antibody with the appropriate antigen before assay and by testing uninfected liver controls. The persistence and high frequency of HBxAg in liver cells from patients with chronic liver disease suggest that it may play one or more important roles in the pathogenesis of chronic infection. It is possible that detection of HBxAg in the liver could be an additional new diagnostic marker for hepatitis B virus infection. However, the function(s) of HBxAg in the pathogenesis of the chronic liver disease, if any, remains to be explained. (HEPATOLOGY 199

ISSN:0270-9139    

DOI:10.1002/hep.1840140106

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractTo assess possible role of testing for IgM‐specific antibody in the diagnosis and monitoring of patients with hepatitis C, we tested sera from 14 patients with acute and 97 patients with chronic non‐A, non‐B hepatitis for IgG and IgM antibody to hepatitis C virus. IgG antibody to hepatitis C virus was detected in 93% of acute cases and 91% of chronic cases. Of the 101 patients with IgG antibody to hepatitis C virus, 57% had IgM antibody to hepatitis C virus. None of the 20 healthy subjects or 40 patients with acute or chronic hepatitis A or hepatitis B had IgM antibody to hepatitis C virus. At the onset of clinical symptoms in acute hepatitis C, IgG antibody to hepatitis C virus was detected in 8 (57%) and IgM antibody to hepatitis C virus in 9 of 14 patients (64%). Eventually, both IgG and IgM antibody to hepatitis C virus became detectable in 13 of 14 patients with acute hepatitis C. Seven patients with antibody to hepatitis C virus resolved the acute infection within 6 mo and all seven cleared IgM antibody to hepatitis C virus, whereas two cleared IgG antibody to hepatitis C virus. Six patients had a chronic outcome of the acute infection and IgM antibody to hepatitis C virus persisted in detectable amounts for more than 6 mo in all (mean = 15.5 mo). Among 88 patients with chronic non‐A, non‐B hepatitis with IgG antibody to hepatitis C virus, IgM antibody to hepatitis C virus was detected in 45(51%). Twenty‐four chronic cases were followed for at least 1 yr: IgM antibody to hepatitis C virus was detected in 13 (54%) at baseline and 8 of these remained positive for at least 1 yr. Patients who lost IgM antibody to hepatitis C virus did not have remission of disease activity. In summary, IgM antibody to hepatitis C virus persists after acute infection in patients who contract chronic hepatitis C; therefore, testing for this antibody may be useful in early identification of patients for antiviral therapy. (HEPATOLOGY 199

ISSN:0270-9139    

DOI:10.1002/hep.1840140107

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractProduction of the antiviral cytokine, tumor necrosis factor‐α is increased in chronic hepatitis B virus infection, and clinical studies of tumor necrosis factor‐α have indicated a proviral effect at higher doses. To determine whether this might be related to abnormal cell surface tumor necrosis factor‐α receptor expression, binding characteristics of cell surface tumor necrosis factor‐α receptor on peripheral blood mononuclear cells in chronic hepatitis B virus carriers were studied using radioiodinated recombinant tumor necrosis factor‐α. The specific binding curves generated were analyzed according to the method of Scatchard to determine cell surface receptor numbers and dissociation constants.A single class of cell surface tumor necrosis factor‐α receptor was demonstrated on peripheral blood mononuclear cells and mononuclear subsets. The median number (range) of cell surface tumor necrosis factor‐α receptors on peripheral blood mononuclear cells from controls (n = 11), chronic hepatitis B virus patients seropositive for hepatitis B virus DNA (n = 8) and seronegative for hepatitis B virus DNA (n = 8) were 2,329 (range = 1,538 to 3,133), 3,375 (range = 2,300 to 6,718) (p<0.01) and 3,113 (range = 2,229 to 5,246) (p<0.05) sites/cell, respectively. They all had similar dissociation constants of 8.4 × 10−10mol/L (range = 4.1 to 16.9), respectively. Further dissection of the peripheral blood mononuclear cells showed that this increase in cell surface receptor number was confined to the monocyte fraction (p<0.01). Plasma tumor necrosis factor‐α levels in five patients with increased monocyte cell surface tumor necrosis factor‐α receptor numbers were also elevated. No correlation between cell surface tumor necrosis factor‐α receptor number and serum AST, HBsAg, hepatitis B virus DNA or liver histology was observed.These data indicate that cell surface tumor necrosis factor‐α receptor number is increased in monocytes but normal in lymphocytes and support previous observations that monocytes are activated in chronic hepatitis B virus in

ISSN:0270-9139    

DOI:10.1002/hep.1840140108

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractThe recently introduced antibody test for hepatitis C virus infection has already proved to be valuable in many situations such as screening blood donors and diagnosing chronically infected patients, but this antibody assay has certain limitations. Hepatitis C virus itself is usually present in clinical specimens at very low titers; therefore a useful assay for the virus must have very high sensitivity. We have developed a simple, highly sensitive assay for hepatitis C virus RNA based on the polymerase chain reaction. In this test RNA extracted from hepatitis C virus—infected serum or plasma is used as the template for double polymerase chain reaction with nested primers. Sensitivity studies demonstrate that this assay is able to detect hepatitis C virus at or beyond the sensitivity level of chimpanzee infectivity. Preliminary studies in chronic non‐A, non‐B hepatitis showed that 16 of 36 patients positive for antibody to hepatitis C virus and 2 of 4 patients negative for antibody to hepatitis C virus were positive in the polymerase chain reaction test. By retesting the polymerase chain reaction—negative patients with several sets of polymerase chain reaction primers, we found hepatitis C virus RNA in 35 of the 40 patients including all 4 seronegative patients. Normal human plasma and plasma from patients with hepatitis B infection did not react in this test. This assay has proved to be valuable for determining the presence of hepatitis C virus RNA in various samples. Furthermore, it offers the possibility of diagnosis of hepatitis C virus infection in patients who do not react in the presently available antibody tests. (HEPATOLOGY 1991;14

ISSN:0270-9139    

DOI:10.1002/hep.1840140109

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractChronic hepatitis B virus infection is a major medical problem worldwide. Apart from HBsAg carriers, hepatitis B virus has also been identified in some HBsAg—individuals with or without antibodies to viral antigens. The molecular mechanisms underlying hepatitis B virus persistence in HBsAg—individuals are unresolved, however. To identify a possible genetic basis for viral persistence, we cloned the viral genome from the liver of a patient serologically immune to hepatitis B virus infection. DNA sequence analysis of the complete viral genome identified numerous mutations in all viral genes. Analysis of the biological effects of these mutations revealed three major findings: a low level of HBsAg synthesis, absence of HBeAg production and a defect terminating viral replication. These data suggest that mutations accumulating during the natural course of hepatitis B virus infection may be a mechanism underlying viral persistence in HBsAg—individuals, presumably through escape from immune surveillance. (HEPATOLOGY 1991;14:5

ISSN:0270-9139    

DOI:10.1002/hep.1840140110

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractWe assessed the prevalence and clinical significance of antibodies to hepatitis C virus among a cohort of 148 patients with chronic hepatitis B virus infection. Sixteen patients (11%) had anti‐hepatitis C virus detectable by enzyme‐linked immunoassay. The results from eight of these patients were positive by recombinant immunoblot assay. The results of recombinant immunoblot assay testing were not consistent; therefore the analysis of the patients' data was based on anti‐hepatitis C virus enzyme‐linked immunoassay results. Patients with chronic hepatitis B with anti‐hepatitis C virus were more likely to be cirrhotic (44% vs. 21%) and to have decompensated liver disease (24% vs. 6%). Hepatitis B virus replication appeared to be suppressed in patients with both infections as measured by hepatitis B virus—associated DNA polymerase activity (mean = 2,055 vs. 2,555 cpm). Human immunodeficiency virus infection was more common in the anti‐hepatitis C virus positive group (36% vs. 11%). Thus hepatitis C virus appears to suppress hepatitis B virus replication and to cause more severe liver disease in patients with chronic hepatitis B infection. (HEPATOLOGY 1

ISSN:0270-9139    

DOI:10.1002/hep.1840140111

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY