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Biomedical subjects

Warren N Schmidt

Publications and source records attributed to Warren N Schmidt.

15 recordsLinked to original sources
PubMed2007

Clinical implications of hepatic steatosis in patients with chronic hepatitis C: a multicenter study of U.S. veterans.

Studies have indicated a high prevalence of hepatic steatosis in patients with chronic hepatitis C (CHC). To address the impact of steatosis on the clinical course of CHC and treatment response requires large multicenter studies. The present study analyzed hepatitis C virus (HCV)-infected veterans enrolled in a U.S. Veteran Administration multicenter study of the epidemiology and response to interferon alpha-2b and ribavirin treatment. Of the 357 patients, 97.1% were males, with a mean age of 48.7+/-6.4 years, and 184 (51.5%) had hepatic steatosis. The mean body mass index (BMI) was 29.3+/-5.2 kg/m(2), including 37.1% who were obese (BMI, > or =30 kg/m(2)). Stage III-IV fibrosis was present in 111 of 334 (33.3%) of the patients. After adjusting for age, race, and history of alcohol use in the past 12 months, only stage III-IV fibrosis was independently and significantly associated with hepatic steatosis (P=0.03). There was a trend of association between obesity and steatosis independent of the other factors. Only HCV genotype was independently associated with a sustained virological response (SVR) to interferon alpha-2b and ribavirin treatment after adjusting for age, alcohol use, steatosis, BMI, stage III-IV fibrosis, serum AFP, and HCV load. In conclusion, analyses of our multicenter trial data demonstrated that the prevalence of hepatic steatosis is 51.5% in HCV-infected U.S. veterans. We found that steatosis is independently associated with stage III-IV fibrosis. However, only HCV genotype, and not steatosis, obesity, or stage III-IV fibrosis, was associated with SVR to interferon alpha-2b and ribavirin treatment.

Adult↗
PubMed2006

Increased hepatic telomerase activity in a rat model of iron overload: a role for altered thiol redox state?

Telomeres are repeated sequences at chromosome ends that are incompletely replicated during mitosis. Telomere shortening caused by proliferation or oxidative damage culminates in replicative arrest and senescence, which may impair regeneration during chronic liver injury. Whereas the effects of experimental liver injury on telomeres have received little attention, prior studies suggest that telomerase, the enzyme complex that catalyzes the addition of telomeric repeats, is protective in some rodent liver injury models. Thus, the aim of this study was to determine the effects of iron overload on telomere length and telomerase activity in rat liver. Mean telomere lengths were similar in iron-loaded and control livers. However, telomerase activity was increased 3-fold by iron loading, with no change in levels of TERT mRNA or protein. Because thiol redox state has been shown to modulate telomerase activity in vitro, hepatic thiols were assessed. Significant increases in GSH (1.5-fold), cysteine (15-fold), and glutamate cysteine ligase activity (1.5-fold) were observed in iron-loaded livers, whereas telomerase activity was inhibited by treatment with N-ethylmaleimide. This is the first demonstration of increased telomerase activity associated with thiol alterations in vivo. Enhanced telomerase activity may be an important factor contributing to the resistance of rodent liver to iron-induced damage.

Animals↗
PubMed2006

Treatment of hepatitis C cryoglobulinemia: mission and challenges.

Mixed cryoglobulinemia (MC) is a syndrome resulting from cold-insoluble immunoglobulin complexes or cryoglobulins (CGs) that precipitate in the serum of 40% to 50% of patients with chronic hepatitis C virus (HCV) infection. The pathogenesis of cryoglobulinemia likely occurs due to chronic viremia and generation of rheumatoid factor following continuous presentation of antigen-immunoglobulin complexes to B cells. CGs are thought to be responsible for a variety of extrahepatic manifestations associated with HCV, including vasculitis, glomerulonephritis, arthritis, and neuropathies, which occur in approximately 10% of HCV patients with CGs. CGs also are a powerful predictive factor for progressive liver disease and the aggressive reoccurrence of liver disease in HCV-positive patients after liver transplantation. First-line therapy for MC due to HCV infection is antiviral therapy with pegylated interferon-alpha and ribavirin. Viral eradication usually produces marked reduction of physical complications and arrests end organ damage concomitant with clearance of CG. Additional prospective, controlled studies are necessary to determine whether CG influences patient virologic response and/or its durability to antiviral therapy. Immunomodulators such as corticosteroids and cyclophosphamide are efficacious for palliative treatment of the symptomatology of HCV cryoglobulinemia but may enhance viral replication. Consequently, prolonged therapy with immunomodulatory agents should be limited to severe vasculitis or aggressive glomerulonephritis in patients with MC due to HCV who have failed to respond to antiviral therapy. In acute, fulminant presentations, plasmapheresis may provide temporary relief and arrest the rapid progression of the disease so that additional therapy can be initiated.

Journal Article↗
PubMed2005

Positive serum cryoglobulin is associated with worse outcome after liver transplantation for chronic hepatitis C.

BACKGROUND: Recurrent hepatitis C virus (HCV) infection in patients after liver transplantation is an important clinical problem. Because serum cryoglobulins (CG) are known to be associated with an increased incidence of cirrhosis in nontransplant patients, the authors tested the hypothesis that CG would also predict aggressive recurrent HCV in patients after liver transplantation. METHODS: Using a longitudinal database, the outcomes of 105 allografts transplanted into 97 HCV-positive patients from 1991 through 2002 were analyzed on the basis of CG status using a retrospective cohort design. Fifty-nine CG-negative and 38 CG-positive patients were identified. Histologic outcomes and graft survival were analyzed using Kaplan-Meier estimates and Cox univariate and multivariate analyses. Both overall survival and HCV-specific survival (non-HVC-related deaths and graft losses censored) were analyzed. RESULTS: By Kaplan-Meier estimates, CG-positive patients showed earlier graft failure with decreased time to severe histologic activity and fibrosis as compared with CG-negative patients (P<0.05 for all outcomes). By univariate analysis, CG-positive patients had significantly higher risk ratios for shortened HCV-specific graft survival, severe activity-free survival, and severe fibrosis-free survival as compared with CG-negative patients (P<0.05 for all outcomes). In the multivariate model, CG was an independent predictor for severe activity-free, severe fibrosis-free, and HCV-specific graft survival (P<0.05 for all outcomes). CONCLUSIONS: CG-positivity is associated with severe recurrent HCV disease in liver transplant recipients.

Adult↗
PubMed2005

Hepatitis C virus-core and non structural proteins lead to different effects on cellular antioxidant defenses.

Chronic hepatitis C virus (HCV) infection leads to increased oxidative stress in the liver. Hepatic antioxidant enzymes provide an important line of defense against oxidative injury. To understand the antioxidant responses of hepatocytes to different HCV proteins, we compared changes in antioxidative enzymes in HCV-core and HCV-nonstructural protein expressing hepatocyte cell lines. We found that expression of HCV-core protein in hepatocyte cell lines leads to increased oxidative stress as determined by increased in the oxidant-sensitive probe 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-DCFH(2)) fluorescence, decreased reduced glutathione (GSH), and increased oxidation of thioredoxin (Trx). Although the expression of HCV-nonstructural (HCV-NS) proteins led to increased oxidative stress as well, the antioxidant enzymatic responses were different. Over-expression of HCV-NS proteins increased antioxidant enzymes (MnSOD and catalase), heme oxygenase-1 (HO-1), and GSH, indicating different mechanism(s) of prooxidative activity than HCV-core protein. Our findings show that different HCV proteins induce different antioxidant defense responses in hepatocytes. These findings may facilitate understanding the interaction of different HCV proteins with infected liver cells and help identify possible factors contributing to hepatocyte damage during HCV infection.

Catalase↗
PubMed2005

Expression of HSP47, a collagen-specific chaperone, in normal and diseased human liver.

HSP47 is a collagen-specific chaperone that is required for normal collagen synthesis. In animal models of liver injury, hepatic stellate cells (HSC) have been identified as a source of HSP47. Because expression of HSP47 has not been investigated in human liver, the aim of these studies was to characterize expression of HSP47 in human liver and to investigate its regulation in human HSC in vitro. Immunohistochemistry demonstrated staining for HSP47 along the sinusoids of normal and cirrhotic human livers and in fibrous septa. Dual fluorescence confocal microscopy showed colocalization of HSP47 with synaptophysin, a marker for HSC. Levels of immunoreactive HSP47 and its transcript tended to be higher in cirrhotic livers than in normal livers. The abundance of HSP47 protein was unchanged by treatment of cultured human HSC with TGF-beta1, angiotensin II, hypoxia and a number of other treatments intended to increase collagen synthesis. A modest reduction in HSP47 was achieved by transfection with antisense oligonucleotides and was associated with a significant decrease in procollagen synthesis. These observations suggest that HSP47 is constitutively expressed in human HSC and that HSP47 may be a target for antifibrotic therapy.

Base Sequence↗
PubMed2005

GB virus type C NS5A sequence polymorphisms: association with interferon susceptibility and inhibition of PKR-mediated eIF2alpha phosphorylation.

GB virus type C (GBV-C) causes persistent infection in humans, although the mechanism by which the virus avoids clearance by the host is unknown. To determine if amino acid polymorphisms in the GB virus type C (GBV-C) NS5A and E2 proteins alter response to interferon (IFN) therapy, we studied the sequence of GBVC NS5A and E2 obtained from people receiving IFN therapy. In addition, we expressed recombinant GBVC NS5A protein to determine if it interferes with RNA-activated protein kinase (PKR) function in vitro. GBVC NS5A amplified from a person whose virus was cleared by IFN therapy (IFN sensitive) demonstrated unique amino acid changes occurring in the region that aligns with the hepatitis C virus (HCV) IFN sensitivity-determining region (ISDR) compared with NS5A sequences from individuals who did not clear GBV-C (IFN resistant). There were no differences in the E2 sequences obtained from IFN-sensitive and IFN-resistant isolates. Using a yeast genetic system, IFN-resistant NS5A inhibited PKR-mediated phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) in yeast, whereas IFN-sensitive NS5A did not inhibit PKR function. GBV-C NS5A amino acid polymorphisms appear to be involved in response to IFN therapy, and IFN-resistant GBV-C NS5A inhibited PKR-mediated eIF2alpha phosphorylation in a yeast genetic system, suggesting a mechanism by which GBV-C may evade clearance by naturally occurring host antiviral responses.

Amino Acid Sequence↗
PubMed2005

Hemosiderosis is associated with accelerated decompensation and decreased survival in patients with cirrhosis.

AIM: Although hepatic iron deposition unrelated to hereditary hemochromatosis is commonly observed in cirrhosis, its clinical significance is unclear. The aim of this study was to examine the outcomes of cirrhotic patients with and without hemosiderosis. METHODS: Patients with an initial liver biopsy demonstrating cirrhosis between January 1993 and December 1997 were identified using the Department of Pathology database. Based on iron staining, patients were characterized as siderotic or nonsiderotic. Charts were reviewed to determine outcomes. RESULTS: Siderotic patients had significantly higher Child-Pugh (CP) and model for end-stage liver disease (MELD) scores. Their median survival without transplant was 23 months vs. 85 months in the nonsiderotics (P<0.0001, confidence interval: 95%). On univariate analysis, siderosis was associated with a hazard ratio of 2.74 (P<0.0001). On multivariate analysis, the effect of siderosis was reduced but remained significant after correction for the CP or MELD score (hazard ratios 1.82 and 2.06, P=0.05 and 0.02, respectively). Child's A cirrhotics with hemosiderosis decompensated more rapidly and had shorter median survival than those without siderosis (P=0.007 and P=0.01, respectively). CONCLUSIONS: The presence of siderosis is associated with more advanced liver dysfunction. Even when the effects of baseline liver function are taken into account, siderosis is associated with decreased survival and more rapid decompensation in cirrhosis.

Female↗
PubMed2005

Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection.

BACKGROUND: Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment. METHODS: We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician. RESULTS: Overall, 32.2% (95% CI, 30.8-33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2-42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24-25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85-13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70-13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42-16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0-78.3%) agreed to be treated and multivariable analysis showed that persons >/=50 yr of age (OR = 1.37; 95% CI, 1.07-1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08-1.93) were more likely to decline treatment. CONCLUSIONS: The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.

Antiviral Agents↗
PubMed2004

Down-regulation of heme oxygenase-1 by hepatitis C virus infection in vivo and by the in vitro expression of hepatitis C core protein.

Antioxidant enzymes, including heme oxygenase (HO)-1, are an important line of defense against oxidant-mediated liver injury. Because hepatitis C virus (HCV) infection appears to increase the production of oxidants, we evaluated levels of antioxidant enzymes and HO-1 in liver-biopsy samples from HCV-infected patients by immunoblot and semiquantitative reverse-transcriptase polymerase chain reaction. In HCV-infected liver samples, levels of immunoreactive HO-1 and HO-1 mRNA were >4-fold lower than levels in control samples, but levels of superoxide dismutase and catalase were unaffected. Immunohistochemical results confirmed the decreased expression of HO-1 in hepatocytes from liver samples from HCV-infected patients but not in those from patients with other chronic liver diseases. The expression of HO-1 was also reduced in cell lines that stably express HCV core protein, which suggests that core gene products are capable of regulating the expression of HO-1.

Biopsy↗
PubMed2004

Increased prooxidant production and enhanced susceptibility to glutathione depletion in HepG2 cells co-expressing HCV core protein and CYP2E1.

Hepatitis C virus (HCV) and HCV core protein are hypothesized to induce hepatic oxidative stress and exacerbate injury caused by other toxins such as ethanol that induce the cytochrome P450 enzyme, CYP2E1. In the current study, the effects of HCV core protein [sequence genotype 1b, (nt 342-915)] on parameters indicative of oxidative stress were evaluated in HepG2 cells stably over expressing CYP2E1 (E47), or vector controls (C34). Stable (>10 passages) expression of HCV core protein and CYP2E1 was confirmed in clonal cell lines at the level of mRNA and immunoreactive protein. Prooxidant production, as determined by cellular oxidation of dichlorodihydrofluorescin and dihydroethidium (HE), was increased by expression of HCV core protein in the presence or absence of CYP2E1. Depletion of glutathione (GSH) with buthionine sulfoximine (BSO) enhanced prooxidant production in both C34 and E47 cells. In addition, prooxidant production was greater in BSO-treated cells expressing HCV core protein, and this effect was further enhanced in cells expressing both HCV core and CYP2E1. The CYP2E1 inhibitor, 4-methylpyrazole, could suppress increased prooxidant production in E47 cells. Finally, cells co-expressing both CYP2E1 and HCV core protein showed significantly decreased viability following GSH depletion. These studies show simultaneous expression of HCV core protein and CYP2E1 increases parameters indicative of oxidative stress as well as sensitization to cell injury induced by GSH depletion. These results support the hypothesis that enhanced injury in hepatocytes over expressing both HCV core protein and CYP2E1 is mediated by increases in oxidative stress.

Buthionine Sulfoximine↗
PubMed2002

Hepatitis C virus viremia in HIV-infected individuals with negative HCV antibody tests.

Hepatitis C virus (HCV) viremia may occur in persons without detectable HCV antibodies and has been reported in as many as 5.5% of HIV-positive persons. To better characterize serosilent HCV infection, the authors prospectively tested 131 HIV-positive persons and 102 HIV-negative control subjects with diabetes for the presence of HCV antibody (Ab) and HCV RNA. Thirty of 31 HCV Ab-positive (AbP) HIV-positive people tested positive for HCV RNA as did both HCV AbP, HIV-negative control subjects. Similarly, none of the 100 HIV-negative, HCV Ab-negative (AbN) control subjects was HCV RNA positive (p<.001). In contrast, 19 of 100 HIV-positive, HCV AbN persons met stringent criteria for HCV viremia, and 9 of these 19 people were HCV RNA positive when tested by a commercially available HCV RNA detection method. The mean duration of HCV viremia in HCV AbN people was 26.8 months (range, 1-99 months). None of the subjects developed HCV antibody during the study. The HIV-positive, HCV AbP, and RNA-positive group was significantly more likely to have acquired HIV parenterally (p<.001), have higher initial CD4 counts (p=.029), and have higher ALT values than the HCV AbN group (p<.002). In summary, HCV infection appears to occur more frequently among HIV-infected, HCV-seronegative persons than appreciated, especially if HIV acquisition was through sexual as opposed to parenteral risk factors and was associated with a lower initial CD4 count and lower ALT values.

Adult↗
PubMed2002

Recombinant hepatitis C virus-like particles expressed by baculovirus: utility in cell-binding and antibody detection assays.

Hepatitis C virus (HCV) is difficult to study due to the lack of an efficient cell culture system or small animal model. As a result, HCV-cell interactions are not well-defined. In addition, several studies have identified a subset of patients in whom HCV RNA is present, but HCV antibody is not detected. We produced recombinant baculoviruses that expressed HCV structural proteins (core, E1 and E2, nt 342-2651) or control proteins. The HCV structural protein precursor was processed into immunoreactive proteins of appropriate size, and sucrose density sedimentation and electron microscopy of infected cell lysates demonstrated particle formation. To evaluate HCV antigenicity, particularly in patients who tested negative for HCV antibody in commercial HCV immunoassays but had persistent viremia, we evaluated the virus-like particles (VLPs) in solid-phase immunoassays. VLPs reacted with sera from HCV antibody positive subjects in these solid phase immunoassays, but not with control sera. Plasma samples from 19% (5/26) of HCV antibody negative subjects who were persistently HCV RNA positive also reacted with the HCV VLPs. When incubated with MOLT-4 cells at 4 degrees C, HCV VLPs demonstrated cell binding, and behaved similar to plasma-derived HCV preparations in a flow cytometry-based cell binding assay. These data suggest that recombinant HCV VLPs may allow identification of HCV antibody in patients, including some patients with persistent viremia and who are seronegative with current assays. In addition, HCV VLPs seem useful for evaluating HCV-cell interactions.

Animals↗
PubMed2002

Hepatitis C, cryoglobulinemia, and cirrhosis: a meta-analysis.

Approximately 40% of patients with chronic hepatitis C virus (HCV) infection develop detectable serum cryoglobulins or cryoprecipitates (CP), although most do not show clinical or physical signs of syndromic cryoglobulinemia. Although association of HCV with the extrahepatic complications of cryoglobulinemia is widely recognized, the relationship of cryoglobulinemia with liver disease is unclear. We wished to study the relationship between CP and cirrhosis and to determine whether the development of CP is a true covariate for progressive liver disease or a confounding variable that impacts cirrhosis because of patient age, duration of disease, or differences in gender. We undertook a meta-analysis of 19 studies published between 1994 and 2001. The incidence of cirrhosis was compared in patients with and without CP after logistic regression adjustments for accepted risk factors for progressive liver disease, including age, gender, and estimated duration of disease (EDD). A total of 2,323 patients with chronic hepatitis C were identified, with 1,022 (44%) having detectable CP. Cirrhosis was present in 40% of patients with CP but only 17% of patients without CP (total Chi;(2) = 141.69, P <.001). After adjusting for age, gender, and estimated duration of disease by logistic regression, the combined odds ratio for incidence of cirrhosis in patients CP positive versus CP negative was 4.87, (95% CI: 3.32, 7.15), indicating a highly significant association between cirrhosis and cryoglobulinemia. In conclusion, cryoglobulins may be a useful prognostic indicator for increased risk of cirrhosis with chronic hepatitis C.

Cryoglobulinemia↗