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Biomedical subjects

Roger Williams

Publications and source records attributed to Roger Williams.

At least 19 recordsLinked to original sources
PubMed2007

Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis.

UNLABELLED: Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. CONCLUSION: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.

Adult↗
PubMed2006

Direct evidence for immunomodulatory properties of ribavirin on T-cell reactivity to hepatitis C virus.

BACKGROUND/AIM: An understanding of ribavirin's beneficial effects on treatment outcome in chronic hepatitis C (CH-C) may help to develop new treatment approaches. Here we investigated whether ribavirin directly affects HCV-specific reactivity of CD4+T-lymphocytes from patients with CH-C. METHODS: Peripheral blood mononuclear cells from forty HCV RNA positive patients were cultured ex vivo with HCV core, NS3, NS4 alone, and with different concentrations of ribavirin. Virus-specific CD4+ T-cell reactivity was analysed by a proliferation assay; quantitation of cytokine (interferon-gamma, IL-10, IL-5, IL-12p35, IL-12p40) mRNA levels; measurement of interferon-gamma and IL-10 production (by ELISA) and enumeration of interferon-gamma and IL-10 producing T-cells by Elispot assays. RESULTS: At 2-5 microM ribavirin induced de novo or enhanced T-cell proliferation to HCV antigens in a proportion of patients. Increased T-cell proliferation was associated with decreased IL-10 production in response to HCV core and reduced frequency of IL-10 producing CD4+ T-cells, while interferon-gamma levels remained unchanged. At 20 microM ribavirin markedly suppressed T-cell proliferation, and interferon-gamma mRNA expression to HCV antigens. CONCLUSIONS: Ribavirin, at clinically achievable plasma levels, modulates directly the T-cell responses to HCV antigens in some CH-C patients. Suppression of IL-10 production may represent a useful strategy to induce/augment T-cell reactivity to HCV.

Antiviral Agents↗
PubMed2006

Interorgan ammonia, glutamate, and glutamine trafficking in pigs with acute liver failure.

Ammonia reduction is the target for therapy of hepatic encephalopathy, but lack of quantitative data about how the individual organs handle ammonia limits our ability to develop novel therapeutic strategies. The study aims were to evaluate interorgan ammonia metabolism quantitatively in a devascularized pig model of acute liver failure (ALF). Ammonia and amino acid fluxes were measured across the portal drained viscera (PDV), kidneys, hind leg, and lungs in ALF pigs. ALF pigs developed hyperammonemia and increased glutamine levels, whereas glutamate levels were decreased. PDV contributed to the hyperammonemic state mainly through increased shunting and not as a result of increased glutamine breakdown. The kidneys were quantitatively as important as PDV in systemic ammonia release, whereas muscle took up ammonia. Data suggest that the lungs are able to remove ammonia from the circulation during the initial stage of ALF. Our study provides new data supporting the concept of glutamate deficiency in a pig model of ALF. Furthermore, the kidneys are quantitatively as important as PDV in ammonia production, and the muscles play an important role in ammonia removal.

Ammonia↗
PubMed2006

Global challenges in liver disease.

Immigration, cheap air travel, and globalization are all factors contributing to a worldwide spread of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. End-stage chronic liver disease (ESLD) as a result of co-infection with HBV/HCV is now the major cause of death for individuals who have been infected with the HIV virus. The high incidence of HCV infection in Egypt--the legacy left from the mass use of tartar emetic to eradicate schistosomiasis, as in other high prevalence areas--will take years to reduce. Steatohepatitis due to non-alcoholic fatty liver disease is developing into a new and major health problem as a result of rising levels of obesity in populations worldwide. Hepatic steatosis also has an adverse influence on the progression of other liver diseases including chronic HCV infection and alcoholic liver disease. In many countries, considerable public concern is on the rise due to increased levels of alcohol consumption adversely affecting younger and affluent age groups. With the rising prevalence of cirrhosis, primary hepatocellular carcinoma (HCC) is increasing in frequency as is that of primary intrahepatic cholangiocarcinoma. Finally, despite the successes of liver transplantation, many deserving patients are not getting transplants due to low levels of cadaver organ donation in many countries, thereby increasing pressures on the use of living donor liver transplantation. Only through a concerted effort from governments, health agencies, healthcare professionals at all levels, and the pharmaceutical industry can this grim outlook for liver disease worldwide be reversed.

Global Health↗
PubMed2006

Acute liver failure: a review.

Since publication of the first descriptions of acute liver failure (ALF) as a distinct clinical entity in the 1950's, the understanding of the pathophysiologic mechanisms involved and the management options have increased substantially. ALF still represents a major challenge for todays hepatologists, because it can rapidly lead to multiorgan failure and death that may be preventable with appropriate intervention. This article summarizes the basic patho-physiology underlying ALF, compares epidemiologic trends in the United States, the United Kingdom, and the Far East, and reviews prognostic markers and treatment options for ALF.

Asia, Eastern↗
PubMed2006

Systemic and regional hemodynamics in pigs with acute liver failure and the effect of albumin dialysis.

OBJECTIVE: Acute liver failure (ALF) is haemodynamically characterized by a hyperdynamic circulation. The aims of this study were to investigate the systemic and regional haemodynamics in ALF, to measure changes in nitric oxide metabolites (NOx) and to evaluate whether these haemodynamic disturbances could be attenuated with albumin dialysis. MATERIAL AND METHODS: Norwegian Landrace pigs (23-30 kg) were randomly allocated to groups as controls (sham-operation, n = 8), ALF (hepatic devascularization, n = 8) and ALF + albumin dialysis (n = 8). Albumin dialysis was started 2 h after ALF induction and continued for 4 h. Systemic and regional haemodynamics were monitored. Creatinine clearance, nitrite/nitrate and catecholamines were measured. A repeated measures ANOVA was used to analyse the data. RESULTS: In the ALF group, the cardiac index increased (PGT < 0.0001), while mean arterial pressure (PG = 0.02) and systemic vascular resistance decreased (PGT < 0.0001). Renal resistance (PG = 0.04) and hind-leg resistance (PGT = 0.003) decreased in ALF. There was no difference in jejunal blood flow between the groups. ALF pigs developed renal dysfunction with increased serum creatinine (PGT = 0.002) and decreased creatinine clearance (P = 0.02). Catecholamines were significantly higher in ALF, but NOx levels were not different. Albumin dialysis did not attenuate these haemodynamic or renal disturbances. CONCLUSIONS: The haemodynamic disturbances during the early phase of ALF are characterized by progressive systemic vasodilatation with no associated changes in metabolites of NO. Renal vascular resistance decreased and renal dysfunction developed independently of changes in renal blood flow. After 4 h of albumin dialysis there was no attenuation of the haemodynamic or renal disturbances.

Albumins↗
PubMed2006

Effect of albumin dialysis on intracranial pressure increase in pigs with acute liver failure: a randomized study.

BACKGROUND: Increased intracranial pressure (ICP) worsens the outcome of acute liver failure (ALF). This study investigates the underlying pathophysiological mechanisms and evaluates the therapeutic effect of albumin dialysis in ALF with use of the Molecular Adsorbents Recirculating System without hemofiltration/dialysis (modified, M-MARS). METHODS: Pigs were randomized into three groups: sham, ALF, and ALF + M-MARS. ALF was induced by hepatic devascularization (time = 0). M-MARS began at time = 2 and ended with the experiment at time = 6. ICP, arterial ammonia, brain water, cerebral blood flow (CBF), and plasma inflammatory markers were measured. RESULTS: ICP and arterial ammonia increased significantly over 6 hrs in the ALF group, in comparison with the sham group. M-MARS attenuated (did not normalize) the increased ICP in the ALF group, whereas arterial ammonia was unaltered by M-MARS. Brain water in the frontal cortex (grey matter) and in the subcortical white matter at 6 hrs was significantly higher in the ALF group than in the sham group. M-MARS prevented a rise in water content, but only in white matter. CBF and inflammatory mediators remained unchanged in all groups. CONCLUSION: The initial development of cerebral edema and increased ICP occurs independently of CBF changes in this noninflammatory model of ALF. Factor(s) other than or in addition to hyperammonemia are important, however, and may be more amenable to alteration by albumin dialysis.

Albumins↗
PubMed2005

Equivalence studies for complex active ingredients and dosage forms.

This article examines the United States Pharmacopeia (USP) and its role in assessing the equivalence and inequivalence of biological and biotechnological drug substances and products-a role USP has played since its founding in 1820. A public monograph in the United States Pharmacopeia-National Formulary helps practitioners and other interested parties understand how an article's strength, quality, and purity should be controlled. Such a monograph is a standard to which all manufactured ingredients and products should conform, and it is a starting point for subsequent-entry manufacturers, recognizing that substantial additional one-time characterization studies may be needed to document equivalence. Review of these studies is the province of the regulatory agency, but compendial tests can provide clarity and guidance in the process.

Biotechnology↗
PubMed2005

Analysis of CD4+ T-Cell responses to a novel alpha-fetoprotein-derived epitope in hepatocellular carcinoma patients.

PURPOSE: Alpha-fetoprotein (AFP) is a tumor-associated antigen in hepatocellular carcinoma and is a target for the development of cancer vaccine. Four immunodominant AFP-derived HLA-A*0201-restricted peptides have been identified and the administration of these peptides with an adjuvant has stimulated AFP-specific CTL responses in hepatocellular carcinoma patients. However, no AFP-derived CD4 T-cell epitope has yet been reported and the status of AFP-specific CD4(+) T-cell responses in hepatocellular carcinoma patients is not fully understood. The aim of this study was to analyze naturally occurring CD4(+) T-cell responses to AFP. EXPERIMENTAL DESIGN: We analyzed the ability of CD4(+) T cells to recognize an HLA-DR-restricted AFP-derived epitope in 41 hepatocellular carcinoma patients and 24 non-hepatocellular carcinoma control patients using intracellular cytokine assays for IFN-gamma. RESULTS: Here, for the first time, we report the identification of an AFP-derived CD4(+) T-cell epitope that is recognized by circulating lymphocytes from hepatocellular carcinoma patients in association with HLA-DR. The absence of detectable responses in healthy donors and patients with chronic liver disease suggests that AFP-specific CD4(+) T cells in the responder patients had been previously expanded in vivo in response to the tumor. The anti-AFP CD4(+) T-cell response was only detected in hepatocellular carcinoma patients with normal or mildly elevated serum AFP levels who were in the early stage of disease. CONCLUSION: Our data will be instrumental in the development of cancer vaccine using AFP-derived immunogens.

Adult↗
PubMed2005

Relationship between early HCV kinetics and T-cell reactivity in chronic hepatitis C genotype 1 during peginterferon and ribavirin therapy.

BACKGROUND/AIMS: To gain understanding of inter-individual differences of treatment response in hepatitis C virus genotype 1 (HCV-G1) patients, we investigated simultaneously the early HCV kinetics and virus-specific T-cell reactivity. METHODS: Thirty, treatment-naïve HCV-G1 patients received peginterferon-alfa2a 180 microg/week plus ribavirin 1000-1200 mg/day, with blood samples collected prospectively at protocol time-points. HCV RNA was quantitated with a TaqMan assay with mathematical modelling of HCV decay. Virus-specific CD4+/CD8+ T-cells were enumerated by Elispot assays. RESULTS: HCV kinetic analysis identified two subgroups: fast (18/30) and slow (12/30) treatment-responders. Although these subgroups did not differ in any baseline characteristics, fast responders (FR) showed greater antiviral efficacy (epsilon) than slow responders (SR) (84.5+/-3.2 vs. 65.2+/-7.0%, P=0.002), and a higher rate of infected cell loss (delta) (0.56+/-0.2 vs. 0.04+/-0.02, P=0.038). The viral load drop (baseline to treatment week 4) was higher in FR vs. SR group (3.5+/-1.1 vs. 1.4+/-0.6 log10IU/mL, P<0.001). T-cell reactivity to HCV increased only in FR (after the loss of viraemia), but not in SR patients. CONCLUSIONS: Assessment of early viral and T-cell kinetics during treatment reveals marked differences amongst HCV-G1 patients and may provide a basis for treatment individualization. Enhancement of antiviral T-cell reactivity requires rapid viraemia clearance, rather than immunostimulation alone.

Adult↗
PubMed2005

Albumin dialysis reduces portal pressure acutely in patients with severe alcoholic hepatitis.

BACKGROUND/AIMS: In patients with alcoholic hepatitis (AH), inflammation contributes to the severity of portal hypertension. This study evaluates the acute effects of albumin dialysis, using the Molecular Adsorbents Recirculating System (MARS), on portal pressure in AH. METHODS: Eleven patients with AH and portal hypertension were treated with MARS (n=8) or haemofiltration (n=3). All patients had associated organ failure manifested by hepatic encephalopathy (Grade 2 or more) or renal failure. Hepatic venous pressure gradient (HVPG) was measured before, during and after the treatment session. RESULTS: A rapid significant reduction of HVPG was observed by 6 h (falling by > or =20% in 7/8 patients, reaching 12 mmHg in 6/8), which was sustained up to 18 h after stopping dialysis. Similar rapid sustained improvements of systemic haemodynamics were also observed. No changes occurred in three patients receiving haemofiltration alone. CONCLUSIONS: Albumin dialysis produces clinically significant, acute reduction in portal pressure but the mechanism by which this effect is achieved is not clear. Our results suggest that MARS may be a useful adjunct in management of portal hypertension, particularly in patients with severe AH with associated organ failure.

Adult↗
PubMed2005

Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia.

Although it is life saving, transfusion therapy has resulted in the majority of sickle cell anemia and thalassemia patients being at risk for hemosiderosis-induced organ damage. It is unknown whether the complications of iron overload are affected by the underlying disease. In order to address this problem, we compared the prevalence of organ dysfunction in both groups of patients receiving chronic transfusion therapy (beta thalassemia, N = 30; sickle cell anemia, N = 43). Both groups had similar quantitative liver iron. Thalassemia patients had greater cardiac disease (20% vs. 0%), growth failure (27% vs. 9%), and endocrine failure (37% vs. 0%). The strongest predictors of combined endocrine and cardiac disease in multivariate analysis were duration of chronic transfusion (P = 0.03) and diagnosis (P = 0.03). Quantitative liver iron concentration on a single liver biopsy was not predictive of cardiac or endocrine injury. Viral hepatitis is the strongest predictor of hepatocellular damage (P = 0.009), while the development of liver fibrosis is more closely related to liver iron concentration (P = 0.04). In conclusion, sickle cell anemia and thalassemia differ in the prevalence of organ injury. This difference is related to the duration of iron exposure and the specific hemoglobinopathy. A prospective study with a larger number of subjects is needed to confirm the relationships between specific diagnosis, liver iron concentration over time, and organ dysfunction.

Adolescent↗
PubMed2005

Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity.

Interleukin-12 (IL-12) is an immunomodulatory cytokine that promotes cellular immunity. Pre-clinical data suggest that IL-12 inhibits hepatitis B virus (HBV) replication by stimulating interferon-gamma (IFN-gamma) production. We investigated whether a combination treatment with lamivudine plus recombinant human interleukin-12 (rhIL-12) will result in a greater and prolonged suppression of HBV replication in comparison with lamivudine monotherapy. Fifteen patients with HBeAg-positive chronic hepatitis B were randomized to receive either lamivudine alone for 24 weeks (group 1); combination of lamivudine for 16 weeks and rhIL-12 (200 ng/kg twice weekly), starting 4 weeks after initiation of lamivudine, for 20 weeks (group 2), or the same schedule as for group 2, with lamivudine and a higher dose of rhIL-12 (500 ng/kg, group 3). Serum HBV DNA levels, T-cell proliferation, frequency of virus-specific T-cells, and IFN-gamma production were evaluated serially during and 24 weeks posttreatment. Lamivudine plus rhIL-12/500 showed greater antiviral activity than lamivudine monotherapy. However, after stopping lamivudine in groups 2 and 3, serum HBV DNA increased significantly despite continuing rhIL-12 administration. Lamivudine plus rhIL-12 treatment was associated with a greater increase in virus-specific T-cell reactivity, IFN-gamma production, and an inverse correlation between the frequency of IFN-gamma-producing CD4+ T-cells and viremia. The T-cell proliferative response to HBcAg did not differ between the three groups. In conclusion, the addition of IL-12 to lamivudine enhances T-cell reactivity to HBV and IFN-gamma production. However, IL-12 does not abolish HBV replication in HBeAg-positive patients and does not maintain inhibition of HBV replication after lamivudine withdrawal.

Adjuvants, Immunologic↗