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Biomedical subjects

Roger Williams

Publications and source records attributed to Roger Williams.

At least 73 records · Page 4Linked to original sources
PubMed2003

Validation and refinement of survival models for liver retransplantation.

Orthotopic liver retransplantation (re-OLT) is highly controversial. The objectives of this study were to determine the validity of a recently developed United Network for Organ Sharing (UNOS) multivariate model using an independent cohort of patients undergoing re-OLT outside the United States, to determine whether incorporation of other variables that were incomplete in the UNOS registry would provide additional prognostic information, to develop new models combining data sets from both cohorts, and to evaluate the validity of the model for end-stage liver disease (MELD) in patients undergoing re-OLT. Two hundred eighty-one adult patients undergoing re-OLT (between 1986 and 1999) at 6 foreign transplant centers comprised the validation cohort. We found good agreement between actual survival and predicted survival in the validation cohort; 1-year patient survival rates in the low-, intermediate-, and high-risk groups (as assigned by the original UNOS model) were 72%, 68%, and 36%, respectively (P <.0001). In the patients for whom the international normalized ratio (INR) of prothrombin time was available, MELD correlated with outcome following re-OLT; the median MELD scores for patients surviving at least 90 days compared with those dying within 90 days were 20.75 versus 25.9, respectively (P =.004). Utilizing both patient cohorts (n = 979), a new model, based on recipient age, total serum bilirubin, creatinine, and interval to re-OLT, was constructed (whole model chi(2) = 105, P <.0001). Using the c-statistic with 30-day, 90-day, 1-year, and 3-year mortality as the end points, the area under the receiver operating characteristic (ROC) curves for 4 different models were compared. In conclusion, prospective validation and use of these models as adjuncts to clinical decision making in the management of patients being considered for re-OLT are warranted.

Adult↗
PubMed2003

Mechanisms of hepatocyte injury, multiorgan failure, and prognostic criteria in acute liver failure.

Acute liver failure (ALF) occurs when the rate and extent of liver cell death are not adequately balanced by regenerative activity. Two forms of liver cell death are recognized: apoptosis and necrosis. A number of causes of ALF have been shown, predominantly in experimental animal models, to induce one or the other form of liver cell death. Nonetheless, an insult capable of inducing apoptosis may cause cell death by necrosis, particularly if the degree of mitochondrial damage is sufficient to exhaust stores of adenosine triphosphate. Here we consider mechanisms of liver cell injury in ALF, including evolving knowledge of signaling pathways leading to hepatocellular apoptosis and necrosis. Factors that have an impact on the adequacy of hepatic regeneration along with the pathophysiology of complicating multiorgan failure are also reviewed. Prognostic criteria are discussed, especially in relation to current concepts of mechanisms of liver cell death and multiorgan dysfunction.

Animals↗
PubMed2003

New liver support devices in acute liver failure: a critical evaluation.

Acute liver failure remains a condition with substantial mortality in spite of the best available medical care. Liver transplantation is often not possible or delayed, and liver support systems can be used to maintain the patient during the crisis by bridging to transplantation or allowing recovery of the native liver. Bioartificial devices, using porcine or human hepatocytes, have yielded encouraging results on consciousness levels in a number of studies and have generally been found to be safe, although in one large controlled trial reported to date, benefit was restricted to certain subgroups. Artificial devices, like those based on albumin dialysis, are undoubtedly effective in removing protein-bound toxins, and uncontrolled evidence shows some survival benefit. The large multicenter controlled trials necessary for proving the value of these systems are difficult to design. They have to take into account the influence of transplantation, etiology, and other factors on outcome. Achieving a standard medical regime for these critically ill patients between different centers is also difficult.

Animals↗
PubMed2003

Endocytosis of hepatitis B immune globulin into hepatocytes inhibits the secretion of hepatitis B virus surface antigen and virions.

Hepatitis B immunoglobulin is used for prophylaxis against hepatitis B virus (HBV) and is thought to act by neutralization of virions and hepatitis B virus surface antigen (HBsAg)-containing particles in circulation. Using a panel of hepatocyte-derived cell lines, the present study investigated in vitro whether HBs-specific immunoglobulin G (IgG) is internalized in hepatocytes and whether it interacts with HBsAg in the cells. By immunoelectron microscopy and immunoblotting, human IgG and FcRn receptor for IgG were demonstrated on cellular membranes and in cytoplasmic extracts, irrespective of the HBsAg status of the cells. Furthermore, HBsAg and anti-HBs were shown to be colocalized in the same cellular compartment by two-color confocal microscopy. Endocytosis of HBs-specific IgG caused intracellular accumulation of HBsAg in a dose-dependent manner and inhibited the secretion of HBsAg and HBV virions from the cells. These effects were not observed with F(ab)(2) fragments or nonimmune IgG as controls. The specificity of intracellular HBsAg- anti-HBs interaction was further investigated in cells transfected with HBV genomes expressing wild-type HBsAg or immune escape HBsAg (with a G145R mutation). Monoclonal anti-HBs markedly reduced the secretion of wild-type HBsAg, while the secretion of mutant HBsAg was not affected. These results suggest that HBs-specific IgG binds to hepatocytes and interacts with HBsAg within the cells. This may be relevant for the selection of surface antibody escape mutations.

Base Sequence↗
PubMed2002

Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection.

Deletion, anergy, and a spectrum of functional impairments can affect virus-specific CD8 cells in chronic viral infections. Here we characterize a low frequency population of CD8 cells present in chronic hepatitis B virus (HBV) infection which survive in the face of a high quantity of viral antigen. Although they do not appear to exert immunological pressure in vivo, these CD8 cells are not classically "tolerant" since they proliferate, lyse, and produce antiviral cytokines in vitro. They are characterized by altered HLA/peptide tetramer reactivity, which is not explained by TCR down-regulation or reduced functional avidity and which can be reversed with repetitive stimulation. CD8 cells with altered tetramer binding appear to have a specificity restricted to envelope antigen and not to other HBV antigens, suggesting that mechanisms of CD8 cell dysfunction are differentially regulated according to the antigenic form and presentation of individual viral antigens.

Adult↗
PubMed2002

Regulation of the growth hormone receptor/binding protein, insulin-like growth factor ternary complex system in human cirrhosis.

BACKGROUND/AIMS: The liver is the central organ of the endocrine growth hormone/insulin-like growth factor I (GH/IGF-I) axis and cirrhosis effects a state of acquired GH resistance. Low IGF-I levels are associated with adverse clinical outcomes in cirrhotic patients and may be pathogenic to the complications of cirrhosis. We examined the impact of cirrhosis on hepatic mRNA and serum protein levels for the GH receptor (GHR)/binding protein (GHBP), IGF-I, IGF binding protein (IGFBP)-3 and the acid-labile subunit (ALS). METHODS: Fifty patients with cirrhosis were studied and liver tissue was obtained from 18. Gene expression was assessed by Northern analysis and serum protein levels by immunoassay. RESULTS: In cirrhotic liver GHR mRNA and GH binding to microsomal membranes were decreased by 61 and 56%, respectively. Serum GHBP levels were decreased only in severe disease, not correlating with GHR mRNA or GH binding. Hepatic IGF-I and ALS mRNA were significantly decreased by 84 and 68%, respectively, in parallel with serum protein, suggesting transcriptional regulation. Hepatic IGFBP-3 mRNA was unchanged but low serum IGFBP-3 suggested post-transcriptional regulation. CONCLUSIONS: The decreased mRNA and serum levels for the GH-dependent, hepatocyte produced proteins IGF-I and ALS confirm the importance of GH receptor loss to the GH resistance of cirrhosis.

Adolescent↗
PubMed2002

Chemistry, manufacturing, and controls information in NDAs and ANDAs, supplements, annual reports, and other regulatory filings.

Advice to the pharmaceutical industry regarding the chemistry, manufacturing, and controls and microbiology (sterility assurance) information to be included in regulatory submissions to the Center for Drug Evaluation and Research (CDER) can be found in the pertinent statutes, regulations, and guidances. The primary statute is the Federal Food, Drug and Cosmetic Act (the Act); applicable regulations appear in 21 CFR 312 and 314. Neither the Act nor the regulations provide sufficient detail on the information that should be included in these submissions. Over the past 14 years CDER has issued a series of guidelines and guidances that provide specific detail related to the recommended filing mechanisms and information that CDER expects applicants to provide. Some of these guidances are applicable to original submissions and some are applicable to post-approval changes. This article will provide an overview of The Act, the pertinent regulations, and the pre- and post-approval guidances.

Annual Reports as Topic↗
PubMed2002

The pathophysiological basis of acute-on-chronic liver failure.

The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short and long-term prognosis. This review focuses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that the liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver support strategies to enhance the recovery process.

Acute Disease↗
PubMed2002

Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen.

BACKGROUND & AIMS: Impaired T-cell reactivity is believed to be the dominant cause of chronic hepatitis B virus (HBV) infection. We characterized HBV-specific T-cell responses in chronic hepatitis B surface antigen carriers who received bone marrow from HLA-identical donors with natural immunity to HBV and seroconverted to antibody to hepatitis B surface antigen. METHODS: T-cell reactivity to HBV antigens and peptides was assessed in a proliferation assay, the frequency of HBV core- and surface-specific T cells was quantified directly by ELISPOT assays, and T-cell subsets were analyzed by flow cytometry. RESULTS: CD4+ T-cell reactivity to HBV core was common in bone marrow donors and the corresponding recipients after hepatitis B surface antigen clearance, whereas none reacted to surface, pre-S1, or pre-S2 antigens. Furthermore, CD4+ T cells from donor/recipient pairs recognized similar epitopes on hepatitis B core antigen; using polymerase chain reaction for the Y chromosome, the recipients' CD4+ T lymphocytes were confirmed to be of donor origin. The frequency of core-specific CD4+ and CD8+ T cells was several-fold higher than those specific for surface antigen. CONCLUSIONS: This study provides the first evidence in humans that transfer of hepatitis B core antigen-reactive T cells is associated with resolution of chronic HBV infection. Therapeutic immunization with HBV core gene or protein deserves further investigation in patients with chronic hepatitis B.

Adolescent↗
PubMed2002

Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson's disease.

Wilson's disease presenting as acute liver failure (ALF) is potentially fatal, and liver transplantation (LTx) is the only option. We report two patients with Wilson's disease and ALF treated with the Molecular Adsorbents Recirculating System (MARS). Both patients fulfilled criteria for poor prognosis. Because LTx was not available immediately in either case, MARS was used as a bridge to LTx. In Case 1, serum bilirubin decreased from 803 to 425 micromol/L after 3 treatments, but increased to 656 micromol/L during a break, decreasing again to 457 micromol/L with further treatment. Serum copper decreased from 53.7 micromol/L, to 35.8 micromol/L after first treatment session, and 17.4 micromol/L at treatment completion. In Case 2, MARS treatment over 2 weeks reduced serum bilirubin from 1200 to 450 micromol/L and copper from 35 to 13 micromol/L with marked improvement in encephalopathy and reduction in ammonia (59 to 34 micromol/L). Both patients were successfully bridged to LTx (days 9 and 28, respectively). Analysis of albumin-dialysate from the MARS circuit suggested that copper removal occurred mostly in the first few hours of treatment, partly being adsorbed by albumin and partly by the MARSFlux membrane (Teraklin AG, Rostock, Germany). These data suggest that MARS removes copper efficiently and can be used to bridge patients with Wilson's disease and ALF to LTx.

Acute Disease↗
PubMed2002

Alcohol exposure and paracetamol-induced hepatotoxicity.

Most instances of hepatotoxicity due to paracetamol in the United Kingdom and Australia are the result of large overdoses of the drug taken with suicidal or parasuicidal intent. In contrast, serious hepatotoxicity at recommended or near-recommended doses for therapeutic purposes has been reported, mainly from the United States and in association with chronic alcohol use, leading to the widely held belief that chronic alcoholics are predisposed to paracetamol-related toxicity at relatively low doses. Yet the effects of alcohol on paracetamol metabolism are complex. Studies performed in both experimental animals and humans indicate that chronic alcohol use leads to a short-term, two- to threefold increase in hepatic content of cytochrome P4502E1, the major isoform responsible for the generation of the toxic metabolite from paracetamol, although increased oxidative metabolism of paracetamol at recommended doses has not been demonstrated clinically. A reduced hepatic content of glutathione, required to detoxify the reactive metabolite, has been documented in chronic alcoholics, due probably to associated fasting and malnutrition, providing a metabolic basis for any possible predisposition of this group to hepatotoxicity at relatively low paracetamol doses. Simultaneous alcohol and paracetamol ingestion reduces oxidative metabolism of paracetamol in both rodents and humans, predominantly as a consequence of depletion in cytosol of free NADPH. The possibilities that chronic alcohol use may predispose to paracetamol-related hepatotoxicity and that alcohol taken with paracetamol may protect against it, based on these metabolic observations, are examined in this review.

Acetaminophen↗
PubMed2002

Immunohistochemical differences in the portal tract and acinar infiltrates between primary biliary cirrhosis and autoimmune cholangitis.

BACKGROUND: Antimitochondrial antibody-negative primary biliary cirrhosis, or autoimmune cholangitis, may be indistinguishable clinically and histologically from antimitochondrial antibody-positive primary biliary cirrhosis. AIMS: We aimed to compare the phenotypic markers of the portal and acinar infiltrates in autoimmune cholangitis and antimitochondrial antibody-positive primary biliary cirrhosis. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded liver sections were identified from 32 patients with a clinical and histological diagnosis of primary biliary cirrhosis. Thirteen were antimitochondrial antibody-negative (autoimmune cholangitis group) and 19 were antimitochondrial antibody-positive. The groups were well matched for age, histological stage, liver biochemistry and drug treatment. Immunohistochemical staining was performed using monoclonal antibodies against CD3 (pan T cell), CD8 (cytotoxic), CD45RO (memory), CD45RA (naive), CD68 (macrophages) and against the secreted form of eosinophilic cationic protein (EG2). RESULTS: In autoimmune cholangitis, both portal and acinar CD3 cell counts were significantly higher than in antimitochondrial antibody-positive primary biliary cirrhosis (median portal count 421 vs 257 cells/graticule, P< 0.03; median acinar count 18 vs 9 cells/graticule, P< 0.02). There were no differences between the groups in portal or lobular CD8, CD45RO, CD45RA, CD68 or EG2. Of the total group (antimitochondrial antibody positives and negatives), there were significantly more CD45RA cells in early (stage 1) compared with cirrhotic (stage 4) disease (median 19.3 vs 14 cells/graticule, P< 0.03). EG2 staining was found in eight of the 32 sections overall, but not in the patients with stage 1 disease (P< 0.04). CONCLUSION: CD3 counts are higher in autoimmune cholangitis than in antimitochondrial antibody-positive primary biliary cirrhosis in both portal and acinar areas. However, there are no significant differences in memory/naïve T-cell subsets between both conditions and, in both, loss of naive T lymphocytes and secretion of eosinophilic cationic protein occur with disease progression. This implies that the effector pathways of bile duct destruction are similar in autoimmune cholangitis and primary biliary cirrhosis.

Antibodies, Monoclonal↗
PubMed2002

Acute-on-chronic liver failure: pathophysiological basis of therapeutic options.

The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short- and long-term prognosis. This review focusses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver-support strategies to enhance the recovery process.

Animals↗