PubMed Health⌕ Search

Biomedical subjects

R Sallie

Publications and source records attributed to R Sallie.

At least 19 recordsLinked to original sources
PubMed1999

Influence of the vitamin D receptor gene polymorphism on bone loss in men after liver transplantation.

BACKGROUND: Bone loss is a frequent complication after liver transplantation. OBJECTIVE: To investigate whether vitamin D receptor gene polymorphism influences bone loss in men after liver transplantation. DESIGN: Prospective cohort study. SETTING: University hospital. PATIENTS: 55 male candidates for liver transplantation. MEASUREMENTS: Lumbar spine bone mineral density was measured before and 3, 6, 12, and 24 months after liver transplantation. Vitamin D receptor genotype was determined by restriction endonuclease Bsml. RESULTS: Vitamin D receptor genotypes were significantly associated with post-transplantation changes in bone mineral density (P = 0.028). Within 3 months after transplantation, patients with the genotypes Bb or BB showed a vertebral bone loss substantially greater than that in patients with the bb genotype (between-group difference in the percentage change with respect to baseline bone mineral density, 3.7% [95% CI, 0.6% to 6.9%1). In 3 to 24 months after transplantation, bone mineral density increased steadily in the three allelic groups. CONCLUSIONS: Vitamin D receptor gene polymorphism influences bone loss after liver transplantation. Patients with the bb genotype are, to some extent, protected against post-transplantation bone loss.

Bone Density↗
PubMed1997

Hepatitis B virus replication and mutation are autoregulated by interactions between surface antigen and HBeAg and the HBV DNA polymerase: a functional model with therapeutic implications.

Infection with hepatitis B virus can result in asymptomatic seroconversion with viral clearance, fulminant hepatic failure and death, or chronic, typically lifelong, transmissible infection. The mechanism(s) of viral persistence are poorly understood but viral clearance and fulminant hepatic failure are generally thought to result from co-ordinated and effective and abnormally vigorous immune responses, respectively, whereas viral persistence results from immunological failure in addition to poorly characterized viral factors promoting persistence. This paper proposes (1) that the predominant viral factor(s) promoting persistence of hepatitis B virus are homeostatic mechanism(s) responsible for modulating its replication and mutation and (2) that chronic hepatitis B results when these mechanisms are successful and other outcomes occur when these homeostatic mechanism(s) fail. Furthermore, it is proposed that seroconversion (e.g. from HBsAg to anti HBsAg positivity), when it occurs, is a consequence facilitated by restricted viral antigenic diversity and reduced viral replication rather than a proximate cause of it. The specific homeostatic mechanisms proposed--negative feedback inhibition of hepatitis B virus DNA polymerase/reverse transcriptase mediated by HBs antigen and a hepatitis B virus DNA polymerase fidelity modulating function of HBeAg--are consistent with the available data and resolve many paradoxical clinical observations. But, more importantly, this model has clear implications for therapy, including the rational design of drugs and therapeutic vaccines.

DNA-Directed DNA Polymerase↗
PubMed1997

Histopathologic changes associated with fialuridine hepatotoxicity.

Chronic hepatitis B is a widespread viral illness with the serious sequelae of cirrhosis and hepatocellular carcinoma. Current therapy with interferon is not universally efficacious, and this has led to the evaluation of other antiviral agents. A recent Phase II trial of the nucleoside analogue, fluoroiodoarabinofuranosyluracil (fialuridine, FIAU) was halted because of the sudden development of severe multisystem toxicity characterized by hepatic failure, lactic acidosis, and pancreatitis, which resulted in the deaths of five patients. We systematically evaluated pre- and post-therapy biopsy, explant, and autopsy specimens from the 15 patients involved in this trial to define the hepatic changes of fialuridine toxicity and to determine whether the degree of pre-existing hepatitis contributed to the severity of toxicity. Severe hepatotoxicity from fialuridine was characterized by hepatomegaly with diffuse, predominantly microvesicular steatosis, hepatocellular glycogen depletion, marked bile ductular proliferation, and cholestasis. Ultrastructural examination revealed intracytoplasmic lipid droplets and marked mitochondrial injury. Patients in whom severe toxicity did not develop mainly showed changes caused by the underlying chronic hepatitis B alone. There was a subtle increase in the amount of microvesicular steatosis in two of six patients with mild or no symptoms of toxicity. The microscopic and ultrastructural pattern of injury and systemic symptoms in patients with fialuridine toxicity are consistent with severe mitochondrial and metabolic derangements. Similar hepatic pathologic findings have been reported rarely for other antiviral nucleoside analogues, which suggests that the mechanisms of toxicity might be related.

Adult↗
PubMed1996

Prevalence of herpesviridae and hepatitis B virus DNA in the liver of patients with non-A, non-B fulminant hepatic failure.

Members of the herpes virus family and hepatitis B virus (HBV) have been implicated as etiologic agents in non-A, non-B (NANB) fulminant hepatic failure (FHF), but the frequency of infection with these agents has not been established using appropriate controls. To examine this issue, we studied 50 NANB FHF patients and 104 liver transplant recipients from North America and Europe. Hepatic DNA was analyzed by polymerase chain reaction (PCR) for evidence of Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus I (HSV I) and II (HSV II), varicella-zoster virus (VZV), and human herpes virus-6 (HHV-6) nucleic acid sequences. The prevalence of HBV was assessed in North American subjects only. HSV I, HSV II, VZV, and HHV-6 viral sequences were not observed in any samples. Three of 50 FHF (6%) and 14 of 104 control patients (13%) were positive for CMV DNA. Two of 50 FHF (4%) and 10 of 104 control patients (10%) had EBV DNA, and HBV DNA was observed in 3 of 10 North American FHF patients (30%) and 3 of 59 controls (5%) without serum markers for HBV infection. The finding of HBV DNA in the liver of seronegative controls from North America but not Europe suggests that occult hepatitis B sequences in patients with NANB FHF may simply reflect geographic differences. The majority of cryptogenic FHF cases cannot be attributed to infection with herpes viruses or HBV.

Adolescent↗
PubMed1996

Gene identification by chromosomal in-situ hybridization, microdissection and polymerase chain reaction amplification.

This paper describes a theoretical method by which candidate genes for inherited diseases can be identified by polymerase chain reaction amplification and subsequent cloning of organ-specific complementary deoxyribonucleic acid libraries hybridized in situ to, and subsequently dissected from, the cognate chromosome. A specific application of this technique to isolate genes related to genetic haemochromatosis is outlined.

Chromosome Mapping↗
PubMed1996

Genetic heterogeneity of hepatitis C virus. The clinical significance of genotypes and quasispecies behavior.

Knowledge of the molecular biology of the hepatitis C virus (HCV) has increased exponentially since its identification in 1989. Paradoxically, the understanding of many clinical aspects of HCV pathobiology has lagged behind, partly because of lack of suitable models of disease. The genomic variability of HCV is central to viral pathogenesis. This article briefly reviews some clinical and laboratory aspects of HCV variability, such as investigatory method, pitfalls in data interpretation, and possible directions for future research. The profound implications of stable quasispecies behavior, conserved genotype replication, and the unexpectedly low frequency of infection with multiple genotypes in susceptible individuals are discussed.

DNA-Directed RNA Polymerases↗
PubMed1995

Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate ribavirin, an oral antiviral agent, as therapy for chronic hepatitis C. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Clinical Center of the National Institutes of Health, a tertiary referral research hospital. PATIENTS: 29 patients with chronic hepatitis C who received oral ribavirin (600 mg twice daily) for 12 months and 29 controls with chronic hepatitis C who received placebo for 12 months. MEASUREMENTS: Effects of therapy were evaluated by measuring serum aminotransferase and hepatitis C virus (HCV) RNA levels before, during, and for 6 months after therapy and by histologic examination of liver specimens before and at the end of treatment. RESULTS: Patients treated with ribavirin had a prompt decrease in serum aminotransferase levels (54% overall) compared with levels before treatment and levels in controls (5% decrease). Serum aminotransferase levels became normal or nearly normal in 10 patients treated with ribavirin (35% [95% CI, 18% to 54%]) but in no controls (0% [CI, 0% to 12%]). Aminotransferase levels remained normal in only 2 patients after ribavirin therapy was discontinued (7% [CI, 1% to 23%]). Serum HCV RNA levels did not change during or after therapy. Liver biopsy specimens showed a decrease in hepatic inflammation and necrosis among ribavirin-treated patients whose aminotransferase levels became normal. CONCLUSIONS: Ribavirin has beneficial effects on serum aminotransferase levels and histologic findings in the liver in patients with chronic hepatitis C, but these effects are not accompanied by changes in HCV RNA levels and are not sustained when ribavirin therapy is discontinued. Thus, ribavirin alone for periods as long as 12 months is unlikely to be of value as therapy for chronic hepatitis C.

Administration, Oral↗
PubMed1995

Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B.

BACKGROUND: We describe severe and unexpected multisystem toxicity that occurred during a study of the antiviral nucleoside analogue fialuridine (1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil, or FIAU) as therapy for chronic hepatitis B virus infection. METHODS: Fifteen patients with chronic hepatitis B were randomly assigned to receive fialuridine at a dose of either 0.10 or 0.25 mg per kilogram of body weight per day for 24 weeks and were monitored every 1 to 2 weeks by means of a physical examination, blood tests, and testing for hepatitis B virus markers. RESULTS: During the 13th week lactic acidosis and liver failure suddenly developed in one patient. The study was terminated on an emergency basis, and all treatment with fialuridine was discontinued. Seven patients were found to have severe hepatotoxicity, with progressive lactic acidosis, worsening jaundice, and deteriorating hepatic synthetic function despite the discontinuation of fialuridine. Three other patients had mild hepatotoxicity. Several patients also had pancreatitis, neuropathy, or myopathy. Of the seven patients with severe hepatotoxicity, five died and two survived after liver transplantation. Histologic analysis of liver tissue revealed marked accumulation of microvesicular and macrovesicular fat, with minimal necrosis of hepatocytes or architectural changes. Electron microscopy showed abnormal mitochondria and the accumulation of fat in hepatocytes. CONCLUSIONS: In patients with chronic hepatitis B, treatment with fialuridine induced a severe toxic reaction characterized by hepatic failure, lactic acidosis, pancreatitis, neuropathy, and myopathy. This toxic reaction was probably caused by widespread mitochondrial damage and may occur infrequently with other nucleoside analogues.

Acidosis, Lactic↗
PubMed1995

Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features. The Hepatitis C Study Group.

OBJECTIVE: To assess the clinical significance of antibody to hepatitis C virus (anti-HCV) in volunteer blood donors. DESIGN: Prospective cohort study. SETTING: National Institutes of Health Clinical Center, a tertiary referral research hospital. PATIENTS: 60 anti-HCV-positive blood donors, divided into three groups of 20 persons each: Group I had normal alanine aminotransferase levels, group II had levels elevated to values less than twice the normal range, and group III had levels elevated to values greater than twice the normal range. MEASUREMENTS: Medical history, results of laboratory and virologic testing, and percutaneous liver biopsy findings. RESULTS: Participants with normal alanine aminotransferase levels were older and more often female than those with abnormal levels. The source of infection, duration of disease, symptom score, and amount of alcohol consumed were similar in the three groups. Hepatitis C virus RNA was detectable in 85% of participants, more commonly in the groups with elevated alanine aminotransferase levels (95%) than in the group with normal levels (65%); however, titers were similar in all groups. Examination of liver biopsy specimens showed chronic hepatitis in 54 participants (90%) and cirrhosis in 1 participant. The only normal liver biopsy specimens (n = 3) were those from participants who were HCV RNA negative and had normal alanine aminotransferase levels. CONCLUSIONS: Most blood donors with anti-HCV have chronic hepatitis C regardless of their serum alanine aminotransferase levels. Donors with normal alanine aminotransferase levels and no HCV RNA in their serum generally have normal liver histologic findings or minimal changes and have probably recovered from HCV infection.

Adult↗
PubMed1995

Clinical recurrence of hepatitis A following liver transplantation for acute liver failure.

This paper documents clinically significant recurrence of hepatitis A virus (HAV) infection in a 63-year-old man transplanted for HAV-related acute liver failure. HAV RNA was documented in the explant and, following early clearance from the blood and graft, was again detected in post-operative biopsies at the time of an acute hepatic illness. Although the clinical and biochemical abnormalities resolved completely, the patient had a second episode of graft dysfunction 6 months later and investigations revealed hepatitis C virus (HCV)-related chronic active hepatitis consistent with acquired HCV infection at the time of transplantation. The possible interaction with hepatitis A may have delayed the appearance of hepatitis C. Administration of HAV immunoglobulin at the time of transplantation should be considered in all cases of HAV-related fulminant hepatic failure.

Base Sequence↗
PubMed1995

Intrahepatic expression of hepatitis C virus antigens in chronic liver disease.

Localization of hepatitis C virus (HCV) antigens was studied in fresh frozen and formalin-fixed, paraffin-embedded liver tissue by immunoperoxidase using monoclonal antibodies to nucleocapsid protein and polyclonal human immunoglobulin G purified from plasma containing antibodies to structural and non-structural antigens of hepatitis C virus. The results observed using monoclonal antibody to HCV core were similar to those of polyclonal IgG against HCV antigens in the majority of cases and both correlated well with HCV status as defined by 'nested' polymerase chain reaction. HCV antigens were detected in both hepatocytes and mononuclear cells. Using polyclonal human IgG, a small proportion of biliary epithelial cells were also positive in 6/29 patients. In most of the specimens examined, relatively few cells (1-5 per cent) were found to be positive for HCV antigens. The cryostat sections, using polyclonal IgG against HCV antigens, exhibited greater immunohistochemical staining, suggesting that the fixation and processing of the tissue may be a major factor in the conservation and the outcome of HCV antigen(s) findings. However, the results using monoclonal antibodies may reflect the specificity of antigen expression.

Antibodies, Monoclonal↗
PubMed1995

Detection of hepatitis E virus genome and gene products in two patients with fulminant hepatitis E.

Non-isotopic in situ hybridization (digoxigenin-labeled probe directed towards hepatitis E virus ORF1) and immunohistochemistry (against hepatitis E virus ORF2 and ORF3) were applied to detect hepatitis E virus genome and gene product in the liver tissue of two patients with fulminant hepatitis E seropositive for hepatitis E virus RNA. Both hepatitis E virus RNA and hepatitis E virus antigens were detected exclusively in the cytoplasm of hepatocytes and not detected in other cell types. In both patients, more than 50% of the hepatocytes were positive for both hepatitis E virus RNA and hepatitis E virus antigens, most of which showed degenerative changes. This is consistent with the histological appearance of marked loss of hepatocytes with acinar collapse. Interestingly, denaturation of the RNA before in situ hybridization was found to enhance hepatitis E virus RNA detection. We conclude that: (1) hepatitis E virus RNA and hepatitis E virus antigens can be demonstrated in the liver in hepatitis E virus-related fulminant hepatitic failure, (2) hepatitis E virus is hepatocyte-tropic within the liver, (3) cytoplasmic localization of hepatitis E virus RNA and hepatitis E virus antigens is consistent with cytoplasmic replication, and (4) the presence of degenerative changes in hepatitis E virus positive cells, together with the histological appearance of hepatocyte loss in the absence of significant inflammatory infiltrate, suggests that hepatitis E virus-related fulminant hepatitic failure is mediated by a cytopathic mechanism.

Acute Disease↗
PubMed1995

Detection of hepatitis B virus transcriptional activity: an hypothesis.

This paper outlines a method of demonstrating hepatitis B virus (HBV)-related transcriptional activity based on the random amplification of cDNA ends (RACE) protocol. Following RNA extraction from the appropriate tissue, cDNA is synthesized using a long oligo d(T) based primer containing unique 5' oligonucleotide sequences. Nested polymerase chain reaction (PCR) is then carried out using virus-specific oligonucleotides and standard PCR (approximately 20 base pairs) oligonucleotides homologous to 5' regions of the long oligo-d(T) primer used to initiate the cDNA reaction. This technique is particularly applicable to the study of HBV transcription in small samples of tissue, for example, from renal biopsies obtained from patients with HBV-related nephritis.

Base Composition↗
PubMed1995

A strategy for the detection of de novo synthesis of nucleic acids: an hypothesis.

This paper outlines novel strategy for demonstrating de novo synthesis of nucleic acids applicable, at least, to the detection of viral replication within cell culture or other in vitro systems. The method uses an incorporation capture technique which is suitable for the detection of new and on-going synthesis of both RNA and DNA of any specific sequence. When combined with random RNA (or DNA) amplification by polymerase chain reaction (PCR), and subsequent application of well established cloning techniques, this strategy will allow the construction cDNA libraries of newly synthesized RNAs.

Animals↗
PubMed1995

Sequence-independent identification of infectious pathogens: an hypothesis.

This paper presents a theoretical polymerase chain reaction (PCR)-based strategy for identification of infectious pathogens independent of either the sequence or the nature of the genomic nucleic acid. Total nucleic acid purified from simple clinical fluids (such as serum or cerebrospinal fluid) from a patient is randomly amplified and cloned and then probed with labeled nucleic acid similarly amplified from a second patient. Positive clones are then characterized by standard sequencing techniques. Such methodology is applicable to the investigation of diseases in which chronic infection may play an etiologic role.

Base Sequence↗
PubMed1995

Isolation of candidate genes by subtractive and sequential (Boolean) hybridization: an hypothesis.

This paper describes a theoretical method of isolating candidate disease-specific genes by polymerase chain reaction (PCR)-based subtractive hybridization and subsequent (Boolean) hybridization of the subtracted library to arrays of chromosome-specific cosmid clones. A specific application of this technique to isolate genes potentially related to Wilson's disease is outlined.

Base Sequence↗