Biomedical subjects

M Thursz

Publications and source records attributed to M Thursz.

26 records · Page 2Linked to original sources

PubMed1995

Detection of rare allelic variants of the interferon-alpha 2 gene in human genomic DNA.

We have analyzed human donor DNA for the presence of sequences corresponding to allelic variants of the IFN-alpha 2 locus. Using both restriction enzyme digestion of PCR-amplified fragments and sequence analysis of these fragments, we have identified the three reported allelic variants, IFN-alpha 2a, IFN-alpha 2b, and IFN-alpha 2c, in genomic DNA derived from donors of African or Afro-Caribbean origin. This is the first report of the IFN-alpha 2a and IFN-alpha 2c alleles occurring in human donor DNA and supports the view that these are variants of the predominant IFN-alpha 2b allele rather than arising from mutations occurring in cultured cells.

Alleles↗

PubMed1995

Hepatitis B e antigen negative chronic active hepatitis: hepatitis B virus core mutations occur predominantly in known antigenic determinants.

In chronic hepatitis B virus (HBV) infection seroconversion from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb) may be followed either by remission of the disease with low-level viraemia, or by continuing inflammation with high-level viraemia. In both situations the virus may acquire a mutation in the precore sequence which prevents it from encoding HBeAg. We now show that the number of amino acid substitutions in the HBV core is low in viral sequences from patients with HBeAg positive chronic liver disease and HBeAg negative HBeAb positive patients in remission, but the frequency of substitutions is high in HBeAg, negative HBeAb positive patients with active liver disease. Furthermore we show that these substitutions cluster in the promiscuous CD4+ T-helper-cell epitope and in HBV core/e antibody binding determinants, but are not found in regions recognized by major histocompatability complex (MHC) restricted cytotoxic T lymphocytes. Sequential viral sequences from patients before and after HBeAg/HbeAb seroconversion shows that core mutations arise either at the same time or after the precore stop mutation which prevents the virus from encoding HBeAg. These results are consistent with the hypothesis that after clearance of HBeAg, mutations in regions of the virus recognized by CD4+ helper T cells and B cells allow persistence of the HBe negative virus in HBeAb positive patients with viraemia and active hepatitis.

CD4-Positive T-Lymphocytes↗

PubMed1995

Fulminant hepatitis associated with hepatitis B virus e antigen-negative infection: importance of host factors.

The precore stop-codon variant of hepatitis B virus (HBV) has been implicated in fulminant hepatitis. The precore/core regions of such variants from two sets of patients with interpartner transmission resulting in fulminant hepatitis in the contact, were sequenced to establish whether further sequence variations in the core region are specifically associated with the fulminant disease. In both sets of patients, there was sequence diversity of the precore/core region from the wild type, leading to numerous amino acid substitutions in the core region. Between the infecting source and the contact, there was only one amino acid change in one set of patients and none in the other. In addition, in the second set of patients, serum samples from four different time points were investigated. Sequence data showed no variation in each patient at the nucleotide level in the core region, even in the case of the source, who was followed for 3 years. In this same pair of subjects, the remainder of the genome was sequenced and was identical at the nucleotide level. Therefore, it appears that, at least in some cases of fulminant hepatitis caused by infection with the precore variant, the nucleotide sequence of the patient with fulminant hepatitis is identical to that observed in the asymptomatic source of infection. These data indicate that the severity and outcome of infection in such cases are unrelated to any additional variation in the entire HBV genome, and that the changed clinical picture is dependent on host factors, possibly the HLA environment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1995

Hepatitis B virus precore/core variation and interferon therapy.

Precore/core genes from hepatitis B e antigen (HBeAg)-positive and antibody to HBeAg (anti-HBe) positive individuals with active hepatitis have been analyzed to search for correlations with response to interferon before and after treatment. Pretreatment, no precore stop codon mutants were detected, even at the 3% level, in HBeAg-positive responders or nonresponders. In anti-HBe-positive patients, precore mutants did not influence response. No significant core amino acid variability was observed in HBeAg-positive patients, irrespective of interferon response. However, anti-HBe-positive cases had multiple core protein substitutions, mostly in B- ant T-helper cell epitopes, but responders had fewer (P = .02 for responders versus nonresponders and reactivators). None of four responders, three of seven reactivators, and three of three nonresponders had mutations within the major T-helper epitope from aa50 to aa69 (P = .03). Precore mutants appeared in eight of nine natural seroconverters compared with 3 of 10 interferon-induced anti-HBe seroconverters (P = .01). Those in whom precore wild-type remained after treatment often tested negative in the last available sample using polymerase chain reaction (PCR), whereas emergence of mutants led to ongoing viremia in all cases. In anti-HBe-positive cases, precore sequences remained stable during therapy, except for 2 cases in whom a precore mutant appeared accompanied by reactivation. In the core protein, anti-HBe-positive cases selected a mean of 3.5, 1.6, and 1.7 amino acid substitutions in responders, nonresponders, and reactivators respectively (P = NS). In conclusion, core but not precore sequence before therapy may predict response. Appearance of precore mutants during therapy usually predicts failure to clear virus but substitution in core does not influence outcome.

Adolescent↗

PubMed1995

Hepatitis B virus markers, hepatitis D virus antigen and hepatitis C virus antibodies in Nigerian patients with chronic liver disease.

Although carrier rates for the HBsAg as well as the prevalence of HBV-associated chronic liver disease (CALD) are known to be high in Nigeria, not much is known about the role of the hepatitis C (HCV) and D (HDV) viruses. We undertook a prospective serological study of a cohort of 50 new patients and attending a Nigerian teaching hospital for various forms of histologically characterised chronic liver disease. Forty-five patients (90%) had antibodies to HBcAg (anti-HBcAb). Thirty one patients (62%) were HBsAg-positive, out of whom 15 were HbeAg-positive. Two (4%) of the HbsAg-positive patients, both suffering from liver cancer, were also hepatitis D antigen positive. Similarly, two (4%) patients were positive for anti-HCV antibodies. There were no cases of co-infection by the HBV and HCV. This study suggests that while the HBV is the major aetiological agent of chronic liver disease in Nigeria, the HDV is not an important aggravating factor save in a small number of patients. The HCV is probably not yet an important cause of chronic liver disease but this situation might change when HBV infection is controlled.

Carrier State↗

PubMed1994

Interferon (IFN)-alpha 2 genotype analysis of Chinese chronic hepatitis B patients undergoing recombinant IFN-alpha 2a therapy.

Sixteen Chinese chronic hepatitis B virus (HBV)-infected patients were treated with recombinant interferon-alpha 2a (rIFN-alpha 2a). Of these, 8 made a response to IFN, with titers of neutralizing antibody of 141-4525 as determined by an antiviral neutralization bioassay. To determine whether the immunogenicity of the IFN was directly linked to the patients' genotype, their genomic DNA was analyzed for the presence of the human IFN-alpha 2a gene. None of the patients possessed the gene for IFN-alpha 2a, but only 50% developed neutralizing antibodies. The hypothesis, therefore, of a direct link between antibody formation and genotype cannot be sustained. Alternative explanations of the immunogenicity of IFN-alpha 2a must be sought.

Adult↗

PubMed1993

Intraperitoneal haemorrhage from anterior abdominal wall varices.

Patients with oesophageal varices frequently present with gastrointestinal haemorrhage but bleeding from varices at other sites is rare. We present a patient with hepatitis C-induced cirrhosis and partial portal vein occlusion who developed spontaneous haemorrhage from anterior abdominal wall varices into the rectus abdominus muscle and peritoneal cavity.

Abdominal Muscles↗

PubMedDate not supplied

Influence of MHC class II genotype on outcome of infection with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research.

BACKGROUND: The outcome of infection with hepatitis C virus (HCV) varies substantially among individuals. Host genetic factors are likely to give rise to some of this variability. Polymorphisms in the MHC class II loci may influence the outcome of HCV infection; however, reports of MHC class II allele associations have been inconsistent. We aimed to confirm these associations in a cohort of European patients with different clinical outcomes. METHODS: The distribution of MHC class II alleles was compared between patients with self-limiting infection (n=85) and matched patients with persistent infection (n=170); between patients with mild (n=321) and severe (n=321) histological injury; and between patients who responded to interferon (n=96) and those who did not (n=192). The results of these comparisons were confirmed with a second-stage study of self-limiting infection (n=52) versus persistent infection (n=152). FINDINGS: Self-limiting HCV infection was associated with HLA-DRB1*1101 (odds ratio 2.14 [95% CI 1.11-4.12]; p=0.013) and HLA-DQB1*0301 (2.22 [1.24-3.96], p=0.004). Persistent HCV infection was associated with HLA-DRB1*0701 (2.04 [1.03-4.17], p=0.027), and HLA-DRB4*0101 (2.38 [1.29-4.35], p=0.002). These results were confirmed in the second-stage study. No significant associations (p<0.05 after Bonferroni correction) were found between MHC class II alleles and severe histological injury or response to interferon therapy. INTERPRETATION: Specific MHC class II alleles influence susceptibility or resistance to persistent HCV infection.

Cohort Studies↗