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Biomedical subjects

H C Thomas

Publications and source records attributed to H C Thomas.

At least 109 records · Page 6Linked to original sources
PubMed1995

Association of hepatitis B surface antigen carriage with severe malaria in Gambian children.

Severe malaria is a major cause of childhood mortality in sub-Saharan Africa but the factors predisposing children to severe forms of malaria have not been fully elucidated. In a case-control study of over 1,200 Gambian children hepatitis B virus carriage was significantly increased amongst cases of severe malaria compared to matched controls. We suggest that this association may relate to impaired clearance of liver stage parasites in the presence of the reduced level of HLA class I antigen expression on hepatocytes infected by hepatitis B virus. If this association is causal and viral carriage predisposes to severe malaria, widespread vaccination against hepatitis B virus may reduce mortality from severe malaria.

Animals↗
PubMed1995

Cytotoxic T cell responses in patients with chronic hepatitis B virus infection undergoing HBe antigen/antibody seroconversion.

Cytotoxic T cells have been identified in the peripheral blood of patients with acute hepatitis B virus infections for a short period after clinical presentation. However, in patients in whom the virus persists these have been difficult to demonstrate. In the chronic infection during HBe antigen clearance, when there has been an exacerbation of the disease, we have been able to demonstrate an MHC class I-restricted cytolytic response directed against the nucleocapsid antigens. In an HLA-A2 patient this was induced in vitro with the peptide p18-27, previously described as an HLA-A2-restricted T cell epitope. In patients of other HLA types, recombinant core antigen was used to induce antigen-specific lysis: statistical analysis of the cytolytic responses of chronically infected patients demonstrated a nucleocapsid antigen-specific lysis in patients who were seroconverting. Removal of CD4+ cells reduced non-MHC-restricted cytolysis, allowing an MHC class I-restricted cytolytic component to be demonstrated.

Amino Acid Sequence↗
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

Precore and X region mutants in hepatitis B virus infections among renal dialysis patients.

Hepatitis B virus (HBV) variants containing mutations within the X and the precore regions of the viral genome were demonstrated by polymerase chain reaction (PCR) amplification and DNA sequencing in renal dialysis patients with different serological patterns of HBV infection. Among carriers, X region deletion mutants predominated in patients who lost hepatitis B e antigen (HBeAg), or developed anti-HBe, but not in persistently HBeAg-positive patients. The precore region remained wild type in all carriers whether or not they seroconverted from HBeAg to anti-HBe. The frequency of precore and X region mutants was greatest among non-carrier patients with viral antibodies as the only indication of infection and among patients with non-A, non-B hepatitis (NANBH), suggesting an inverse relationship between the presence of wild type HBV markers and the presence of HBV mutants. Furthermore, the detection of one but not the other mutation in many serum samples suggests that these mutations are independently selected for during infection. Finally, the absence of HBV DNA in 21 'uninfected' dialysis patients with normal transaminases and no viral serology, suggests that replication of these mutants is associated with hepatitis. These results have important implications for HBV screening and treatment, as well as for the pathogenesis of chronic infection.

Biomarkers↗
PubMed1995

Recombinant vaccinia viruses expressing hepatitis A virus structural polypeptides: detection of an anti-VP0 response in convalescent-phase sera.

We have generated a number of recombinant vaccinia viruses which expressed the hepatitis A virus (HAV) structural polypeptides VP1, VP2, VP3, and VP4, either alone or in combination. The relevant sequences encoding these polypeptides were amplified from cloned cDNA by PCR and then cloned into the insertion vector pGS62. The presence of the HAV structural polypeptide-encoding sequences in the recombinant viruses was confirmed by Southern blot analysis, whilst their transcription and translation were demonstrated by Northern (RNA) blot analysis and immunodetection, respectively. Immunoprecipitation studies using these constructs have detected the presence of an anti-VP0 response in human convalescent sera following HAV infection. The significance of this finding and the usefulness of these constructs in studying cell-mediated immunity during recovery from HAV infection are discussed.

Antibodies, Viral↗
PubMed1995

Chronic hepatitis C virus infections: predictive value of genotype and level of viraemia on disease progression and response to interferon alpha.

The effects of hepatitis C virus genotype and viraemia on disease outcome in patients with chronic hepatitis C virus infection were studied. Patients infected with genotype 1 tended to develop more severe disease, and to respond less well to interferon (IFN) treatment, but no pretreatment variable successfully predicted either the severity of the disease or the response to IFN. Failure to eliminate the virus during the first three months of therapy, however, predicted a failure to derive long term benefit from the current IFN regime. Hence pretreatment variables cannot be used to determine whether individual patients will respond to IFN, but observations during the first three months of therapy can be used to decide which patients will not respond to prolonged therapy. In these patients consideration should be given to changing the IFN dosing regime or using alternative treatments.

Base Sequence↗
PubMed1995

Hepatitis C virus replication in hepatocellular carcinoma.

Hepatitis C virus (HCV) replication is reported in both tumour and non-tumour tissue in a case of hepatocellular carcinoma. Viral replication was established by showing the presence of minus strand HCV RNA by PCR amplification, after excluding residual reverse transcriptase activity of Taq polymerase. No minus strand was found in serum derived virion RNA. PCR amplified products from both tumour and non-tumour parenchyma were sequenced in the 5' non-coding region and shown to be identical. The genotype of this Indonesian patient was found to be 1b (or II), the most prevalent type in the Far East.

Base Sequence↗
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

The emergence of envelope and precore/core variants of hepatitis B virus: the potential role of antibody selection.

The appearance of replication-competent variants of hepatitis B virus (HBV) with mutations in the envelope and precore/core proteins emphasizes that these proteins are the focus of immune selection pressure in the human host. The sequence and speed of application of the multiple selection pressures (humoral and possibly cellular) determine the virologic and clinical outcome. When these variant viruses are passed to a new host, in the absence of the immune selection pressures or modified immune pressures which resulted in their selection, a clinical picture different from that seen in the original host may emerge.

Genetic Variation↗
PubMed1995

Pseudomembranous colitis following clarithromycin therapy.

OBJECTIVE: To describe the association of clarithromycin, used to treat Helicobacter pylori infection and duodenal ulceration, with pseudomembranous colitis in two patients. SETTING: St Mary's Hospital, London, UK. PATIENTS: Two female patients aged 77 and 78 years, admitted with duodenal ulceration and H. pylori infection. INTERVENTION: Clarithromycin (500 mg three times daily) was administered concurrently with omeprazole (40 mg once daily). OUTCOME MEASURES: After an initial improvement in symptoms both patients experienced persistent Clostridium difficile-associated diarrhoea. CONCLUSIONS: High-dose clarithromycin should be used with caution for the treatment of H. pylori infection associated with gastroduodenal ulceration. The drug may induce antibiotic-associated colitis which can lead to morbidity and mortality, particularly in the elderly.

Aged↗
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

Hypervariable region of hepatitis C virus envelope glycoprotein (E2/NS1) in an agammaglobulinemic patient.

In an agammaglobulinemic patient with chronic hepatitis C, a previously identified hypervariable region of the major envelope glycoprotein remained unchanged for 2.5 years. Serum-derived RNA amplified by reverse transcription-polymerase chain reaction was cloned in a bacterial vector, and a minimum of three independent clones were sequenced by dideoxy chain termination reaction. Comparison of consensus sequences from three different time points during the chronic phase of infection showed absolute homology at both amino acid and nucleotide levels. This finding provides support for the role of antibody selection in generating genetic variation and viral persistence; also, it is consistent with the hypothesis that an epitope within this region is the site of virus neutralization. The observations show that the hepatitis seen in hepatitis C virus infection is not dependent on the humoral immune response.

Agammaglobulinemia↗
PubMed1994

Serum HCV RNA levels in chronic HCV hepatitis measured by quantitative PCR assay; correlation with serum AST.

A quantitative PCR assay is described for serum HCV RNA which is based on a recombinant competitive titrating RNA template. This template is derived from the 5' non-coding region of the genome and generates a shorter PCR product (93 bp) than that from the serum-derived wild type genomes (279) bp from the same sets of primers. By using this assay we have found serum HCV RNA concentrations ranging between 3.3 x 10(2) and 6.6 x 10(8) viral genomes/ml of serum in 15 samples from 10 different patients, 9 cases of chronic hepatitis and one case of fulminant hepatitis. Comparison of viraemias with serum transaminase levels has shown a good correlation for individual patients between these two parameters during chronic HCV hepatitis.

Adult↗
PubMed1994

Effects of hepatitis B and hepatitis C virus replication on the actions of interferon.

Many patients chronically infected with hepatitis B or C do not respond to interferon therapy. For hepatitis B infections it is now clear that a viral factor down regulates the cells ability to respond to interferon and hence prevents effective therapy in some patients. In chronic hepatitis C infections, interferon therapy leads to the selection of interferon-resistant viral strains, but the mechanism of this resistance is not yet known.

Chronic Disease↗
PubMed1994

In situ hybridization studies of hepatitis A viral RNA in patients with acute hepatitis A.

In situ hybridization with oligonucleotide probes has been used to localise hepatitis A virus RNA genomic sequences in formalin-fixed and routinely processed human liver biopsies from three patients. Using radiolabelled Sulphur-35 antisense probes, viral genomic sequences were found in all three cases, but signal intensity was greatest in cases 1 and 2 with fulminant hepatitis, and was minimal in the third case of resolving hepatitis biopsied 2 months after acute illness. Localisation showed the viral RNA to be present in hepatocytes, sinusoidal cells and inflammatory cells in and around the portal tracts. Both cases showed signal in similar cell types, but the distribution of staining was predominantly periportal in case 1, whereas lobular staining was more apparent in case 2. Hybridization with sense polarity probes failed to detect any evidence of replicative intermediates of antigenomic viral RNA. The presence of hepatitis A RNA in phagocytic cells was confirmed using immunohistochemistry for a macrophage marker, CD68, combined with in situ hybridization. In all cases the signal was predominantly cytoplasmic, and this was confirmed with the use of tritiated probes.

Acute Disease↗