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Biomedical subjects

H C Thomas

Publications and source records attributed to H C Thomas.

At least 145 records · Page 8Linked to original sources
PubMed1992

Seroprevalence of hepatitis C virus nucleocapsid antibodies in patients with cryptogenic chronic liver disease.

The serological responses to two different hepatitis C virus antigens were studied by enzyme-linked immunosorbent assay in a variety of chronic liver diseases and in healthy blood donors. The study population comprised 97 cases of cryptogenic chronic liver disease (40% with a history suggestive of parenterally transmitted non-A, non-B hepatitis and 60% without such a history), 87 cases of other well-characterized chronic liver diseases and 96 voluntary blood donors. The commercially available C100-3 assay and a new assay utilizing a 22 kD recombinant protein (c22) from the nucleocapsid region of the virus were used for antibody detection. Overall in the non-A, non-B hepatitis group, 77% were positive for anti-c22, 55% were positive for anti-C100-3 and 24% were negative by both tests. In the parenterally transmitted chronic liver disease group, 82% were positive for anti-C100-3 and 90% were positive for anti-c22 (not significant). In the cryptogenic chronic liver disease cases 36% were positive for anti-C100-3 and 67% were positive for anti-c22 (p less than 0.001). Only in one case (a patient with hepatitis B virus infection) was anti-C100-3 detected without concomitant anti-c22. None of the voluntary blood donors had detectable hepatitis C virus antibodies. The new enzyme-linked immunosorbent assay test for anti-c22 would appear to be a more sensitive indicator of chronic hepatitis C virus infection than the existing commercial test, suggesting a useful diagnostic role in both cases of cryptogenic chronic non-A, non-B hepatitis liver disease and for the screening of blood products for prevention of hepatitis after transfusion.

Base Sequence↗
PubMed1992

In situ hybridization studies in hepatitis A infection.

An in situ hybridization method using radiolabeled oligonucleotide probes was developed to study primary sites of hepatitis A virus replication in an experimental animal model of infection. Hepatitis A genomic sequences were demonstrated in hepatocytes of four marmosets with acute hepatitis A by use of antisense probes. In two of these animals, staining was also found when a sense probe was used, which is consistent with active replication in the hepatocytes. The specificity of the hybridization signal was confirmed by neutralization with "cold" (i.e., unlabeled) probes and by absence of hybridization with non-A hepatitis and reverse antisense probes. The hepatocyte appeared to be the only cell type showing staining. No hybridization was found in other organs, including the intestine (n = 4) and, in one animal, the kidney and spleen.

Alanine Transaminase↗
PubMed1992

Effect of cyclosporin-A in woodchucks with chronic hepatitis delta virus infection.

Four woodchucks chronically infected with hepatitis delta virus (HDV) were treated with cyclosporin-A (CyA) for 11 weeks. All animals had detectable HDAg in the liver and two of them were also positive for HDAg and HDV-RNA in serum. Reappearance of HDV in serum was noted in one of the two non-viraemic animals and increased viraemia in the two viraemic. HDV-RNA levels became elevated within a week of starting treatment and an inverse relationship between HDV-RNA and WHV-DNA became apparent during the treatment period. With discontinuation of treatment, HDV-RNA levels either returned to pretreatment levels or became negative. The remaining animal showed no return of viraemia during CyA treatment; HDV-RNA remained negative and WHV-DNA levels did not change. Liver biopsies revealed a slight increase in lobular activity during CyA treatment in the animals showing increased viraemia. These data are consistent with the hypothesis that the host immune response exerts a negative control on the level of HDV viraemia and that HDV influences HBV replication independently of the host immune response. In an animal that may have been clearing HDV, immunosuppression did not result in recurrence of viraemia.

Animals↗
PubMed1992

Interferon therapy is effective in treatment of hepatitis B-induced polyarthritis.

A patient with acute hepatitis B developed significant polyarthritis. After 10 months of observation he had not cleared the virus and continued to have symptomatic joint problems, with migratory polyarthralgia, tenosynovitis of the left wrist, and a large knee effusion. Hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels were measured in the synovial fluid and were found to be virtually identical to serum levels, indicating the potential infectivity of this fluid. The patient was treated with 14 weeks of thrice-weekly lymphoblastoid interferon and cleared all markers of viral replication. The arthritis resolved with the disappearance of measurable HBsAg. Interferon may be effective therapy for this disorder.

Acute Disease↗
PubMed1992

Mapping of 5' ends of virion-derived HBV DNA.

Mapping of the 5' ends of virion-derived hepatitis B virus DNA molecules was carried out after cloning and sequencing linearized genomes made fully double stranded. Of five clones obtained, three of four minus strand termini mapped to the G in position 1826 and one to the T in position 1827. Plus strand 5' ends were more heterogeneous with evidence from one clone for the presence of an RNA-translocated primer from the 5' end of pregenomic RNA as well as two other termini, mapped to positions 1599 and 1601, the second 3' nucleotide of DR2 and the first nucleotide 3' to DR2, respectively. These molecules were also shown to be functional templates for expression of HBcAg after tranfection or microinjection of Huh-7 human hepatoma cells.

Base Sequence↗
PubMed1992

Analysis of the antigenic epitopes of hepatitis B surface antigen involved in the induction of a protective antibody response.

Vaccination with hepatitis B surface antigen (HBsAg) has shown that antibody directed against the common 'a' determinant of this antigen is protective against infection with hepatitis B virus (HBV). In this study the antigenic epitopes of the 'a' determinant have been analysed by competitive inhibition assays and by binding studies to synthetic peptides using a panel of monoclonal antibodies prepared against HBsAg, all of which are shown to recognise the common group determinant. One murine monoclonal antibody used in this study, RFHBs1, has been shown previously to block infectivity of HBV in susceptible chimpanzees ((1983) J. Med. Virol. 16, 89-95). This antibody bound to a cyclical synthetic peptide analogue of amino acids 124 to 137 of the major HBsAg polypeptide.

Antibodies, Monoclonal↗
PubMed1992

Precore sequence variation in Chinese isolates of hepatitis B virus.

Direct sequencing of polymerase chain reaction-amplified serum hepatitis B virus (HBV) DNA was used to characterize the precore region of HBV from Chinese patients with chronic hepatitis. Two types of mutually exclusive variants were found in hepatitis B e antigen (HBeAg)-negative patients. The first (M1) contains a substitution from proline to serine at codon 15. A second group were infected with a previously described mutant (M2) containing a translational stop codon. HBeAg-positive patients were infected with the wild-type virus or the M1-containing strain. M2 emerged in patients with wild-type infection after seroconversion to anti-HBe, whereas M1 was present during the HBeAg-positive phase. In those with fluctuating HBe status, there was no correlation between prevailing HBe serology and sequence. There was an association between infection with variants and severe chronic hepatitis. Patients infected with strains containing M1 while HBeAg positive had a worse prognosis after seroconversion to anti-HBe.

Alanine Transaminase↗
PubMed1992

Loss of the common "A" determinant of hepatitis B surface antigen by a vaccine-induced escape mutant.

A previous study (Carman, W. F., A. R. Zanetti, P. Karayiannis, J. A. Waters, G. Manzillo, E. Tanzi, A. J. Zuckerman, and H. C. Thomas. 1990. Lancet. 336:325-329) demonstrated a variant hepatitis B surface antigen (HBsAg) in a vaccinated child born to a hepatitis B virus-infected mother. A substitution of arginine for glycine at amino acid 145 in HBsAg was observed. In this study the effect of this substitution on the common "a" determinant of this protein, against which protective immunity is directed, is investigated. Using recombinant HBsAg with and without the amino acid substitution, the binding of monoclonal antibodies that recognize different epitopes of the "a" determinant, was shown to be destroyed by the presence of arginine at amino acid 145. In convalescent and vaccinee sera, antibody binding to HBsAg was not inhibited by the variant HBsAg. Immunization with the variant HBsAg, although eliciting a high titer antibody that recognized the variant, produced a low titer of antibody recognizing the native protein. Studies in mice demonstrate that the immunogenicity of the variant protein is also substantially altered. The data presented here demonstrate that this variant evades the known protective anti-HBs response and lends support to the suggestion that this mutation arose as the result of immune pressure.

Animals↗
PubMed1992

The host immune response may be responsible for selection of envelope and precore/core variants of HBV.

The appearance of replication-competent variants of 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) will determine the virological 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. Although HBV would seem to be highly evolved, it still seems to have the capacity for further diversity. A number of the reported variations have an obvious clinical relevance, but others do not, and further study is required to elucidate their importance. Whether they represent independently transmissible strains of HBV or are all selected during the course of infection, only to be lost in favor of the original strain on infection of another host, also remains to be determined.

Genetic Variation↗
PubMed1992

Retinotopic organization of striate and extrastriate visual cortex in the golden hamster (Mesocricetus auratus).

The visual topography within striate and lateral extrastriate visual cortices was studied in adult hamsters. The cortical areas 17 and 18a in the left hemisphere were electrophysiologically mapped upon stimulation of the right eye, correlating receptive field positions in the visual field with cortical recording sites. Reference lesions were placed at selected cortical sites. Like in rats and other mammals, the lateral extrastriate cortex contained multiple representations of the visual field. Rostral area 18a contained the rostrolateral maps, with medial and lateral divisions. More caudally and sharing a common border with V1, maps in lateromedial, posterolateral and posterior areas were found. More laterally and forming a "third tier" of visual maps, anterolateral, laterolateral-anterior, laterolateral and laterolateral-posterior areas were found. There was also an indication of a possible pararhinal map. The plan so defined is virtually identical to that of rats. The results may be useful to understand a basic mammalian plan in the organization of the visual cortex.

Animals↗
PubMed1991

Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA.

Constructs expressing the core, surface, X, or polymerase proteins of hepatitis B virus were transfected into human cells. In transient assays, only the polymerase inhibited the responses to interferons alpha and gamma (IFN-alpha and -gamma). Stable expression of the polymerase was achieved in the cell line 2fTGH, which carries an IFN-inducible marker gene, by growth under conditions that select for inhibition of the response to IFN-alpha, but the clones grew poorly. When expressed alone, the terminal protein domain of the polymerase gene inhibited the response to IFN-alpha and the reverse transcriptase plus RNase H domains appeared to be toxic. Clones of cells expressing terminal protein alone, selected for the loss of response to IFN-alpha, grew normally and had no detectable response to IFN-alpha, IFN-gamma, or double-stranded RNA. Binding of IFN-alpha to these cells was not impaired but did not lead to activation of the E alpha subunit of the IFN-induced transcription factor E. These observations are of potential importance in relation to the pathogenesis of chronic hepatitis B virus infection and the resistance of such infection to IFN-alpha therapy.

Cell Line↗
PubMed1991

Incidence of hepatitis B viraemia, detected using the polymerase chain reaction, after successful therapy of hepatitis B virus carriers with interferon-alpha.

Thirty-nine patients (62 sera) who, after interferon-alpha therapy for chronic hepatitis B virus (HBV) infection, were seronegative for HBeAg and HBV-DNA by dot blot hybridisation, were tested using the polymerase chain reaction (PCR) for residual viraemia. Overall, 59% of the HBsAg-positive sera and 43% of the HBsAg-negative sera were positive by PCR. All except one of the HBsAg-negative patients had seroconverted to anti-HBs. Between 13 and 18 months after therapy, 33% of the HBsAg-positive and 20% of the HBsAg-negative patients remained viraemic. Eighteen months after the end of treatment, no patient tested was positive. Twenty-three patients were tested sequentially over periods from 1 to 43 months: Thirteen lost HBV-DNA by PCR, three remained positive, five remained negative, and two patients relapsed. The merits and disadvantages of PCR for assessing interferon treatment of HBV carriers are discussed.

Base Sequence↗
PubMed1991

Serum HBV DNA detected by PCR in dot blot negative HBV chronic carriers with active liver disease.

A group of forty-nine HBV chronic carriers with histologically confirmed active liver disease and undetected serum HBV DNA by dot-blot hybridisation were re-investigated using the polymerase chain reaction (PCR) for amplification of serum DNA. The group comprised 16 persistently serum HBeAg-negative and thirty-three anti-HBe-positive patients. The use of PCR followed by Southern blot analysis has increased the sensitivity of HBV DNA detection to about 10-50 virions per ml of serum. Our results showed 14/16 (87.5%) of the HBeAg-positive group and 27/33 (81.8%) of the anti-HBe group to be positive for HBV DNA using PCR. Of the nine cases where HBV DNA was undetected four were positive for markers of hepatitis delta virus (HDV) infection. Demonstration of low level HBV replication associated with active liver disease in chronic HBV carriers where it was previously undetected meets a basic requirement for the proposed role of cytotoxic T lymphocyte-mediated immunopathogenesis in chronic hepatitis B and suggests a combined antiviral and immunotherapeutic approach to achieve eradication of the infection.

Base Sequence↗