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Biomedical subjects

G R Foster

Publications and source records attributed to G R Foster.

At least 55 records · Page 3Linked to original sources
PubMed1997

The relationship of histology to genotype in chronic HCV infection.

The histological description of chronic hepatitis is undergoing considerable change at present. It has become important to define chronic hepatitis aetiologically and then define levels of necro-inflammatory change (grade) and fibrosis (stage). The aim of this study was to compare the ability of different histological scoring systems to detect differences in the pathological changes associated with infection with the different HCV genotypes that are known to have different natural histories. The histological appearances of liver biopsies from 29 HCV infected patients were compared by the Knodell histological activity index (HAI), modified histological activity index and the Scheuer histological scoring system. HCV genotyping was performed for each patient by sequence analysis of the 5' non-coding region. The histological appearances from HCV 1 infected patients showed a tendency towards more active necro-inflammatory changes when compared with those from HCV 2 or 3 infected patients. The levels of fibrosis were similar for all genotypes. The modified HAI and Scheuer scoring systems detected differences, not revealed by the Knodell system, in the types of inflammatory pathology produced by the different genotypes of HCV. In particular these scoring systems noted significant differences in the component scores of inflammation, in addition to the total inflammatory scores. In conclusion, the recently introduced scoring systems were able to detect differences in liver pathology produced by infection of similar duration with different viral genotypes. As genotype is considered an important determinant of disease progression and response to anti-viral therapy, it is likely that those scoring systems correlating with genotype will yield more useful histological information than those that do not.

Adult↗
PubMed1996

Mutation of gene of mannose-binding protein associated with chronic hepatitis B viral infection.

BACKGROUND: Persistent with hepatitis B virus (HBV) affects 350 million people worldwide, and 20-40% of infected patients die of cirrhosis and liver cancer. Little is known about the host factors that determine the variable natural history. Studies have focused on the role of acquired rather than innate immunity. We have investigated the prevalence of mutations in the gene for mannose-binding protein (MBP), which have been associated with susceptibility to bacterial and fungal infections. METHODS: Mutations in the MBP gene were sought by sequence-specific oligonucleotide hybridisation, site-directed sequencing in Caucasian and Asian patients with HBV infection, and in HBsAg-negative controls. FINDINGS: A mutation in codon 52 of the MBP gene was present in two (11%) of 19 Caucasian patients with acute hepatitis B and nine (27%) of 33 Caucasian patients with chronic hepatitis B, compared with four (4%) of 98 Caucasian controls (p = 0.0004). By contrast the prevalence of the mutation was similar in Asian patients with chronic hepatitis B and in Asian controls (one [5%] of 20 vs two [2%] of 117). Mutations in codon 54 and codon 57 were found in similar proportions of patients and controls. INTERPRETATION: These findings show in Caucasian, but not Asian, patients an association of the codon 52 mutation of the MBP gene with persistent HBV infection. They suggest an important role for this gene, or a gene in linkage disequilibrium with MBP, in determining outcome after HBV infection in adult but not neonatal life.

Acute Disease↗
PubMed1996

Characterization of beta-R1, a gene that is selectively induced by interferon beta (IFN-beta) compared with IFN-alpha.

We report preliminary characterization of a gene designated beta-R1, which is selectively expressed in response to interferon beta (IFN-beta) compared with IFN-alpha. In human astrocytoma cells, beta-R1 was induced to an equivalent extent by 10 IU/mL IFN-beta or 2500 IU/mL IFN-alpha2. To address the mechanism of this differential response, we analyzed induction of the beta-R1 gene in fibrosarcoma cells and derivative mutant cells lacking components required for signaling by type I IFNs. beta-R1 was readily induced by IFN-beta in the parental 2fTGH cell line, but not by recombinant IFN-alpha2, IFN-alpha Con1, or a mixture of IFN-alpha subtypes. IFN-alpha8 induced beta-R1 weakly. beta-R1 was not induced by IFN-beta in mutant cell lines U2A, U3A, U4A, and U6A, which lack, respectively, p48, STAT1, JAK1, and STAT2. U5A cells, which lack the Ifnar 2.2 component of the IFN-alpha and -beta receptor, also failed to express beta-R1. U1A cells are partially responsive to IFN-beta and IFN-alpha8 but lacked beta-R1 expression, indicating that TYK2 protein is essential for induction of this gene. Taken together, these results suggest that the expression of beta-R1 in response to type I IFN requires IFN-stimulated gene factor 3 plus an additional component, which is more efficiently formed on induction by IFN-beta compared with IFN-alpha.

Astrocytoma↗
PubMed1996

Granulomas and hepatitis C.

Hepatitis C (HCV) is associated with a number of characteristic histological features. A recent paper has identified an increased frequency of granulomas in resection specimens from cases of HCV. We have carried out a retrospective study of 155 cases of HCV to assess the frequency of granulomas in biopsy specimens. We had two control groups: 151 cases of hepatitis B (HBV) and 129 cases of alcohol induced liver disease. Granulomas were found in 14 cases of HCV (10%), three cases of HBV (2%) and three cases of alcohol induced liver disease (2%). Granulomas were significantly commoner in cases of HCV than in the other two groups. Of the 14 cases of HCV, the granulomas could be ascribed to another cause in seven cases. When the analysis was carried out, excluding those granulomas which could be ascribed to another cause, they were still significantly commoner in cases of HCV. We conclude that granulomas are more frequent in HCV but that in half of cases in which they are found another cause can be identified. This means that if granulomas are seen in association with hepatitis C another aetiology should be sought before ascribing them to HCV.

Granuloma↗
PubMed1996

Different relative activities of human cell-derived interferon-alpha subtypes: IFN-alpha 8 has very high antiviral potency.

Interferon-alpha (IFN-alpha) subtypes were separated by HPLC from the IFN mixtures produced by virus-stimulated human lymphoblastoid cells and leukocytes. Together with preparations of lymphoblastoid IFN and recombinant IFN-beta, these were tested in three human tumor cell lines derived from liver, lung, and neuroblasts. Their relative antiviral activities differed markedly: subtype IFN-alpha 8 was the most potent and IFN-alpha 1 the least. The results were broadly similar in all three cells, with some minor differences. when the same preparations were tested for inhibition of thymidine incorporation, the relative activities were quite different: subtypes IFN-alpha 10, IFN-alpha 17, IFN-alpha 21, and IFN-alpha 5 were now the most active, and IFN-alpha 2 was the least active. IFN-alpha 1 and IFN-alpha 8 had comparable intermediate activity. Thus, the differences in activity were not caused by degradation of some subtypes during their separation. IFN-alpha 8 not only had the greatest antiviral activity but also, like IFN-beta, induced an antiviral state in U1 mutant cell lines, which lack the tyrosine kinase, Tyk2, required for signal transduction by other IFN-alpha subtypes.

Antiviral Agents↗
PubMed1995

Reversible AIDS-related sclerosing cholangitis.

Although hepatobiliary involvement is common in the acquired immunodeficiency syndrome, it infrequently leads to biliary tract abnormalities. We describe a 39-year-old man with human immunodeficiency virus infection and no previous acquired immunodeficiency syndrome-defining illnesses, who presented with malaise, right upper quadrant pain, lymphadenopathy and cholestasis. An endoscopic retrograde cholangiopancreatography demonstrated sclerosing cholangitis due to disseminated B-cell nonHodgkin's lymphoma. Following chemotherapy, his symptoms and signs rapidly improved, so that 1 month later his endoscopic retrograde cholangiopancreatography had returned entirely to normal.

Adult↗
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↗
PubMed1994

Secretion of human hepatitis B virus is inhibited by the imino sugar N-butyldeoxynojirimycin.

The imino sugar N-butyldeoxynojirimycin (NBDNJ) is a potent inhibitor of the oligosaccharide-trimming enzyme alpha-glucosidase I. Hepatitis B virus (HBV) contains three surface proteins (HBs proteins) of different sizes that are singly or doubly N-glycosylated and are essential for the formation of infectious virus. Therefore, the replication and secretion of HBV in the human hepatoma cell line HepG2 were studied in the presence of NBDNJ. In the stably HBV-transfected HepG 2.2.15 cells and in HBV-infected HepG2 cells, NBDNJ suppressed secretion of HBV particles and caused intracellular retention of HBV DNA. The secretion of subviral particles was less affected. These data suggest that inhibitors of oligosaccharide trimming may be useful for antiviral therapy of hepatitis B and for the study of the intracellular transport of the viral glycoproteins.

1-Deoxynojirimycin↗
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

Expression of the gene for inducible nitric oxide synthase in experimental glomerulonephritis in the rat.

Nitrite, a stable product of nitric oxide (NO), is synthesized in vitro by glomeruli in experimental glomerulonephritis. We have now studied the expression of the gene for inducible NO synthase (iNOS) in accelerated nephrotoxic nephritis (NTN). The purpose of the study was to confirm in vivo induction of iNOS in this model of immune complex disease, and to relate the onset of induction and the level of expression to pathogenic events in the model. Glomeruli from rats with NTN were isolated at 6 h, 24 h and 2, 4 and 7 days and total RNA extracted. RNA (10 micrograms) was reverse transcribed and polymerase chain reaction (PCR) was performed with primers homologous to rat vascular smooth muscle iNOS and rat beta actin. A 222-base PCR product corresponding to iNOS mRNA was present in all experimental animals. iNOS expression was also found in activated macrophages, neutrophils and IL-1-stimulated but not unstimulated mesangial cells. Quantitative competitive PCR was carried out on glomerular samples using a 514-bp mutant of a 735-bp PCR product. iNOS expression was present at low levels in normal glomeruli and was markedly enhanced at 6 h after the induction of glomerulonephritis and peaked at 24 h. Increased iNOS expression persisted to day 7. beta actin mRNA levels were similar in all glomerular specimens. This study demonstrates that there is in vivo induction of iNOS in immune complex glomerulonephritis, corresponding to the generation of nitrite we have previously reported. iNOS gene expression is detectable within 6 h of induction of NTN, indicating the onset of gene transcription is closely related to the initial formation of immune complexes.

Amino Acid Oxidoreductases↗
PubMed1993

Expression of the terminal protein of hepatitis B virus is associated with failure to respond to interferon therapy.

The terminal protein domain of the hepatitis B viral polymerase can inhibit the cellular response to interferon. To clarify the clinical relevance of this inhibitory effect, we examined the expression of terminal protein in liver biopsy specimens from patients with chronic hepatitis B infection. We found that expression of terminal protein is associated with a failure of hepatocytes to respond to interferon, as assessed by expression of the interferon-inducible protein beta 2-microglobulin. Patients whose liver specimens contained large numbers of cells expressing terminal protein tended not to respond to treatment. During interferon therapy the percentage of cells expressing terminal protein remained constant, but treatment significantly reduced the number of cells that expressed the hepatitis B nucleocapsid protein. Hence expression of terminal protein in a cell may prevent elimination of the virus by interferon therapy.

Adult↗
PubMed1991

Serum F-protein concentration following halothane or isoflurane anaesthesia.

We have investigated the prevalence of hepatic injury following uncomplicated anaesthesia using a sensitive and specific marker of hepatic damage, the serum F-protein concentration. The median variation in serum F-protein in fit adults over six days is 16 ng/ml, minimum 0 ng/ml, maximum 36 ng/ml. A significant rise in serum F-protein was demonstrated six days following anaesthesia and surgery, but not earlier after 3 or 24 h. There was no significant difference between patients who received halothane (n = 12) or isoflurane (n = 13). These changes were not related to duration of anaesthesia, quantity of delivered volatile agent or mode of ventilation. Hepatocellular damage may occur following anaesthesia for minor surgery.

Adult↗
PubMed1991

Inhibition of the cellular response to interferons by products of the adenovirus type 5 E1A oncogene.

Expression of the E1A oncogene of adenovirus type 5 inhibits the response of interferon (IFN)-inducible constructs to Type I (alpha,beta) and II (gamma) IFNs in transient transfection assays. In human cell lines stably expressing E1A mRNA and protein acquisition of an antiviral state and the induction of a number of genes in response to alpha- and gamma-IFNs is inhibited. A short IFN-stimulable response element (ISRE) present in the 5' flanking region of a number of genes mediates induction by alpha- and gamma-IFNs. In cells expressing E1A there is a substantial reduction in the levels of the ISRE-binding factors E and M, inducible by alpha-IFN, and of factor G, inducible by gamma-IFN. In E1A-expressing cells the E alpha subunit of factor E is activated normally in response to alpha-IFN; the defect is in the production or activation of the E gamma subunit. The inhibitory activity of E1A is lost upon deletion of the CR1 domain. The induction of HLA class II genes by gamma-IFN, which involves a different DNA response element(s), and of beta-IFN mRNA in response to double-stranded RNA are also inhibited by E1A. An essential component(s) of a number of signalling pathways must, therefore, be subject, directly or indirectly, to inhibition by E1A.

Adenovirus Early Proteins↗
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

Liver damage in long-term anticonvulsant therapy: a serological and histological study.

The prevalence of liver damage in patients receiving long-term anticonvulsant therapy was determined, using a new marker of liver disease, the serum F protein concentration. Abnormal serum F protein concentrations were detected in 50 per cent of 34 patients receiving anticonvulsant therapy. A retrospective analysis of post-mortem liver samples showed common histological abnormalities in three out of seven patients who had died whilst receiving anticonvulsant therapy. These changes were not seen in control patients. We suggest that chronic anticonvulsant therapy may cause significant hepatocellular damage.

Adult↗