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Biomedical subjects

G R Foster

Publications and source records attributed to G R Foster.

At least 19 recordsLinked to original sources
PubMed2000

Therapeutic options for HCV--management of the infected individual.

Patients with chronic hepatitis C infection should be assessed by liver biopsy prior to consideration of anti-viral therapy. Patients with histologically mild disease should be observed at regular intervals and assessed with a repeat liver biopsy after an interval of 3-4 years. Those with severe disease should receive early treatment with interferon-alpha and ribavirin. The duration of therapy is determined by the genotype of the infecting virus-viral genotypes 2 and 3 require only 6 months of treatment but other genotypes should be treated for 12 months. Approximately 35-40% of treated patients will respond to therapy with a permanent cessation of viral replication and improvement in liver histology. New therapies including polyethylene glycol, PEGylated, interferons and combination regimes involving amantadine are currently under evaluation and it is hoped that improved regimes will be developed in the near future.

Antiviral Agents↗
PubMed2000

Prevalence of hepatitis C among pregnant women attending an inner London obstetric department: uptake and acceptability of named antenatal testing.

OBJECTIVE: To examine the value of universal antenatal screening for hepatitis C virus (HCV) infection among an inner London population, with regard to prevalence, uptake, and acceptability of testing, and identification of new cases. DESIGN: Serum analysis for antibodies against HCV in pregnant women following informed consent ("opt out" policy). Samples positive for HCV antibodies were tested for the presence of HCV RNA by polymerase chain reaction. Information on hepatitis C was provided for all women. Acceptability of antenatal HCV testing and identification of risk factors for infection were assessed through the use of questionnaires randomly distributed among a cohort of 300 pregnant women. SETTING: Antenatal clinics at St Mary's Hospital, London, serving a multiethnic population. SUBJECTS: A total of 4825 pregnant women booking for antenatal care between November 1997 and April 1999. RESULTS: The overall prevalence of anti-HCV was 0.8% and HCV viraemia was 0.6%. Ninety eight per cent of samples (n=4729) were tested; 0.2% of women had a false positive result. In 207 women who completed a questionnaire regarding our testing policy, 84% made a positive decision to be tested for anti-HCV and 92% said that HCV testing should be offered to all pregnant women. The majority (22/32-69%) of HCV infected women were newly diagnosed and although HCV positive women were significantly more likely to have a history of drug abuse, most (16/22-73%) new cases had no identified risk factors for HCV infection at booking. CONCLUSION: The prevalence of anti-HCV in an inner London multiethnic antenatal population is high (0.8%). Routine screening for HCV is acceptable to pregnant women. The majority of women diagnosed during their current pregnancy would not have been identified as HCV infected by epidemiological risk factors at the time of booking.

False Positive Reactions↗
PubMed1999

Hepatitis C virus NS5A protein inhibits interferon antiviral activity, but the effects do not correlate with clinical response.

BACKGROUND & AIMS: Patients with chronic hepatitis C virus infection are commonly treated with interferon alfa (IFN-alpha), but the long-term response rate is poor. A region of NS5A of hepatitis C virus genotype 1 (the ISDR) has been associated with treatment outcome in some patients. NS5A binds to and inhibits PKR in vitro and inhibits IFN-alpha in human cells. We examined the effects of the NS5A protein from patients who did or did not respond to IFN-alpha to determine whether NS5A from IFN-alpha nonresponders inhibited the effects of IFN-alpha in vitro. METHODS: We cloned NS5A from patients who had well-characterized responses to IFN-alpha and expressed them in a human fibroblast cell line under the control of an inducible promoter. The NS5A expression levels were controlled, and the effects of different proteins on the protective actions of IFN-alpha against encephalomyocarditis virus were investigated. RESULTS: NS5A expression blocked the antiviral effects of IFN-alpha in human cells. This inhibition was dependent on the level of NS5A expression. Although ISDR changes gave only small differences in IFN-alpha inhibition, clones derived from a patient who did not respond to IFN-alpha and one who did respond to treatment differed greatly: the clones from a patient with response to IFN-alpha were much more inhibitory than those derived from the patient with no response. CONCLUSIONS: The inhibition of the antiviral effects of IFN-alpha by NS5A is not regulated exclusively by the ISDR, and the effects of NS5A in vitro do not correlate with treatment outcomes.

Antiviral Agents↗
PubMed1999

Hepatitis C virus infection: quality of life and side effects of treatment.

Studies of the subtle symptoms associated with chronic diseases and detected by quality of life questionnaires are still in their infancy. The techniques used to examine these impairments in well being are still being developed and their use is far from routine. There is a growing body of evidence to show that patients with chronic hepatitis C virus (HCV) without major disease related complications do perceive themselves to be unwell and do have significant changes in their physical and mental well being. These abnormalities cannot be attributed to the mode of acquisition of the infection or to the severity of liver damage. The mechanism of these changes is unknown but the symptoms do remit following successful therapy, indicating that the presence of the virus plays a role in their aetiology. These symptoms require careful evaluation and may be sufficiently severe to justify therapy in the absence of advancing liver damage. Treatment of chronic HCV significantly impairs a patient's quality of life. The decision as to whether an individual patient's symptoms are sufficient to justify therapy in the absence of progressive liver damage is one which must be based on an assessment of the individual's current and future status as well as the individual's ability to tolerate current therapy.

Antiviral Agents↗
PubMed1999

Human type I interferons differ greatly in their effects on the proliferation of primary B cells.

We examined the effects of eight subtypes of human interferon-alpha (IFN-alpha) and human IFN-beta on primary human B cells. In costimulation with antibodies to IgM (but not to CD40), some of these induced the cells to proliferate (but not to differentiate). Individual IFN differed greatly in their relative proliferative effects. IFN-alpha8 at 0.1-0.5 ng/ml induced proliferation, whereas most other subtypes were active only at concentrations >5 ng/ml, and IFN-alpha1 was inactive. These marked differences were not due to a selective overall increase in B cell response only to some IFN subtypes, as all those tested similarly induced the IFN-inducible genes 6-16 and HLA class I. Our results show that human B cells must respond to type I IFN via two distinct pathways. One is specific for IFN-alpha8 but can be activated by other IFN at relatively high concentrations. The other responds to them all and causes activation of IFN-inducible genes.

B-Lymphocytes↗
PubMed1999

The use of CT scanning in dementia. A systematic review.

While reversible cases of dementia are rare once detected, the patient may benefit from treatment. This paper examines the cost-effectiveness of computerized tomography (CT) scanning as a screening test for potentially reversible dementia. A systematic review was carried out to identify the proportion of patients with dementia above and below the age of 65 years with a theoretically treatable condition and the proportion of these patients who would benefit from neurosurgery. Information was combined with epidemiological and financial data relating to Scotland to model the costs and benefits of implementing a national screening program. Subdural hematoma, normal pressure hydrocephalus, and brain tumours are rare conditions treatable by neurosurgery. A scanning and treatment program for Scotland would cost 4.6 million Pounds per annum. Of 531 reversible cases detected, 136 would benefit from neurosurgery, 369 would not benefit, and 26 would die as a result of surgery. Treating normal pressure hydrocephalus reduces overall quality-adjusted survival. The most cost effective screening strategy is to scan all patients but treat only subdural hematomas, gaining 178 quality-adjusted life-years (QALYs) at a cost of 14,171 Pounds per QALY for patients aged 65 at the time of the scan. The corresponding figures for patients above and below 65 years are 9,000 Pounds and 23,000 Pounds, respectively. CT scanning appears cost-effective in dementia patients under 65 years. It should be undertaken selectively in more elderly patients. Surgical treatment of normal pressure hydrocephalus may reduce quality adjusted survival and should only be undertaken within clinical trials.

Age Factors↗
PubMed1998

Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis.

The effects of chronic hepatitis C virus (HCV) infection, in the absence of cirrhosis, on patients' quality of life was assessed using the short form 36 (SF36) symptomatology questionnaire. Patients with chronic hepatitis C were polysymptomatic and had significant reductions in their SF36 scores for all of the modalities tested. Patients with chronic hepatitis B virus (HBV) infection showed a reduction in the SF36 scores that assessed mental functions, but they had no decrease in the scores that measured physical symptoms, indicating that the symptoms associated with chronic HCV infection are qualitatively different from those associated with chronic HBV infection. Patients with chronic HCV infection who had used intravenous drugs in the past had the greatest impairment in quality-of-life scores, but the reduction in quality-of-life scores was still found in patients who had never used drugs. The reduction in quality of life could not be attributed to the degree of liver inflammation or to the mode of acquisition of the infection. Hence, chronic infection with HCV per se gives rise to physical symptoms that reduce the quality of life of infected patients.

Adult↗
PubMed1998

Spontaneous seroconversion in chronic hepatitis B: role of mutations in the precore/core gene.

The mechanism underlying spontaneous clearance of hepatitis B e antigen (HBeAg) and the appearance of antibodies (anti-HBe seroconversion) in chronic hepatitis B is not known. Previous studies have demonstrated mutations within the precore/core gene before, during, and after seroconversion, suggesting that the emergence of mutations in the core gene may abrogate tolerance and that this event may act as a general principle for the initiation of the clearance of HBeAg. To investigate this hypothesis, we studied three patients with adult-acquired chronic hepatitis B virus (HBV) infection before spontaneous seroconversion by sequential sequencing and single-stranded conformation polymorphism (SSCP) analysis of the entire precore/core genome. In one patient, a new viral strain appeared six months before seroconversion, but no mutations or new viral strains could be detected in the other two patients. SSCP analysis confirmed the sequencing results and revealed no evidence for the emergence of new viral subpopulations before seroconversion. These results suggest that the appearance of nucleotide changes within the precore/core region of the dominant viral strain is not a prerequisite for the induction of seroconversion in patients with chronic hepatitis B virus infection acquired during adulthood.

Adult↗
PubMed1998

Are all type I human interferons equivalent?

The Type I interferons are a family of closely related cytokines that have antiviral and immunostimulatory properties. There has been prolonged debate regarding the different interferon-alpha subtypes: with some authorities suggest that the different interferons have essentially similar properties but others argue that there are significant differences between them. Recent work has shown that the various interferon-alpha subtypes can interact with the interferon receptor components in different ways and can activate a number of different signalling pathways. Recent studies on the immunomodulatory properties of the Type I interferons indicate that there are profound differences between the subtypes. The clinical significance of all these differences remains to be determined.

Animals↗
PubMed1997

Management of chronic hepatitis C: clinical audit of biopsy based management algorithm.

OBJECTIVE: To assess the attendance, outcome, compliance with treatment, and response to interferon alfa in patients with chronic hepatitis C who attended during 1995 and were treated according to a biopsy based algorithm. DESIGN: Retrospective audit of all patients with chronic hepatitis C attending outpatient clinics over one year. SETTING: The liver unit at a London teaching hospital. SUBJECTS: 255 patients with chronic hepatitis C. MAIN OUTCOME MEASURES: Patient survival, attendance, and compliance with diagnostic and therapeutic regimens. Response to interferon alfa treatment, based on loss of viraemia three months after cessation of treatment. RESULTS: A large proportion of patients (39%) with newly diagnosed chronic hepatitis C infection do not want to undergo further investigation. Of those patients who do attend for further treatment, a large proportion with severe hepatic fibrosis (42%) do not want to undergo currently available treatment. The response rate to interferon (21%) in treated patients was similar to that previously reported in a trial setting. There was no significant difference in response rates in patients with or without severe fibrosis not amounting to cirrhosis. In patients with cirrhosis there was a high incidence of hepatocellular carcinoma (18%) over a follow up period of 20 months. CONCLUSION: Current strategies aimed at investigating and treating patients with chronic hepatitis C are not acceptable to a large proportion of patients. Many patients with cirrhosis related to hepatitis C infection develop hepatic neoplasms, and management strategies to deal with this problem are urgently required.

Adult↗
PubMed1997

Interferons in host defense.

The Type I interferons are a group of related glycoproteins that play a key role in host defenses against viral infections. The interferons bind to a cell surface receptor and initiate the transcription of a wide range of proteins that have potent antiviral properties. The mechanism by which interferon binding to the cell surface initiates gene transcription has recently been elucidated and involves activation of protein kinases (JAK 1 and Tyk 2) followed by phosphorylation and activation of transcriptional regulators (the STAT proteins). These signal transduction molecules are not unique to the interferon signaling pathway, and other cytokines as diverse as erythropoietin and IL-2 use the same, or related proteins. To overcome the antiviral effects of the type I interferons, some viruses that cause chronic infections have developed interferon inhibitors that reduce the effectiveness of endogenous and exogenous interferon.

Binding Sites↗
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↗