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Biomedical subjects

M F Bassendine

Publications and source records attributed to M F Bassendine.

At least 73 records · Page 4Linked to original sources
PubMed1996

Hepatitis C virus: epidemiology and genotypes in the north east of England.

The epidemiology of hepatitis C virus (HCV) infection was studied in an English teaching hospital over an 18 month period. A total of 104 HCV antibody positive patients were referred for further investigation. They were divided into those diagnosed through screening (blood donors and intravenous drug abusers) and those diagnosed for other reasons, and their mean ages, known risk factors for HCV transmission, genotypes, and liver biopsy histology were analysed. Screened patients were significantly younger than the others. No significant difference in age was found between genotypes. Most patients genotyped (69%) were genotype 1. Intravenous drug abusers had a higher proportion of subtype 1a, and patients who acquired HCV through blood transfusion had a higher proportion of subtype 1b. Liver biopsy specimens were scored using a histological activity index for liver inflammation and fibrosis. Patients with subtype 1b had significantly more severe liver disease than other genotypes when the histological activity index scores for fibrosis were analysed (p < 0.05). Liver disease worsened significantly with age according to all three histological activity index scores (portal activity: p < 0.01, acinar activity: p < 0.001, fibrosis: p < 0.0001). Liver disease worsened with increased duration of infection (p < 0.002), and patients who also abused alcohol presented at a significantly younger age (cirrhosis, p < 0.05, hepatocellular carcinoma, p < 0.02).

Adult↗
PubMed1996

Non-Hodgkin's lymphoma and hepatitis C virus infection.

The hepatitis C virus (HCV) is a recently described and important cause of acute and chronic liver disease. A hallmark of HCV is its propensity to become chronic, some patients with chronic HCV progressing to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotrophic and we report 2 patients with HCV cirrhosis who developed non-Hodgkins lymphoma (NHL). These cases raise the possibility that chronic HCV infection of lymphocytes plays an aetiological role in this malignancy. However screening of a further 63 consecutive patients over the age of 50 years with NHL for HCV antibody by second generation enzyme linked immunoassay (ELISA) failed to identify any patients with evidence of HCV infection. This suggests that HCV is an uncommon contributory factor for the development of non-Hodgkins lymphoma in the United Kingdom.

Aged↗
PubMed1995

Prokaryotic expression and analysis of the antibody response to a Newcastle isolate of the core gene of hepatitis C.

The full length hepatitis C virus (HCV) core gene was isolated from a Newcastle strain and expressed in E. coli. A truncated HCV core gene which lacks the hydrophobic carboxyl-terminal sequence was also expressed. The truncated HCV core was expressed at higher levels with fewer cleavage products. Antibody reactivity to the recombinant HCV core antigen was analysed by ELISA and Western blotting in 60 HCV antibody-positive patients with a broad spectrum of liver disease. There was no significant difference between the presence of IgG to recombinant HCV core and reactivity to the core antigen in the RIBA-2 test. There was also no significant difference between the presence of IgG to recombinant core and diagnostic PCR as a marker for active liver inflammation.

Antigens, Viral↗
PubMed1995

Immunogenicity of biliary epithelial cells: study of the expression of B7 molecules.

Efficient antigen presentation requires the provision of a co-stimulatory signal, the best characterized of which is provided by the B7 molecules. It is unclear whether biliary epithelial cells expressing Class II major histocompatibility complex molecules can function as antigen presenting cells, although this has been suggested as an important mechanism in the initiation and/or perpetuation of some immune-mediated liver diseases, including primary biliary cirrhosis and liver allograft rejection. We have found that human intrahepatic biliary epithelial cells do not express B7-1 (CD80) or B7-2 in vitro, even after activation with high doses of interferon-gamma, tumour necrosis factor-alpha or phorbol myristate acetate, or in vivo. However, they express similar levels of class II major histocompatibility complex antigens to those expressed by professional antigen presenting cells (Epstein-Barr virus transformed B cells). It is therefore unlikely that biliary epithelial cells stimulate efficient primary T cell activation. It may be possible that these non co-stimulatory class II major histocompatibility complex positive cells play a role in modulating immune responses in the liver.

Antigen-Presenting Cells↗
PubMed1995

CD4+ T cell subsets defined by isoforms of CD45 in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune condition characterized by destruction of the intrahepatic bile ducts. Autoreactive CD4+ T cells have been reported both in the peripheral circulation and in the mononuclear cell infiltrate in the affected portal tracts. In this large study we have used two- and three-colour flow cytometry to determine the phenotypes of the CD4+ T cell subsets in the peripheral blood and liver-infiltrating lymphocytes of PBC patients (n = 43), normal controls (n = 19) and patients with alcoholic cirrhosis (n = 15), according to a novel classification based on the simultaneous expression of different isoforms of CD45. In PBC patients the proportion of peripheral blood CD4+ cells possessing the CD45ROhighRA- 'memory' phenotype was significantly increased, and the CD45RO-RAhigh 'naive' population was significantly decreased, compared with the two control groups. No significant differences in peripheral blood CD4+ T cell subsets were seen between patients with pre-cirrhotic and cirrhotic PBC. A similar, but more marked, shift towards the CD45ROhighRA- 'memory' phenotype was seen in the liver-infiltrating CD4+ T cells in PBC patients compared with alcoholic cirrhotics. Cells within the CD4+ memory subpopulation were further subgrouped according to expression of CD45RB, the level of expression of which has been associated with functional differences in the memory subset. In peripheral blood no differences were seen between PBC patients and controls with respect to the proportion of CD45ROhighRBhigh and CD45ROhighRBdim memory subsets. A statistically significant difference in the distribution of these memory subsets, with an increased memory-2/memory-1 ratio was observed in the liver-infiltrating CD4+ T cells of PBC patients compared with those from alcoholic cirrhotic patients. The potential implications of this observation are discussed.

Adult↗
PubMed1995

T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune condition that results in destruction of the intrahepatic biliary epithelial cells and is characterized by autoantibodies to pyruvate dehydrogenase complex (PDC). The portal tract T-cell infiltrate and up-regulation of HLA class I, HLA class II, and cell adhesion molecules such as intercellular adhesion molecule-1 on the biliary epithelial cells suggest that T cells play a significant role in mediating this damage. The authors have characterized the peripheral blood T-cell proliferative responses of 24 PBC patients and 48 controls (20 normal, 28 non-PBC chronic liver disease) to the dominant autoantigen PDC, and its constituent components E1, E2 and protein X (which co-purify), and E3. A significant proportion of both PBC patients and controls showed T-cell responses to whole PDC (12 of 24 vs. 24 of 48 SI > 2.5 P = NS) and E1 (15 of 24 vs. 25 of 48 P = NS). Responses to PDC and E1 are thus seen in normal individuals and are not limited to PBC patients. T-cell responses to E2/X were seen in most PBC patients (14 of 24), but in only a small number of controls (6 of 48, P < .0001), responses to E2/X being significantly more frequent in pre-cirrhotic PBC patients (stages I to III, 12 of 15) than cirrhotic (stage IV, 2 of 9 P < .05). Peripheral blood T-cell responses to E2/X are thus strongly associated with early PBC. Responses to E3 were low in both PBC patients and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Clinical features and prognosis of hepatocellular carcinoma in Britain in relation to age.

A retrospective review of 110 cases of hepatocellular carcinoma (HCC) from the North East of England was undertaken to examine clinical features and prognosis in the 52 patients 65 years of age or more at presentation in comparison with 58 patients under 65. Symptoms and signs at the time of presentation were similar in the two age groups. Only 25% of patients were known to be cirrhotic at the time of presentation, but this increased to 75% after investigation. Although tumour stage at diagnosis was no worse in the elderly group, these patients received less intensive investigation and were significantly more likely to receive conservative therapy (p = 0.03). Although median survival was significantly worse in those aged > or = 65 years than in those < 65 years (10.5 and 18.5 weeks respectively; p = 0.02) this adverse effect disappeared when adjusted for the effects of treatment.

Adolescent↗
PubMed1994

Expression of mutant p53 protein in hepatocellular carcinoma.

p53 mutations are a common genetic finding in hepatocellular carcinoma from areas of high aflatoxin exposure. Recent small studies have shown that p53 gene mutations may be less common in areas with a low prevalence of hepatocellular carcinoma such as Great Britain. The protein product of mutant p53 can be detected immunohistochemically because of its longer half life in comparison with native protein. This study used a novel monoclonal antibody DO-7, raised against recombinant p53 and effective in routinely processed biopsy specimen tissue, to detect the mutant protein in a series of 45 cases of hepatocellular carcinoma occurring in white subjects resident in the United Kingdom. Focal nuclear labelling was seen in four cases (9%); surrounding cirrhotic tissue in one of these was negative for p53 expression. This study shows that p53 mutations are a rare event in hepatocarcinogenesis in Great Britain, an area of low aflatoxin exposure, and supports the concept of geographical variations in the cause and pathogenesis of hepatocellular carcinoma.

Adult↗
PubMed1994

Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis.

This study reports on a group of 20 patients with an initial diagnosis of primary biliary cirrhosis (PBC) whose serum tested negative for antimitochondrial antibodies by immunofluorescence. All had a clinical history compatible with primary biliary cirrhosis, and results of biochemical, histological, and radiological investigations were consistent with this diagnosis despite the absence of antimitochondrial antibodies by immunofluorescence. For comparison, these patients were matched for sex and serum bilirubin with 20 antimitochondrial antibody positive (> 1:160) and histologically confirmed primary biliary cirrhosis patients who served as controls. Serum samples from both groups were retested blindly for antimitochondrial antibodies using immunoblotting and for antibodies to the major M2 mitochondrial autoantigens by enzyme linked immunosorbent assay (ELISA). Three antimitochondrial antibody immunofluorescence negative patients had antimitochondrial antibodies by immunoblotting and ELISA; the remaining 17 patients were confirmed negative by all methods. The antimitochondrial antibody immunofluorescence positive controls were verified by immunoblotting or ELISA, or both. All 17 patients negative for antimitochondrial antibodies had antinuclear antibodies, often in high titres, compared with 3/17 of the antimitochondrial antibody positive controls (p = 0.0001). Additionally, the antimitochondrial antibody negative group also had significantly higher smooth muscle antibody titres (p = 0.03) and lower serum IgM (p = 0.01) and aspartate aminotransferase (p = 0.03) activities than the antimitochondrial antibody positive controls. Analysis of clinical findings, histological tests, serum bilirubin, alkaline phosphatase, alanine aminotransferase, and IgG, disclosed no significant differences between the two groups. This paper describes a group of patients with the clinical and histological features of PBC but who do not fulfil the usual criteria necessary to make this diagnosis. Because they also have very high titres of antinuclear antibodies, smooth muscle antibodies, and comparatively low IgM and aspartate aminotransferase activities, we believe they are distinct from PBC and have a syndrome of autoimmune cholangitis.

Adult↗
PubMed1994

Expression of glutathione S-transferases in normal and malignant pancreas: an immunohistochemical study.

The glutathione S-transferases (GSTs) are a family of detoxification and metabolising enzymes, which have been linked with the susceptibility of tissues to environmental carcinogens and resistance of tumours to chemotherapy. Environmental carcinogens have been implicated in the pathogenesis of pancreatic carcinoma, which is also a tumour characterised by marked chemotherapeutic drug resistance. In this study 26 pancreatic adenocarcinoma and 12 normal pancreatic samples were examined immunohistochemically for expression of pi (acidic), alpha (basic), and mu (neutral) GST. Fourteen (54%) of the tumours expressed pi GST alone, two (8%) expressed both pi and alpha GST, and two (8%) showed immunoreactivity with alpha GST alone. In the normal pancreas the intralobular ducts and centroacinar cells expressed pi GST alone whereas the large ducts expressed both pi and alpha GST. The acinar cells showed immunoreactivity only with anti-alpha GST. Mu GST was not expressed by normal or malignant pancreas. Expression of pi GST by pancreatic carcinoma may be a marker of the malignant phenotype and be induced during neoplastic transformation. Alternatively it could possibly reflect cell of origin, suggesting that the tumour arises from the centroacinar cells or intralobular ducts, or both rather than the large ducts.

Adenocarcinoma↗
PubMed1994

Defining the immunogenetic susceptibility to primary biliary cirrhosis.

Primary biliary cirrhosis is a chronic cholestatic disease, thought to be immune-mediated with genetic susceptibility encoded in the major histocompatibility complex. In northern Europeans, the best established associations are with HLA-DR8 and the complement allele, C4B2. These associations could be due to a single susceptibility locus on an extended haplotype linking HLA-DR8 and C4B2 or to both HLA-DR8 and C4B2 independently conferring disease susceptibility. C4B2 genotyping was performed on 64 patients with primary biliary cirrhosis and 61 controls matched for ethnic background and frequency of HLA-DR8. C4B2 was associated with HLA-DR8 (p < 0.05) in PBC. No difference in the frequency of C4B2 was detected between control and disease populations, suggesting that HLA-DR8 and C4B2 are in linkage disequilibrium and that C4B2 is not a susceptibility locus for PBC. Taq I polymorphisms were screened in the disease and control populations with the cosmid probe G91, located midway between the HLA-DR and complement loci. One G91 restriction fragment (G91A) was found to be associated with both HLA-DR8 and C4B2, at equal frequency in health and disease, providing evidence of an HLA-DR8-G91A-C4B2 extended haplotype. The frequency of G91A was the same in the disease and control populations, suggesting that G91A does not confer disease susceptibility. These findings establish G91 as the telomeric boundary for disease susceptibility associated with HLA-DR8, encoded on chromosome six. These studies help define the immunogenetic susceptibility locus for primary biliary cirrhosis.

Alleles↗
PubMed1994

Analysis of HLA-class-II-encoded antigen-processing genes TAP1 and TAP2 in primary biliary cirrhosis.

The search for genes involved in the aetiology of primary biliary cirrhosis (PBC) has centred on the major histocompatibility complex (MHC) on chromosome 6. Genotyping studies have confirmed an association with HLA class II allele DR8. We investigated polymorphisms in two newly identified genes (TAP1 and TAP2) situated close to the DR locus and thought to encode membrane transporter molecules involved in endogenous antigen processing. Genomic DNA extracted from PBC patients was compared with local healthy controls. TAP1 was analysed by amplification refractory mutation system (ARMS) PCR, and two alleles (A and B) were identified. In 126 PBC patients and 116 controls, allele frequencies were (A:B) 81:19% and 79:21%, respectively (NS). TAP2 analysis was by PCR followed by Bfal restriction digest, and again two alleles (A and B) were identified. Their frequencies in 109 PBC patients and 96 controls were (A:B) 76:24% and 73:27%, respectively (NS). No TAP1-TAP2 haplotype was associated with PBC. TAP allele frequencies were estimated within the DR8 subgroups (22 PBC, 14 controls). B allele frequency for TAP1 was increased in both DR8-positive PBC patients and controls compared with DR8-negative patients and controls (41% vs. 14% in PBC; 43% vs. 18% in controls), but no disease association was found. However, the increased frequency of TAP1B in DR8-positive subjects (42% DR8-positive vs. 16% DR8-negative, p < 0.001) indicates linkage disequilibrium between these two loci.

Base Sequence↗
PubMed1993

Deficient repair of DNA lesion O6-methylguanine in cirrhosis.

Cirrhosis is a risk factor for hepatocellular carcinoma. O6-methylguanine is a promutagenic and potentially carcinogenic DNA lesion produced by environmental alkylating agents. If it is not repaired, DNA replication can lead to a G-to-A transition mutation, which is a known mechanism of oncogene activation. We have found that the activity of the repairing methyltransferase enzyme is significantly lower in cirrhotic tissue than in non-cirrhotic diseased liver or in normal liver. This finding suggests a mechanism for cirrhosis being a risk factor for cancer of the liver: increased cellular proliferation together with persistence of O6-methylguanine might lead to malignant transformation of liver cells through mutation and oncogene activation.

Biopsy↗
PubMed1993

M4 and M9 autoantigens in primary biliary cirrhosis--a negative study.

We have investigated the potentially important finding that anti-M9 and anti-M4 antibodies in the sera of patients with primary biliary cirrhosis (PBC) recognise epitopes on the enzymes glycogen phosphorylase and sulphite oxidase, respectively. To test this, preparations of these two enzymes were applied in ELISA and immunoblotting, and the reactivities of sera from large groups of well-defined PBC patients (and other chronic liver disease patients) were studied. No specific reactivity with either putative antigen was observed in ELISA nor immunoblotting. However, with both antigens a positive correlation was observed between ELISA optical density readings and serum IgG levels in both the PBC and chronic liver disease groups which suggests some non-specific binding of immunoglobulin to the proteins. We conclude that antimitochondrial antibodies (AMA) do not specifically recognise glycogen phosphorylase and sulphite oxidase and the use of these antigens to determine the 'AMA profile' and indicate prognosis is not valid.

Autoantigens↗