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Biomedical subjects

O F James

Publications and source records attributed to O F James.

At least 91 records · Page 5Linked to original sources
PubMed1993

The activity of the metabolic form of hepatic phosphatidate phosphohydrolase correlates with the severity of alcoholic fatty liver in human beings.

Increased esterification of fatty acids to triglyceride is common to most of the mechanisms proposed to explain the causation of alcoholic fatty liver. However, it is unclear whether this is caused by increased substrate supply or whether direct stimulation of the enzymes of the esterification pathway occurs after excessive alcohol intake. The rate-limiting step in triglyceride synthesis is catalyzed by the enzyme phosphatidate phosphohydrolase, which is present in the cytosol and microsomes and is sensitive to inhibition by N-ethylmaleimide. This enzyme is physically distinct from a second form of phosphatidate phosphohydrolase that is located predominantly in the plasma membrane, is insensitive to N-ethylmaleimide inhibition and has a putative role in cell-signaling. We have investigated whether the activity of the N-ethylmaleimide-sensitive ("metabolic") form of phosphatidate phosphohydrolase is increased in patients with alcoholic liver disease and whether any increased activity correlates with the severity of steatosis. N-ethylmaleimide-sensitive and -insensitive phosphatidate phosphohydrolase activities were measured in needle liver biopsy specimens from 42 alcoholic patients and 6 patients with primary biliary cirrhosis and in wedge biopsy specimens from 6 normal patients undergoing routine cholecystectomy. Steatosis was "scored" on coded slides from 0 to 3. N-ethylmaleimide-sensitive activity was higher in alcoholic biopsy specimens scoring 3 (3.25 +/- 0.4 units/mg protein, n = 10) than in those scoring either 0 (1.21 +/- 0.2, n = 14) or 1 to 2 (1.58 +/- 0.2, n = 18), and it was also higher than in biopsy specimens from normal and primary biliary cirrhosis patients (1.65 +/- 0.3, n = 12; p < 0.0001, analysis of variance).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Duodenal brush-border mucosal glucose transport and enzyme activities in aging man and effect of bacterial contamination of the small intestine.

Duodenal biopsies were collected from 38 subjects (24 female and 14 male) ranging in age from 55 to 91 years. Evidence of bacterial contamination of the small bowel (BCSB) was sought at the same time by bacterial culture of duodenal aspirates and by hydrogen and [14C]glycocholic acid breath tests; subjects were considered to be positive for BCSB if any one of the three tests was abnormal. Biopsies were analyzed for six brush-border membrane enzyme activities: maltase, sucrase, lactase, alkaline phosphatase, leucine aminopeptidase, and alpha-glucosidase. Analysis of covariance with age as the covariate indicated no significant effect of age on the specific activities of these enzymes. Mucosal Na(+)-dependent glucose transport was quantified in brush-border membrane vesicles prepared from the biopsies. In all groups, glucose transport at 20-30 sec was greater (ranging from mean values of 2.45 to 3.66 times) than at 45 min, consistent with Na(+)-coupled glucose transport, and no significant effect of age was observed. BCSB had no significant effect on specific activities of any of the duodenal mucosal hydrolases but was associated with reduced (P = 0.05) brush-border glucose transport. None of the variables studied was significantly affected by the gender of subjects. In conclusion, these biochemical data do not support the contention that reduced capacity for carbohydrate absorption in the elderly is explained by reductions in duodenal brush-border mucosal disaccharidase activities or glucose transport.

Aged↗
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↗
PubMed1993

Plasma membrane form of phosphatidate phosphohydrolase: a possible role in signal transduction during liver fibrogenesis.

1. Several growth factors important in liver regeneration and fibrosis stimulate phospholipase D in plasma membranes via a receptor/G-protein-coupled mechanism resulting in hydrolysis of phosphatidylcholine to phosphatidate. Phosphatidate can be further hydrolysed to diacylglycerol by phosphatidate phosphohydrolase. Phosphatidate and diacylglycerol can act as 'second-messengers' and regulation of phosphatidate phosphohydrolase activity could control the balance between them. 2. A form of phosphatidate phosphohydrolase, located in the plasma membrane and insensitive to inhibition by N-ethylmaleimide, has recently been identified that is distinct from the 'metabolic' form, which is present in the cytosol and microsomes and is sensitive to N-ethylmaleimide. 3. We have investigated the hypothesis that the balance between regeneration and fibrosis is, in part, determined by the activity of plasma membrane phosphatidate phosphohydrolase through its effect on the phosphatidate/diacylglycerol ratio. N-Ethylmaleimide-insensitive and -sensitive phosphatidate phosphohydrolase activities were measured in three hepatic conditions characterized by regeneration and/or fibrosis: alcoholic liver disease in humans (regeneration and fibrosis) and rat livers after either acute CCl-4-induced injury (regeneration) or common bile duct ligation (fibrosis). 4. In patients with alcoholic liver disease, N-ethylmaleimide-insensitive phosphatidate phosphohydrolase activity was higher in cirrhotic biopsies (5.82 +/- 0.3 nmol of Pi min-1 mg-1 of protein, n = 19) than in non-cirrhotic biopsies (2.17 +/- 0.2, n = 23) or in wedge biopsies from healthy subjects undergoing routine cholecystectomy (2.16 +/- 0.5, n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Human pyruvate dehydrogenase complex as an autoantigen in primary biliary cirrhosis.

1. The sera of more than 90% of patients with primary biliary cirrhosis contain antimitochondrial antibodies which react with the E2 component of the pyruvate dehydrogenase complex, identified as the major autoantigen in primary biliary cirrhosis. All previous studies in this area have utilized protein derived from animal tissue or have used recombinant human pyruvate dehydrogenase complex E2 expressed in Escherichia coli. 2. We report the preparation and characterization of native pyruvate dehydrogenase complex and pyruvate dehydrogenase complex E2 from human heart tissue and its application in studies of immune reactivity with the sera of patients with primary biliary cirrhosis. 3. The immune reactivity of sera from patients with primary biliary cirrhosis versus the bovine and human E2/X components of pyruvate dehydrogenase complex was indistinguishable in both immunoblotting and the more sensitive e.l.i.s.a. 4. These findings suggest that the reactivity of sera from patients with primary biliary cirrhosis against the major autoantigen of the disease is a property of that antigen, independent of its human or bovine origin. Furthermore, this justifies the use of bovine pyruvate dehydrogenase complex in past and future work on primary biliary cirrhosis antibody reactivity.

Animals↗
PubMed1993

Gastrointestinal responses to oats consumption in young adult and elderly rats: digestion, large bowel fermentation and crypt cell proliferation rates.

The present experiment was designed to test the hypothesis that ageing modifies the gastrointestinal responses to a change in diet composition. Rats of the Wag/Rij strain, either young adult (4 months of age) or elderly (27 months of age), were given a basal semi-purified diet or a diet of similar major nutrient composition containing 500 g oatmeal/kg for 17-18 d. Elderly rats digested the dry matter (DM) and organic matter (OM) of both diets less well than did their young adult counterparts, with more of this digestion occurring in the distal intestine. The greater flow of OM to the caecum of oats-fed animals was accompanied by significant reductions in caecal pH and increases in caecal total short-chain fatty acids (SCFA) concentration which appeared to be independent of age. However, young adults responded to feeding on oats by showing a much larger increase in the molar proportion of butyrate (332%) than did elderly animals (79%). Elderly rats had longer duodenal villi than did young adults but effects of age or diet were not detectable at other sites. With both age-groups oats consumption was associated with significant stimulation of crypt cell proliferation rate (CCPR) in the small intestine and caecum, but for the colon there was a significant reduction in CCPR with oats feeding. A reduced ability of the aged large bowel (LB) to produce butyrate may contribute to the prevalence of LB disorders in the elderly.

Aging↗
PubMed1993

Is caffeine a factor in subjective insomnia of elderly people?

Subjective insomnia is more prevalent in elderly than in young populations. In order to examine the relationship between caffeine and sleep quality we studied 181 community-dwelling subjects over a wide age range and 53 elderly patients receiving continuing hospital care. Subjects completed a sleep questionnaire and data concerning smoking, alcohol, use of hypnotics and caffeine-containing substances were recorded. Late afternoon plasma caffeine concentrations were measured in a sub-group of 87 of the community-dwelling subjects and in the hospitalized patients. For the group as a whole, there was a significant negative correlation between age and coffee but not tea consumption (p < 0.001). A global score of sleep quality was significantly inversely related to age (p < 0.001). For the community-dwelling population, the median plasma caffeine concentration was 1.71 micrograms/ml (range 0.10-6.74) and showed a significant correlation with sleep quality (p < 0.05). In contrast, for the hospital dwelling population, median caffeine concentration was higher in patients reporting sleep problems than in those without (p < 0.05). Self-reported consumption of coffee and tea did not correlate with plasma caffeine concentrations. It is possible that people with poor sleep quality, residing in the community, are aware of the stimulatory effects of caffeine and lower their intake accordingly, whereas hospitalized elderly patients, who have less control over their environment, do not.

Adult↗
PubMed1993

A study of nutritional deficits of long-stay geriatric patients.

Current information suggests that dietary intake of nutrients declines with age and that undernutrition in elderly long-stay hospital patients may be under-recognized. We undertook to describe the daily dietary intakes of a group of elderly long-stay hospital patients (n = 92) (group A), using 7-day weighed dietary records. The aim of the study was to determine the adequacy of the diet and investigate whether any differences existed in the intakes of the hospital patients. An assessment of nutritional status was carried out by anthropometry, haematology and biochemistry and was validated by comparison with two further groups: fit young subjects (n = 41) (group B) and fit community elderly subjects (n = 92) (group C). Men in group B had the highest mean values for mid-arm circumference, arm-muscle circumference, corrected arm-muscle area and arm-fat area while women in group A had the lowest mean values for all measured anthropometric indices. There were significant correlations between daily energy intake and anthropometry for men in groups B and C. In group A 68% had intakes < 2/3 recommended daily allowance for energy, 100% for vitamin D, E, B6, folic acid; 98% for magnesium and zinc; and 90% for retinol. Serum calcium and serum alkaline phosphatase were correlated with vitamin D intake in men in group A. There was no biochemical or haematological evidence of undernutrition in the three groups. Elderly long-stay hospital patients were grossly undernourished and their dietary intake did not satisfy basal metabolic demands, based on recommended daily allowances.

Adult↗
PubMed1993

Re-evaluation of the metabolism of carbocisteine in a British white population.

It has been claimed that the amino acid derivative carbocisteine is predominantly metabolized by sulfoxidation and that this pathway exhibits a genetic polymorphism. Moreover, those subjects with a 'poor metabolizer' phenotype have been thought to have a genetic predisposition to developing certain diseases. We have confirmed the observations of others that this marker drug does not undergo significant S-oxidation. Furthermore, a novel urinary metabolite, S-(carboxymethylthio)-L-cysteine (CMTC) has recently been identified. To determine if a genetic polymorphism for this biotransformation pathway exists, metabolic ratios (% urinary excretion carbocisteine/% urinary excretion CMTC) for 120 healthy volunteers were assessed using high-performance thin-layer chromatography. Urinary excretion of the parent drug ranged from 6% of the dose administered to 56% (mean +/- SD, 23.4 +/- 0.8%). No cysteinyl sulfoxide metabolites were identified in the urine samples. The amount excreted as CMTC exhibited a 12-fold variation but only accounted for mean of 4.4% (1-12%) of the dose given. Two individuals initially had high metabolic ratios (> 30), however, on rechallenge both their MRs were less than 5. Therefore, carbocisteine is not an appropriate probe drug for sulfoxidation. The formation of the novel metabolite CMTC appears to exhibit polymorphism, although the considerable intra-subject variation for its formation does not allow assignment of a phenotype.

Adult↗
PubMed1993

Alcohol and stroke. A case-control study of drinking habits past and present.

BACKGROUND AND PURPOSE: Previous studies have reported a U-shaped relation between alcohol consumption and stroke. Those studies have been criticized for failing to distinguish between lifelong abstainers from alcohol and those who have given up drinking. METHODS: We examined current and previous drinking habits of 364 cases of acute stroke and 364 community-based control subjects matched for age, sex, and family practitioner. RESULTS: Stroke patients were more likely to have been lifelong abstainers from alcohol than were the control subjects. The odds ratio (OR) or lifelong abstainers versus those who had ever drunk regularly was 2.36 (95% confidence interval [CI], 1.67 to 3.37). No relation was found between stroke and current nondrinkers. Current male heavy drinkers also had an increased risk of stroke (OR, 2.88; 95% CI, 1.08 to 2.31). CONCLUSIONS: Lifelong abstention from alcohol is associated with an increased risk of stroke. Moderate alcohol consumption may protect against cerebrovascular disease.

Aged↗
PubMed1993

Lipoylated and unlipoylated domains of human PDC-E2 as autoantigens in primary biliary cirrhosis: significance of lipoate attachment.

Approximately 95% of patients with primary biliary cirrhosis have antimitochondrial antibodies against the E2 component of the pyruvate dehydrogenase complex (E2p). Immunodominant sites on E2p have been localized to the inner lipoyl domain, which serves as a covalent attachment site for the essential cofactor, lipoic acid. However, it is not clear whether the presence of lipoic acid is necessary for autoimmune recognition of human E2p. To facilitate further studies on the inner lipoyl domain and to assess the importance of lipoic acid in antibody binding, we used the previously cloned human E2p cDNA in the construction and high-level expression in Escherichia coli of a subgene encoding the domain. Purification and analysis of the gene product revealed that both lipoylated and unlipoylated forms of the intact domain are generated. Immunoblotting, enzyme-linked immunosorbent assay inhibition experiments and antibody affinity measurements using isolated lipoylated and unlipoylated domains demonstrated that the presence of the lipoyl residue is crucial for effective recognition by primary biliary cirrhosis patients' autoantibodies, which have a higher relative affinity for the lipoylated form. Contrary to some previous suggestions, these results indicate that antibodies in primary biliary cirrhosis patients' sera bind most effectively to a unique peptide-cofactor conformation in the lipoyl domain of the human E2p polypeptide. Moreover, the availability of large amounts of human lipoyl domain will permit further studies into the role of the antigen (if any) in disease pathogenesis.

Acetyltransferases↗
PubMed1993

Primary biliary cirrhosis: contribution of HLA class II allele DR8.

Primary biliary cirrhosis is a chronic cholestatic disease of unknown aetiology which predominantly affects middle-aged women. It is thought to be autoimmune in nature, but unlike many autoimmune diseases no clear HLA association has been described. Several studies have suggested conflicting associations with HLA class II, although a DR8 association is most frequently described. To test the hypothesis that primary biliary cirrhosis is associated with a certain HLA class II locus we genotyped 130 patients with the disease from the north-east region of England and 363 local healthy controls. HLA-DRB1 and confirmatory DQA and DQB genotypes were determined by TaqI restriction fragment DNA length polymorphism analysis. In addition, a polymerase chain reaction technique (double ARMS) was used to investigate the DRB3 locus (DR52) in 98 primary biliary cirrhosis patients and 107 local controls. We found an increased frequency of HLA-DR8 (18.5% vs 9.2%, p < 0.005, relative risk of 2.0 [1.3-3.1]) in the primary biliary cirrhosis group. HLA-DR8-positive primary biliary cirrhosis patients had a higher serum bilirubin level (p = 0.03) than DR8-negative patients. There was no difference in the DR52 frequencies and no association with markers of disease severity. These results support earlier serological findings, although the association between primary biliary cirrhosis and DR8 is weaker than previously described. In addition, DR8-positivity may identify a clinical subgroup with a worse prognosis.

Adult↗
PubMed1992

A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results.

The results of a 3-year, placebo-controlled trial of prednisolone treatment in primary biliary cirrhosis (PBC) are presented. The active (n = 19) and placebo (n = 17) arms were initially well matched for age, menopausal status and disease severity. At 3 years hepatic symptoms were relatively improved in the prednisolone group. Hepatic mortality was 3/19 (prednisolone), 5/17 (placebo) (p = n.s.). For all liver blood tests the trend favoured prednisolone treatment, though the differences were only significant for alkaline phosphatase and protein. All immunoglobulins fell significantly. Quantitative ELISA determination of antimitochondrial antibody showed a significant fall in the prednisolone group compared with placebo (p less than 0.001 at 1 year, p less than 0.05 at 3 years). Deterioration in histology (appearance of cirrhosis) was more common in the placebo group. Overall hepatic function (hepatic mortality, doubling in bilirubin, 6 milligrams fall in albumin, de novo appearance of cirrhosis or symptoms of portal hypertension) was significantly worse in the placebo group (p less than 0.01). After 3 years no significant differences could be detected in bone mineral content (single photon absorptiometry of radius and femur) between the two groups or in comparison with other PBC patients. Thus, after 3 years, prednisolone treatment was associated with a better overall hepatic outcome and little evidence of increased bone loss.

Absorptiometry, Photon↗
PubMed1992

No evidence for involvement of type 1 collagen structural genes in 'genetic predisposition' to alcoholic cirrhosis.

Type 1 collagen is the predominant collagen in cirrhotic livers. Each type 1 collagen molecule contains three subunits, two are identical (the alpha 1 chains) and the sequence of the third (alpha 2) is very similar. They are encoded at the non-synthenic loci, COL1A1 and COL1A2 and restriction site dimorphisms have been described at each locus. Genetic factors have been invoked as a basis for increased susceptibility to alcoholic cirrhosis. One hypothesis is that genetically determined differences in type 1 collagen may be involved in this predisposition. We have examined this by analysing restriction fragment length polymorphisms at each type 1 collagen locus in leucocyte DNA from 56 unrelated patients with alcoholic cirrhosis and 74 local unrelated healthy controls. Based on the presence or absence of these restriction site dimorphisms four possible haplotypes were generated at COL1A1 and COL1A2. We found no significant difference in allele frequencies between alcoholic cirrhotics and controls and, unlike a previous small study, we found no particular haplotype of either gene was associated with alcoholic cirrhosis. Our study provides no evidence for involvement of type 1 collagen structural genes in a genetic predisposition to cirrhosis in alcoholics.

Collagen↗
PubMed1992

Effect of the risk factors for stroke on survival.

In a case-controlled study into the risk factors for admission to hospital with stroke, 400 subjects and 400 age and sex-matched controls were recruited. All bar two subjects were followed until death or 6 months. Previous stroke and regular snoring (p = 0.0013 and p less than 0.0001 respectively) were the only two risk factors adversely to effect mortality. Transient ischaemic attack, ischaemic heart disease, hypertension, atrial fibrillation, diabetes mellitus did not significantly effect prognosis. An apparent beneficial effect of drinking alcohol and smoking became insignificant when the confounding influence of age was taken into account.

Cerebrovascular Disorders↗