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Biomedical subjects

O F James

Publications and source records attributed to O F James.

At least 163 records · Page 9Linked to original sources
PubMed1988

Primary biliary cirrhosis: identification of two major M2 mitochondrial autoantigens.

Primary biliary cirrhosis (PBC) is characterised by the presence of antimitochondrial antibodies. The PBC-specific, immunoreactive, trypsin-sensitive antigens on the inner mitochondrial membrane (M2) have hitherto not been identified. A major 70 kD M2 autoantigen is the E2 component (lipoate acetyltransferase) of the pyruvate dehydrogenase enzyme complex located within mitochondria. This has been confirmed by immunoblotting of PBC patients' sera against purified E2 protein: sera from 38/40 (95%) patients with established clinical, biochemical, and histological features of PBC (18 stage II/III, 22 stage IV) reacted positively with E2; whilst no sera from 39 controls (27 non-PBC chronic liver disease, 12 healthy normal women) gave a positive response. Immunoblotting showed that a second subunit of the pyruvate dehydrogenase complex, a 50 kD polypeptide of unknown function (component X), is also an M2 autoantigen. Identification of these M2 mitochondrial antigens should facilitate the development of a specific serological test for PBC and the study of autoimmunising epitopes.

Autoantibodies↗
PubMed1988

The value of tumour marker kinetics in the management of patients with primary hepatocellular carcinoma.

Serum alpha-fetoprotein (AFP) has been measured during chemotherapy of ten patients with hepatocellular carcinoma. Whenever the AFP concentration of a sample was lower than that of the previous sample the apparent half-life (AHL) of the protein was calculated. The biological half-life of AFP is 5 days so that values in excess of this were indicative of continuing or increased synthesis and secretion of AFP. The AHL for AFP provided a means of assessing efficacy of treatment. Increases in AHL generally predicted a rise in serum AFP and give advance warning of the need to change therapy.

Biomarkers, Tumor↗
PubMed1988

Intestinal alkaline phosphatase isoenzyme in patients with primary liver cancer during treatment with N10-propargyl 5, 8-dideazafolic acid (CB 3717).

Serum aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (gamma GT) activities and the serum ALP isoenzyme pattern have been measured in eleven patients undergoing treatment with CB3717. There were increases in the activity of all three enzymes. The ALP isoenzyme pattern showed an increased contribution of the intestinal isoenzyme to the serum ALP activity. This may be due to increased intestinal mucosal leakage or impaired uptake and breakdown of the intestinal isoenzyme by the liver.

Adult↗
PubMed1988

Metabolic bone disease in primary biliary cirrhosis at presentation.

Metabolic bone disease, particularly osteoporosis, is a complication of advanced primary biliary cirrhosis, but the extent of the problem is unclear. We present 33 patients who were investigated for bone disease at the time of diagnosis of their liver disease and who had received no prior treatment likely to influence their bones. Iliac crest bone biopsy showed no patient with osteoporosis, and mild osteomalacic changes in 1 patient. Slight elevations in appositional rate, osteoid volume, and resorption surface were compatible with a state of high bone turnover. Photon absorptiometry revealed a low forearm bone mineral content in 3 of 25 patients, calcium absorption was below normal in 14 of 24 patients, and there was evidence of fat malabsorption in 11 of 25 patients. Five patients also had low serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. Thus, little evidence of significant metabolic bone disease was found in this group by these methods, but abnormalities were seen, such as poor calcium absorption, that may predispose to its later development.

Adult↗
PubMed1988

Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the presence of antimitochondrial antibodies in the serum. It is possible that the PBC-specific immunoreactive trypsin-sensitive antigens on the inner mitochondrial membrane, termed M2, are important in the pathogenesis of this autoimmune disease. We have previously shown that a major M2"a" antigen is the E2 component of the pyruvate dehydrogenase multienzyme complex located within mitochondria. Analysis of the primary structure of the E2 components of all three 2-oxo acid dehydrogenase complexes reveals a high degree of homology with a similar highly segmented structure including lipoyl domains, E3-binding domains, C-terminal catalytic domains, and interdomain linker sequences. Immunoblotting of PBC patients' sera against purified E2 protein from 2-oxoglutarate dehydrogenase complex and branched-chain 2-oxo acid dehydrogenase complex reveals that these polypeptides are also autoantigens in this disease. Sera from 29 of 40 (72.5%) PBC patients gave a positive response against bovine 2-oxoglutarate dehydrogenase complex E2 and from 25 of 40 (62.5%) PBC patients gave a positive response against bovine branched-chain 2-oxo acid dehydrogenase complex E2. All 40 PBC patients (100%) have autoantibodies directed against at least one of the E2 components of the family of 2-oxo acid dehydrogenase complexes. Identification of these M2 mitochondrial autoantigens and detailed knowledge of their structure will allow important questions concerning this autoimmune disease to be addressed.

Acetyltransferases↗
PubMed1988

The effect of age upon the affinity of microsomal mono-oxygenase enzymes for substrate in human liver.

Although the clearance of many oxidized drugs falls with age, a corresponding fall in the maximal activities of drug metabolizing enzymes has not been noted. The possibility of a fall in enzyme affinity for substrate with age, which could account for the observed changes, has not previously been investigated in human liver. We have studied the kinetics of the microsomal mono-oxygenase 7-ethoxycoumarin-O-de-ethylase in 17 human liver biopsy specimens. No correlation was observed between age and microsomal protein recovery, maximal enzyme activity or apparent enzyme affinity. Since microsomal mono-oxygenase activities and affinities appear not to change in human liver, other factors such as a fall in liver volume or blood flow must be responsible for the decline in clearance of many oxidized drugs which occurs with ageing.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

The prognostic value of haematocrit in acute stroke.

One hundred and twenty-two consecutive patients admitted with acute stroke in a carotid distribution had venous blood taken for haematocrit (Hct), haemoglobin (Hb), white cell count (WCC) and urea estimations. Patients were followed for 12 weeks to determine the influence of haematocrit upon fatality. There were 96 patients aged greater than or equal to 65 years and 26 patients less than 65 years. No association could be demonstrated between Hct levels and fatality at 4 or 12 weeks. Regression analysis demonstrated that only increasing age (P less than 0.05) and a raised WCC (P less than 0.005) were independent factors significantly associated with fatality at both 4 and 12 weeks. In the elderly stroke patient (greater than or equal to 65 years) only WCC was significantly associated with fatality (P less than 0.005). Haematocrit levels are of no prognostic value for fatality in acute stroke. A raised white cell count is an important and independent prognostic factor for fatality at both 4 and 12 weeks following stroke.

Adult↗
PubMed1988

High erythrocyte water content causes discrepancy between values of automated and micro-centrifuged haematocrit.

Erythrocyte water content, micro-haematocrit (micro-Hct) and haematocrit (Hct) as derived by Coulter Counter were determined on 41 subjects. Significant discrepancies were observed between manual and automated Hct which could not be explained by abnormal red cell morphology and abnormal plasma osmolality, but appeared to be related to high erythrocyte water content (r = 0.54, p less than 0.001). As human ageing is associated with increased erythrocyte water content, these results question the reliability of Hct readings in the elderly. Further studies need to be performed to evaluate which estimation of Hct should be applied for subjects with high erythrocyte cell water.

Adult↗
PubMed1988

Lymphocytes from patients with primary biliary cirrhosis spontaneously secrete high levels of IgG3 in culture.

The origin of the raised serum IgG3 in primary biliary cirrhosis has been examined. Blood lymphocytes from patients with PBC and from age- and sex-matched controls were cultured, and the culture supernatants were assayed for IgG and IgG3. Lymphocytes from PBC patients spontaneously synthesized a higher percentage IgG3/total IgG than did control lymphocytes, as determined by ELISA. The increased synthesis of IgG3 in culture correlated with serum IgG3 in the patients. This strongly suggests that the raised serum IgG3 in these patients is due to increased synthesis of this isotype. Following PWM stimulation, the proportion of IgG3/IgG synthesized by normal (and most PBC) lymphocytes increased and the difference in IgG3 synthesized by PBC and control lymphocytes became less marked. The kappa/lambda light chain ratio of the IgG3 was assayed by ELISA but no evidence was found for clonally restricted synthesis of IgG3 by PBC blood lymphocytes.

Cells, Cultured↗
PubMed1987

Serum vitamin B12 levels in patients with primary hepatocellular carcinoma during treatment with CB3717.

Elevated Serum B12 levels were found at diagnosis in five of eleven patients with primary hepatocellular carcinoma. During chemotherapy either with CB3717 or VP16 the serum B12 rose dramatically, in one case reaching levels ten times the upper limit of normal. However, the serum LD activities did not change in parallel with the serum B12 levels suggesting that there was little necrosis of the tumour or the liver. With two out of five patients with other types of cancer the serum B12 levels also increased but less markedly. This data seems to suggest that the serum B12 level may not be as good a tumour marker for hepatocellular carcinoma as has been suggested and indeed may be influenced by the chemotherapeutic agent.

Adult↗
PubMed1987

7-Ethoxyresorufin deethylase (EROD) in human liver--the effect of alcoholic liver disease.

We have investigated the effect of alcoholic liver disease (ALD) on the metabolism of 7-ethoxycoumarin 0-deethylase in human liver microsomes. EROD activity was significantly reduced in tissue from ALD patients who smoked, compared to smoking controls. A similar trend was seen in non-smokers. These results have implications for the metabolism of environmental carcinogens.

Adult↗
PubMed1987

Induction of remission in hepatocellular carcinoma with a new thymidylate synthase inhibitor, CB3717. A phase II study.

In a Phase II clinical trial, 14 consecutive, unselected patients with primary hepatocellular carcinoma were treated with a new inhibitor of thymidylate synthase, CB3717. On the basis of previously reported criteria, 6 patients were considered to have a good prognosis (Grade A) and 8 a poor prognosis (Grade B). Three Grade B patients died after only one treatment. Six patients responded (4 Grade A and 2 Grade B) with a decrease in tumour size and greater than 50% fall in serum alphafetoprotein levels; 3 of these had a greater than 1 log fall in alphafetoprotein. A further patient (Grade B) showed static disease during treatment. Thus, of 11 patients receiving two or more treatments 7 showed clinical benefit, with a median survival from start of CB3717 therapy of 46 weeks (2 still alive at 33 and 67 weeks). Our results suggest that CB3717 will be a useful new therapeutic agent in hepatocellular carcinoma. Further controlled trials are indicated to confirm these preliminary findings, using the drug both as a single agent and in combination with inhibitors of thymidine uptake by cells, which may further increase efficacy.

Adult↗
PubMed1987

The effect of age on mono-oxygenase enzyme kinetics in rat liver microsomes.

The clearance of many oxidized drugs falls with age. Whilst factors such as reduced liver size, blood flow and specific enzyme activity may be important, the possibility that reduced enzyme affinity for substrate contributes to this fall has not hitherto been investigated. Using liver microsomes from 12 young adult and 12 elderly male Norwegian Brown rats we defined the kinetics of ethoxyresorufin-O-de-ethylation and aldrin epoxidation, specific substrates for the 3-methylcholanthrene inducible and phenobarbitone inducible forms of cytochrome P450, respectively. Our results show a marked fall in the maximal activity of both enzymes in advanced age whether expressed in terms of microsomal protein or unit of cytochrome P450, but with no change in apparent enzyme affinity (Km). Since Km is unchanged, we feel that qualitative age-related changes in cytochrome P450 are unlikely. Reduced metabolism may be due to age-related alterations in coenzymes or smooth endoplasmic reticulum lipid membranes.

Aging↗
PubMed1987

Passive and active carbohydrate absorption by the ageing gut.

We investigated the effects of advanced age, hospitalization and poor nutrition on passive and active carbohydrate absorption using the probe molecules lactulose and mannitol (passive absorption), and 3-O-methylglucose (active absorption). We studied five groups of subjects; healthy controls aged 20-30 years, 40-50 years and over 65 years, respectively, together with long-stay patients and elderly in-patients being investigated for malnutrition. Each subject undertook two separate studies ingesting a drink containing 5 g lactulose, 2 g mannitol and 2.5 mg 3-O-methylglucose (3-O-MG), on one occasion in isotonic solution and in the second study in hypertonic solution, following overnight fast. Urinary recovery of all three probe molecules declined significantly with age (P less than 0.02) and was reduced in malnourished elderly subjects compared to healthy elderly controls (P less than 0.05). Correction of urinary recoveries for renal function on the basis of creatinine clearance abolished significant differences between groups. Thus passive absorption of carbohydrate is not impaired with advanced age in healthy elderly subjects or long-stay hospital patients. The ratio of the percentage recovery of 3-O-MG to the percentage recovery of mannitol was significantly reduced in the healthy elderly subjects compared to middle-aged and young controls in the hypertonic study; similar changes did not occur in the long-stay and malnourished elderly patients, interpretation of this finding is thus difficult. If confirmed, this impairment would suggest a possible defect in active sugar transport in the elderly.

3-O-Methylglucose↗
PubMed1987

Peripheral tissue insulin sensitivity in healthy elderly subjects.

To determine whether the decline in glucose tolerance with age is related to changes in peripheral tissue insulin sensitivity, 11 healthy older (65-85 years) and 12 healthy younger (20-38 years) subjects, matched for physical activity and body mass index, were studied. The glucose-insulin infusion technique, in which glucose and insulin are infused at constant rates over 150 min, was used to assess peripheral tissue insulin sensitivity. The metabolic clearance rate (MCR) of glucose, which reflects peripheral tissue insulin sensitivity, is derived from the resulting steady-state blood glucose. Fasting blood glucose was similar in the two groups, but mean blood glucose 2 h after an oral glucose load was higher in the older group. MCR of glucose expressed per kilogram lean body mass was almost identical in both groups (13.3 +/- 1.3 vs. 13.5 +/- 1.3 ml/kg lean body mass/min, respectively). Evidence of decreased glucose tolerance with normal peripheral tissue insulin sensitivity suggests that changes in other factors may be more important than previously recognised.

Adult↗
PubMed1987

Clinical features and prognosis of alcoholic liver disease in respect of advancing age.

The signs, symptoms, alcohol history, and histological findings together with prognosis of 208 consecutive patients with alcoholic liver disease (ALD) are presented in respect of age. 200 were followed for at least 1 year. 28% of patients first presented over age 60, 6% over 70 years. Signs and symptoms were more severe at presentation in the 70+-year-old age group than in the young patients though the elderly more often presented with symptoms not directly related to liver disease. Prognosis was age-related, 1 year mortality was 50% among cirrhotics over the age of 60 versus 7% under 60 years. Alcohol consumption at presentation was similar in all age groups with no evidence of a significant reduction in the elderly. The care of older patients with ALD will become an increasing problem in developed countries where alcohol consumption has continued to rise.

Adult↗