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Biomedical subjects

P N Durrington

Publications and source records attributed to P N Durrington.

At least 91 records · Page 5Linked to original sources
PubMed1996

Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins.

Human serum paraoxonase is located on an HDL. It has the capacity to retard the accumulation of lipid peroxides in LDL under oxidizing conditions in vitro. Paraoxonase has a genetic polymorphism that results in a single amino acid substitution. Evidence indicates that both the serum concentration of paraoxonase and an individual's genotype are related to plasma lipid and lipoprotein concentrations, and possibly also to coronary heart disease, implicating paraoxonase in the development of atherosclerosis.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1996

A comparative study of six commercial lipoprotein(a) assays in seventeen laboratories within the British Isles.

Seventeen laboratories in the British Isles participated in a study to compare six different commercially available immunoassays for serum lipoprotein(a) (Lp(a)) and to establish reasons for the variations in the measurement of serum Lp(a) concentrations. Pooled serum was distributed neat and after dilution at a central laboratory. In addition, the central laboratory sent unpooled serum sampled monthly from six healthy volunteers to each of the participating laboratories for 12 months. The assays all gave linear dilution curves which were parallel, although the reported values varied twofold. There were major differences in the values assigned to different manufacturers' calibrants which was not explained by whether the units employed were whole Lp(a), the protein moiety of Lp(a) or simply apolipoprotein(a). The coefficient of variation for the reported value of Lp(a) over 12 months was 33%. The component variation was 10% after adjustment for inter-laboratory and intra-laboratory variation. Some individuals clearly had a greater tendency to variable serum Lp(a) concentrations than others, but all the assays responded to this in the same way. Thus, the assays tested probably measured the same analyte. The problem of calibration could largely be addressed if agreement were reached by the manufacturers. Even with improvements in analytical precision it should be realized that multiple measurements of serum Lp(a) levels are necessary if the true mean value is to be appreciated. Individuals showing wide variation in serum Lp(a) may reward further study if its role is to be established.

Clinical Laboratory Techniques↗
PubMed1995

Coronary risk factors in people from the Indian subcontinent living in west London and their siblings in India.

Several reports have shown that migrants from southeast Asia tend to have an increased risk of coronary heart disease when settled in their new country. We compared coronary risk factors in a randomly selected group of 247 migrants from the Indian subcontinent of Punjabi origin living in West London and 117 of their siblings living in the Punjab in India. The West London cohort had a greater body mass index (p < 0.001), systolic blood pressure (p = 0.0087), serum cholesterol (p < 0.001), apolipoprotein B (p < 0.001), lower high-density lipoprotein cholesterol (p < 0.05) and higher fasting blood glucose (p < 0.05) than their siblings in the Punjab. Insulin sensitivity, derived from the homoeostatic assessment mathematical model, was lower in men in West London than in their counterparts in India (p < 0.05). Indians in West London had lower beta cell function than those in the Punjab (p < 0.001). Serum lipoprotein (a) concentrations were similar in both the West London and Punjab population, but were significantly higher (p = 0.01) than those of white European populations in the UK. Increases in serum cholesterol after migration from India lead to increased coronary risk conferred by high serum lipoprotein (a) concentrations and greater insulin resistance. Such between-country comparisons are an important means of establishing the importance of coronary risk factors.

Adult↗
PubMed1995

Spontaneous platelet aggregation in whole blood is increased in non-insulin-dependent diabetes mellitus and in female but not male patients with primary dyslipidemia.

Increased platelet aggregability has been shown in hypercholesterolemia, and stirring-induced spontaneous aggregation in whole blood is increased in insulin-dependent diabetes mellitus (DM). We have determined spontaneous aggregation in citrated (10 mM) whole blood, from 27 primary dyslipidemic patients (DYS; 14F, 13M), 16 male non-insulin-dependent DM (NIDDM) patients, and 17 normolipidemic controls (N; 6F, 11M), using platelet counting to quantify aggregation. Spontaneous aggregation was significantly higher, both in the female DYS group (median 30% [interquartile range 25,50], P < 0.005) and the NIDDM group (33% [25,41], P < 0.005), than in the N group (17% [12,27]), but did not differ significantly in the male DYS group (23% [10,33]). Similar results were obtained in the presence of indomethacin (25 mumol/l) to prevent artefactual thromboxane (TX) A2 formation, indicating that increased spontaneous aggregation was TXA2-independent. Interestingly, increased spontaneous aggregation appeared to be independent of serum cholesterol and triglyceride concentrations, as well as age and sex per se. We conclude that spontaneous platelet aggregation was increased both in female primary dyslipidemic patients and NIDDM patients, but not in male DYS patients. The clinical significance of increased spontaneous platelet aggregability is that it may favour shear-induced aggregation which may occur at critical arterial stenoses in vivo leading to thrombus formation.

Adult↗
PubMed1995

HDL, its enzymes and its potential to influence lipid peroxidation.

In seeking an explanation of the inverse relationship between serum high density lipoprotein (HDL) concentration and coronary heart disease (CHD) incidence, most investigations have been directed at its role in reverse cholesterol transport. However, recently it has become clear that HDL has the potential to limit oxidative modification of low density lipoprotein (LDL) whether induced by transition metals or by cells in tissue culture. In view of the current theory that oxidative modification of LDL is an important element in atherogenesis, this suggests another potential mechanism by which HDL might impede the development of CHD. HDL is the major carrier of cholesteryl ester hydroperoxides, but more than this it appears to have the prolonged capacity to decrease the total amount of lipid peroxides generated on LDL during oxidation while the quantity accumulating on HDL itself reaches an early plateau. These effects are not explained by chain-breaking antioxidants present in HDL and are likely to involve an enzymic mechanism. Several enzymes are present on HDL: paraoxonase, lecithin:cholesterol acyl transferase, platelet activating factor acetylhydrolase, phospholipase D and protease. Apolipoproteins, such as apolipoprotein AI, could also have enzymic activity. Evidence that some of these might act to metabolise lipid peroxidation products, such as oxidised phospholipids and lyso-phosphatidylcholine, is discussed in this review.

Animals↗
PubMed1995

Lipoprotein (a).

Lipoprotein (a) is similar to low-density lipoprotein but is unique in having an additional apolipoprotein called apolipoprotein (a) (apo(a)) covalently linked to it. apo(a), which is a member of the plasminogen gene superfamily, has a protease domain which cannot be activated to cause fibrinolysis. Its sequence of kringles is much longer than that of plasminogen and there is remarkable genetic variation in its length. The consequent inherited differences in apo(a) molecular mass are largely responsible for the wide range of serum Lp(a) concentrations in different individuals with low levels predominating in Europid populations. Physiologically Lp(a) may participate in haemocoagulation or in wound-healing. Epidemiological evidence that it is a risk factor for atherosclerosis, particularly in populations with high serum LDL levels, has led to research to uncover its role in atherogenesis and thrombosis. Diseases such as renal disease, and probably atherogenesis and thrombosis. Diseases such as renal disease, and probably atherosclerosis itself, are associated with an increase in Lp(a) above its genetically determined level and it remains a subject of speculation as to whether such increases are as closely involved in atherothrombosis as are spontaneously high levels resulting from low-molecular-mass apo(a) variants.

Animals↗
PubMed1995

Fetal and maternal lipoprotein metabolism in human pregnancy.

1. Lipid, apolipoprotein concentration and composition were determined in maternal venous and umbilical arterial and venous blood at delivery by elective Caesarean section in 13 full-term pregnancies and in 25 healthy non-pregnant females. The indications of Caesarean section were a previous Caesarean section or breech presentation. None of the women was in labour and there were no other complications of pregnancy or fetal distress. 2. The objectives of the study were to establish whether the placenta has a role in feto-maternal cholesterol metabolism through either synthesis or transplacental cholesterol flux. The potential for free cholesterol diffusion between mother and fetus and rates of cholesterol esterification and transfer between lipoproteins were determined and related to the differences in composition between fetal and maternal lipoproteins. 3. Pregnant women had raised levels of all lipid and lipoprotein fractions compared with control subjects. The greatest increases were in free cholesterol and triacylglycerol (P < 0.0001). Lipoprotein (a) levels were significantly greater in the pregnant women [112 (12.2) mg/l] than in the control women [50 (10.0) mg/l]. 4. The only significant correlation between maternal and fetal lipoprotein concentrations was in lipoprotein (a) levels (r = 0.791, P = 0.002). In both umbilical venous and arterial blood, concentrations of very-low- and low-density lipoproteins, particularly apolipoprotein B, cholesteryl ester and triacylglycerol, were lower than in maternal blood (P < 0.0001), but high-density lipoprotein levels were similar. 5. There was no umbilical arteriovenous differences in lipoprotein concentration or composition. This suggests that cholesterol synthesis or free cholesterol diffusion does not occur in the placenta.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins.

Human serum paraoxonase is physically associated with HDL and has been implicated in the detoxification of organophosphates and possibly in the prevention of LDL lipid peroxidation. We investigated the serum activity and concentration of paraoxonase in 78 patients with type 1 diabetes mellitus, 92 with type 2 diabetes, and 82 nondiabetic control subjects. Paraoxonase activity was generally lower in diabetics than in control subjects. This decrease was unrelated to differences in paraoxonase phenotype distribution or its serum concentration. Rather, the difference in paraoxonase activity was explained by its specific activity, which was lower in diabetics, indicating either the presence of a circulating inhibitor or disturbance of the interaction of paraoxonase with HDL affecting its activity. Paraoxonase specific activity was lowest in patients with peripheral neuropathy, suggesting an association of paraoxonase with neuropathy. In control subjects but not patients with diabetes, paraoxonase correlated with HDL cholesterol and apolipoprotein A-1. Our results indicate that the low paraoxonase activity in diabetes is due to decreased specific activity. In other studies low serum paraoxonase activity has been associated with increased susceptibility to atherosclerosis, and the present results also suggest an association with peripheral neuropathy, which could be due to reduced capacity to detoxify lipid peroxides in diabetes.

Adult↗
PubMed1995

Effect of treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and cholesteryl ester transfer activity in patients with NIDDM.

Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a greater risk of developing coronary heart disease than would be expected from a similar degree of hyperlipidemia in nondiabetic populations. Accelerated transfer of cholesteryl esters (CET) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), a process that is associated with atherosclerosis, may be a possible explanation for this. CET, plasma lipoprotein concentration, and mass in the fasting and postprandial state have been examined in 31 hyperlipidemic patients with NIDDM before and after 8 weeks of treatment with the hydroxymethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor pravastatin in a double-blind, placebo-controlled, parallel group study. Body mass index, glycemic control, and blood pressure remained unaltered during the study period. Compared with placebo, pravastatin decreased fasting serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.002) levels. The high basal CET (34.4 +/- 13.1 nmol.ml-1.h-1) was decreased significantly by pravastatin treatment (27.5 +/- 13.7 nmol.ml-1.h-1, P = 0.013). There was a fall in the total cholesterol, free cholesterol, and phospholipid content of the Sf 0-12, 20-60, and 60-400 lipoproteins (all P = 0.001). Lecithin: cholesterol acyl transferase activity was not altered. The postprandial increase in VLDL cholesterol 5 h after a standardized mixed meal was attenuated after pravastatin treatment (P = 0.011). Inhibition of hepatic cholesterol synthesis with an HMG-CoA reductase inhibitor in hyperlipidemic patients with NIDDM decreased serum cholesterol content of triglyceride-rich lipoprotein, thereby decreasing the transfer of cholesteryl ester from HDL to LDL and VLDL.

Adult↗
PubMed1995

Effect of low-dose cyclosporin on plasma lipoproteins and markers of cholestasis in patients with psoriasis.

The benefits of using cyclosporin in organ transplantation to prevent graft rejection outweigh its potential disadvantages, but with the use of low-dose cyclosporin in relatively healthy individuals, such as those with psoriasis, the risk:benefit ratio is altered. The effects of low-dose cyclosporin (< 5 mg/kg body weight) on liver function and serum lipids and lipoproteins were examined in 40 normolipidaemic, normotensive psoriasis patients with normal renal function. After 3 months of treatment, serum cholesterol and bilirubin concentrations and alkaline phosphatase activity increased significantly (p = 0.001), and glomerular filtration rate (GFR) declined from 107 to 96 ml/min/1.73 m2 (p = 0.05). All these values returned to pretreatment levels 3 months after cessation of cyclosporin. In 15 patients in whom lipoproteins were isolated by ultracentrifugation, there was an increase in plasma low-density lipoprotein (LDL) cholesterol (p = 0.05), but very-low-density lipoprotein cholesterol, high-density lipoprotein (HDL) and HDL2 and HDL3 cholesterol concentrations did not change. The increases in serum bilirubin, alkaline phosphatase activity and LDL cholesterol, seen in individuals with normal baseline liver and renal function, which reverted to baseline following cessation of cyclosporin, suggest that cyclosporin-induced hypercholesterolaemia may be due to either decreased biliary excretion of cholesterol or impaired catabolism of LDL.

Biomarkers↗
PubMed1994

Comparison of lipid-lowering effects of low-dose fluvastatin and conventional-dose gemfibrozil in patients with primary hypercholesterolemia.

A total of 123 patients with primary hypercholesterolemia were randomized on a 2:1 ratio to receive either fluvastatin at 20 mg once daily at night (n = 82) or gemfibrozil at 600 mg twice daily (n = 41) in a double-blind, double-dummy comparison of the effects on plasma lipid parameters and tolerability over 8 weeks. All patients had either low-density lipoprotein cholesterol (LDL-C) concentrations > or = 160 mg/dL (4.1 mmol/L) in association with definite coronary artery disease (CAD) or > or = 2 risk factors, or LDL-C > or = 190 mg/dL (4.9 mmol/L) with no CAD and < 2 risk factors. All had triglyceride (TG) levels < or = 350 mg/dL (4.0 mmol/L). After 8 weeks of treatment, fluvastatin produced significant reductions from baseline of 17.4% (p < 0.001) in LDL-C, 13.2% (p < 0.001) in total cholesterol (TC), 13.8% (p < 0.001) in very low-density lipoprotein cholesterol (VLDL-C), and 6.4% (NS) in TG. High-density lipoprotein cholesterol (HDL-C) was increased by 5.6% (p < 0.001), and the ratio of LDL-C:HDL-C (Friedewald) was decreased by 21.2% (p < 0.001). Gemfibrozil reduced LDL-C by 15.8%, TC by 13.4%, VLDL-C by 32.2%, LDL-C:HDL-C by 24.8%, and TG by 34.2%, and increased HDL-C by 13.9% (all changes were statistically significant, p < 0.001) compared with baseline. Gemfibrozil produced significantly greater changes in VLDL-C (p < 0.01), HDL-C (p < 0.001), and TG (p < 0.001), but not in LDL-C: HDL-C, compared with fluvastatin. Both drugs significantly reduced apolipoprotein (apo) B and lipoparticles (Lp) E:B, and increased apo A-I but had divergent effects on LpA-I (increased with fluvastatin and reduced with gemfibrozil; p < 0.05). At the end of the study, 43.8% of fluvastatin patients and 45% of gemfibrozil patients achieved a reduction of > 20% in LDL-C levels. Normalization of LDL-C levels was achieved (according to European Atherosclerosis Society guidelines) by 13.4% of fluvastatin- and 14.6% of gemfibrozil-treated patients. Both drugs were well tolerated; adverse events occurred in 36.6% of fluvastatin recipients compared with 58.5% of patients taking gemfibrozil. No clinically notable elevations of aspartate or alanine aminotransferases, alkaline phosphatase, or creatine phosphokinase occurred. No patient developed new or worsening lens opacities associated with a reduction in optically corrected visual acuity. The most commonly reported adverse events were headache and gastrointestinal upset. There were no serious drug-related adverse events.

Adult↗
PubMed1994

Suppression of non-esterified fatty acids to treat type A insulin resistance syndrome.

A patient with type A insulin-resistance syndrome resistance presented with severe hypertriglyceridaemia and diabetes. Fasting insulin and non-esterified fatty acids (NEFA) were very high (41 mU/L and 3.3 mmol/L). A low-fat diet failed to correct hyperlipidaemia and diabetes. Sustained suppression of NEFA with slow-release acipimox for 8 weeks resulted in substantial reduction of serum fasting NEFA (0.31 mmol/L). Glucose tolerance became normal and insulin sensitivity increased from 7% to 32%. The glucose fatty-acid cycle may operate in patients with severe insulin resistance and hyperlipidaemia: high serum NEFA aggravates insulin resistance and hyperglycaemia by inhibiting glucose uptake and utilisation.

Acanthosis Nigricans↗
PubMed1994

Serum Lp(a) lipoprotein concentration and outcome of thrombolytic treatment for myocardial infarction.

BACKGROUND: Lp(a) lipoprotein has structural homology with plasminogen and has been shown to inhibit plasminogen activation in vitro. OBJECTIVE: To determine whether the serum concentration of Lp(a) lipoprotein present when streptokinase was given in acute myocardial infarction influenced the outcome as judged by electrocardiographic methods. PATIENTS AND DESIGN: Serum Lp(a) lipoprotein concentration was measured in 135 consecutive patients admitted with a diagnosis of acute myocardial infarction who received streptokinase treatment. Recovery from myocardial injury was assessed by the reduction in the sum of ST segment elevation measured from the J point (STJ) in the electrocardiogram immediately before streptokinase was given compared with that three hours later. RESULTS: The serum Lp(a) lipoprotein concentrations were measured within 12 hours of the onset of symptoms of myocardial infarction and were higher than in healthy reference populations. Recovery from myocardial infarction could be assessed from the STJ in 116 patients (86% of the series). Those in whom it could not had bundle branch block, left ventricular hypertrophy, did not survive three hours, or had started intravenous nitrate treatment or some other clinical procedure before or at the time the second electrocardiogram was to be recorded. Patients with reductions in STJ after streptokinase that were > 4 mm (the median decrease) had mean (range) serum Lp(a) lipoprotein concentrations of 41.0 (0.8-220) mg/dl and those with a smaller reduction in STJ had concentrations of 29.1 (1.7-151) mg/dl. The difference was not statistically significant. CONCLUSION: In this study Lp(a) lipoprotein concentration did not significantly influence the outcome of thrombolytic treatment with streptokinase.

Adult↗