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Biomedical subjects

P Durrington

Publications and source records attributed to P Durrington.

At least 19 recordsLinked to original sources

Apolipoproteins AI and B as therapeutic targets.

Currently the apolipoprotein B:AI ratio integrates information about the potential for cardiovascular disease (CVD) risk reduction better than any other lipid or lipoprotein index. Certainly it could, with benefit, replace serum cholesterol and HDL cholesterol in the estimation of CVD risk. Defining the therapeutic target of statin therapy in terms of serum apolipoprotein B (apo B) rather than LDL cholesterol could also help to optimize statin treatment. Deciding whether a therapeutic response is adequate also requires knowledge of whether there is persisting hypertriglyceridaemia, because this gives an indication of whether small dense LDL is likely to have been satisfactorily reduced. Raising low levels of HDL, probably best measured as apo AI, may also prove to be an important aim of treatment. This is, however, a more complex issue and also depends on the mechanism by which a particular therapy alters HDL levels and on whether the capacity of HDL to perform its anti-inflammatory and antioxidative functions is restored. A meta-analysis of randomized clinical trials of statins in which apo B and apo AI have been reported could provide valuable information.

Anticholesteremic Agents↗

Potential population impact of the UK government strategy for reducing the burden of coronary heart disease in England: comparing primary and secondary prevention strategies.

OBJECTIVE: To use population impact measures to help prioritise the National Service Framework (NSF) strategies recommended by the UK government for reducing the population burden of coronary heart disease (CHD). DESIGN: Modelling study. SETTING: Primary care. DATA SOURCES: Published data on incidence, baseline risk and prevalence of risk factors for CHD and the proportion treated, eligible for treatment, and adhering to the different interventions. Data from meta-analyses and systematic reviews for relative risk and relative risk reduction associated with different risk factors and interventions. MAIN OUTCOME MEASURES: Population impact measures for the decline in the prevalence of a risk factor and the increased uptake of interventions expressed as number of CHD events prevented in the population. RESULTS: If lifestyle targets for primary prevention are met, 73 522 (95% CI 54,117 to 95,826) CHD events would be prevented per year, with the greatest gain coming from reduced cholesterol and blood pressure levels. In those at high risk of developing CHD, achieving target levels for lifestyle interventions would prevent 4410 (95% CI 1993 to 8014) CHD events and for pharmacological treatments 2008 (95% CI 790 to 3627) CHD events. For patients with established CHD, achieving NSF targets will result in the prevention of 3067 (95% CI 1572 to 5878) CHD events through improved drug treatment and 1103 (95% CI 179 to 2097) events through lifestyle interventions. CONCLUSION: Current strategies focus largely on secondary prevention, but many more cardiovascular events would be prevented by meeting the government's public health and primary prevention targets than targeting people at high risk or those with established heart disease.

Age Distribution↗

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India.

AIMS/HYPOTHESES: We previously reported independent links between the IGF system and the development of impaired glucose tolerance and cardiovascular risk. This study tests the hypothesis that the lifestyle change which accompanies population migration, with attendant increases in cardiovascular risk, is reflected by changes in the IGF system. MATERIALS AND METHODS: We compared a specific Gujarati community in Sandwell, UK (n=205), with people still resident in the same villages of origin near Navsari, India (n=246). We performed anthropometry and measured fasting plasma insulin, IGF-I, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3. RESULTS: Daily calorie intake, BMI and WHR were significantly higher in UK Gujaratis than in Indian Gujaratis. IGFBP-1 was significantly lower in UK migrants (mean 29.5 [95% CI 25.9-33.0] vs 56.5 [50.6-62.5] microg/l; F=48.4, p<0.001). Conversely, fasting insulin, IGFBP-3 and IGF-I were all higher in UK Gujaratis (mean IGF-I 145.9 [138.1-153.6]ng/ml in UK Gujaratis and 100.9 [94.6-107.3] ng/ml in Navsari Gujaratis; F=76.6, p<0.001). These differences were still apparent when adjustment was made for BMI by location for IGF-I (F=57.4, p<0.001) and IGFBP-3 (F=5.7, p=0.02), but were no longer apparent for IGFBP-1 and insulin. At the population level, the decrease in IGFBP-1 for a given increase in insulin was significantly smaller in UK Gujaratis, suggesting greater hepatic insulin resistance in this group. CONCLUSIONS/INTERPRETATION: Environmental factors have profound effects on circulating IGF system components and on the relationship between IGFBP-1, IGF-I and related metabolic variables. This may have long-term implications for the development of worsening glucose tolerance and cardiovascular disease.

Blood Glucose↗

Dietary intake and the insulin-like growth factor system: effects of migration in two related populations in India and Britain with markedly different dietary intake.

BACKGROUND: The insulin-like growth factor (IGF) system is implicated in the pathogenesis of diabetes and cardiovascular disease. OBJECTIVE: We report the effects of total energy intake on the IGF system in two populations with markedly different dietary macronutrient intake and cardiovascular event rate. DESIGN, SUBJECTS AND SETTING: Dietary macronutrient intake was measured in a specific Gujarati migrant community in Sandwell, UK (n=205) compared with people still resident in the same villages of origin in India (n=246). Fasting IGF-I, IGF-binding protein (IGFBP)-1 and IGFBP-3, insulin and glucose (0 and 2-hour) were measured. RESULTS: Total energy and total fat intake were higher in UK migrants, as were IGFBP-3 and IGF-I (mean (95% confidence interval): 145.9 (138.1-153.6) vs. 100.9 (94.6-107.3) ng ml(-1); F=76.6, P<0.001). IGFBP-1 was lower in UK migrants (29.5 (25.9-33.0) vs. 56.5 (50.6-62.5) microg l(-1); F=48.4, P<0.001). At both sites, IGF-I correlated positively with total energy (Spearman's rho=0.45, P<0.001) and total fat (rho=0.44, P<0.001) as did IGFBP-3 with total energy (rho=0.21, P<0.05) and fat (rho=0.26, P<0.001). Conversely, in Indian Gujaratis, IGFBP-1 fell with increasing total energy (rho=-0.27, P<0.001) and fat intake (rho=-0.26, P<0.01) but not in UK Gujaratis. Multiple linear regression modelling showed that increasing quartiles of fat intake were associated with higher IGF-I (beta=0.42, P=0.007) independent of age, body mass index, plasma insulin, fatty acids and 2-hour glucose. CONCLUSION: In these genetically similar groups, migration to the UK and adoption of a different diet is associated with marked changes in the IGF system, suggesting that environmental factors profoundly modulate serum concentrations and actions of IGFs.

Blood Glucose↗

Population impact of stricter adherence to recommendations for pharmacological and lifestyle interventions over one year in patients with coronary heart disease.

STUDY OBJECTIVE: To assess the potential number of lives saved associated with the full implementation of aspects of the National Service Framework (NSF) for coronary heart disease (CHD) in England using recently developed population impact measures. DESIGN: Modelling study. SETTING: Primary care. DATA SOURCES: Published data on prevalence of acute myocardial infarction and heart failure, baseline risk of mortality, the relative risk reduction associated with different interventions and the proportion treated, eligible for treatment and adhering to each intervention. MAIN RESULTS: Adopting the NSF recommendations for pharmacological interventions would prevent an extra 1027 (95% CI 418 to 1994) deaths in post-acute myocardial infarction (AMI) patients and an extra 37 899 (95% CI 25 690 to 52 503) deaths in heart failure patients in the first year after diagnosis. Lifestyle based interventions would prevent an extra 848 (95% CI 71 to 1 614) deaths in post-AMI patients and an extra 7249 (95% CI 995 to 16 696) deaths in heart failure patients. CONCLUSIONS: Moving from current to "best" practice as recommended in the NSF will have a much greater impact on one year mortality rates among heart failure patients compared with post-AMI patients. Meeting pharmacological based recommendations for heart failure patients will prevent more deaths than meeting lifestyle based recommendations. Population impact numbers can help communicate the impact on a population of the implementation of guidelines and, when created using local data, could help policy makers assess the local impact of implementing a range of health care targets.

Aged↗

Effect of organophosphate intoxication on human serum paraoxonase.

Recently, interindividual variations in serum paraoxonase (PON1) activity and the differences in its metabolic activity towards different organophosphates (OPs) caused by the coding region polymorphisms L55M and Q192R have been found to be important risk factors in susceptibility to OP poisoning. In this study, we investigated the effect of PON1 on the outcome of acute OP intoxication and the effect of acute OP intoxication on PON1. Twenty-eight OP-poisoned patients and 66 healthy volunteers were studied. Patients were evaluated for the clinical manifestations of OP intoxication as well as PON1 activity, PON1 mass and PON1 polymorphisms. Butyrylcholine-esterase (BChE) activity was 50% lower (2,276 +/- 738 U/L versus 5,037 +/- 1,553 U/L, P<0.01) while PON1 activity was 30% lower [114.2 +/- 67.4 nmol/mL/min versus 152.9 +/- 78.9 nmol/mL/ min, P<0.05) in patients than in controls. We observed that the PON1 and BChE activities of eight of the original subjects returned to normal levels when they were reinvestigated six months after exposure. The frequency of the PON192Q allele was significantly higher in patients than controls (85.7% versus 59.7%, chi2=6.745, P=0.034). QQ/ MM individuals had the lowest activity towards paraoxon, while RR/LL individuals had the highest activity. Our data indicate that interindividual differences in PON1 activity and the PON1-55 and -192 polymorphisms are important risk factors in susceptibility to acute OP poisoning; therefore, identifying an individual's PON1 alloenzymes may play an important role in the treatment of patients suffering from OP intoxication.

Aryldialkylphosphatase↗

The human and economic costs of undertreatment with statins.

Several guidelines for the prevention and management of coronary heart disease (CHD) have been published. These generally recommend lipid-lowering therapy in patients with and without established CHD on the basis of their low-density lipoprotein cholesterol (LDL-C) levels and, for cases without established CHD, their risk-factor profile. Statins are the preferred lipid-lowering agent for the prevention of CHD because of overwhelming clinical trial evidence that they can significantly reduce the occurrence of CHD mortality and morbidity. Despite the guidelines, only approximately one-third of eligible patients receive lipid-lowering therapy in clinical practice--even for secondary prevention of CHD--and many treated patients fail to achieve their target LDL-C levels. This underuse must affect patients' clinical outcome and quality of life and has economic consequences for society. Reasons for the underuse may include physicians' and patients' attitudes and knowledge, and the perceptions of physicians and healthcare purchasers about economic factors. Health economic evaluations have confirmed that secondary prevention with statins is cost-effective, and that primary prevention is also reasonably cost-effective, depending on the absolute CHD risks in targeted individuals. Newer statins with greater efficacy in reducing LDL-C levels may allow patients to reach target levels more quickly and without the need for dose titration, thus improving clinical outcomes and being more cost-effective in the long term. This proposition should be testedin future clinical trials.

Cholesterol, LDL↗

Paraoxonase activity is reduced by a pro-atherosclerotic diet in rabbits.

Serum paraoxonase (PON1) is believed to protect against the development of atherosclerosis because of its ability to retard the oxidation of low-density lipoprotein (LDL) by hydrolysing LDL-associated phospholipid and cholesteryl-ester hydroperoxides. We have examined the relationship between PON1 and atherosclerosis development in transgenic rabbits overexpressing human apolipoprotein (apo) A-I and nontransgenic littermates fed a pro-atherogenic diet. PON1 activity was higher in transgenic (4006.1 +/- 716.7 nmol/min/ml) compared to control (3078.5 +/- 623.3 nmol/min/ml) rabbits (P < 0.01) while high-density lipoprotein (HDL) cholesterol was 1.84 +/- 0.54 mmol/L in transgenic rabbits and 0.57 +/- 0.21 mmol/L in control rabbits (P = 0.0001). After feeding rabbits a high-cholesterol diet for 14 weeks HDL-cholesterol fell by 70% in both transgenic and control rabbits (P < 0.001 compared to week 0) PON1 activity fell by 50% in both groups of rabbits (P < 0. 01 compared to week 0). The amount of thoracic aortic surface area covered by lesions was 29 +/- 16% in the control group and 26 +/- 15% in the transgenic group (P = NS). A pro-atherosclerotic diet reduces PON1 which may exaggerate the effects of the diet on the development of atherosclerosis.

Animals↗

Familial lipoprotein lipase (LPL) deficiency: a catalogue of LPL gene mutations identified in 20 patients from the UK, Sweden, and Italy.

The aim of this study was to identify mutations in the lipoprotein lipase (LPL) gene in 20 unrelated patients with familial lipoprotein deficiency (FLLD) and to investigate the genotype/phenotype relationship. The previously reported G188E mutation (Monsalve et al., J Clin Invest 86:728-734, 1990) was screened for and found to be present in seven individuals (12/40 alleles). In addition, three patients were heterozygous for the 2.0 kb insertion (Langlois et al., Proc Nalt Acad Sci US 86:948-952, 1989). Two approaches were taken for new mutation detection; single-strand conformation polymorphism and sequencing to identify micro-mutations in the proximal promoter and exons 1-9 of the LPL gene and Southern blotting to identify gross mutations. Ten different point mutations were found (W86G, A158T, H183Q, G188E, S193R, P207L, L252X, N291S, M301T, L303P). Additionally, a two nucleotide deletion in exon 6 (delta1006-1007), a six nucleotide deletion in exon 8 (delta1441-1447), and a silent substitution in the wobble position of codon E118 were identified. In vitro mutagenesis and expression in COS-B cells suggested that the A158T and S193R substitutions virtually abolished enzyme activity. In analysing the genotype/phenotype relationship, there was no strong association between age at diagnosis, severity of symptoms, lipid levels, and the nature/position of the mutation. Triglyceride levels, however, were higher in compound heterozygotes compared to true homozygotes, possibly reflecting increased instability of heterodimers. Overall, 29 of 40 (72.5%) mutant alleles were identified. Failure to identify the mutation in 11 alleles might reflect the inadequacy of the method or the possibility that mutations lie within regions of the gene not screened in the study because of lack of availability of sequence.

Adult↗

Florid xanthelasmata (yellow lids) in orbital Wegener's granulomatosis.

AIMS: A new sign of florid xanthelasmata is described in four male patients with orbital manifestations of Wegener's granulomatosis. METHODS: The case notes of four patients with Wegener's granulomatosis, with orbital involvement accompanied by yellow lid lesions, are reviewed. RESULTS: All the patients had active Wegener's granulomatosis at the time the lid lesions were most florid. The lesions gradually resolved as the inflammatory disease was controlled with immunosuppressive agents. The lesions displayed marked asymmetry and predominantly involved the side with the most severe inflammation. Abnormalities of lipid metabolism were not identified and it is believed that the lesions developed in a susceptible anatomical region affected by a vasculitic process. CONCLUSION: A 'yellow lid' associated with orbital inflammation and is a strong pointer to the clinical diagnosis of Wegener's granulomatosis.

Adult↗

Quantification of human serum paraoxonase by enzyme-linked immunoassay: population differences in protein concentrations.

Paraoxonase is a serum protein bound to high-density lipoproteins (HDLs). The physiological function of the enzyme is unknown, but a role in lipid metabolism has been postulated. To date, studies of the protein have had to rely on measurements of enzyme activity with various substrates. We have developed a highly specific, competitive e.l.i.s.a. using a previously characterized monoclonal antibody. The assay can detect 20 ng of paraoxonase with a working range of 75-600 ng. Intra- and interassay coefficients of variation were 6.5 and 7.9% respectively. Serum concentrations of paraoxonase in healthy subjects from Geneva and Manchester ranged from 25 to 118 micrograms/ml. There were significant differences in mean concentrations between the two groups (Geneva, 79.3 +/- 18.7 micrograms/ml; Manchester, 59.9 +/- 24.1 micrograms/ml: P < 0.001), differences also apparent when subjects were compared according to paraoxonase phenotype. These appeared to be largely a consequence of differences in apolipoprotein A-I concentrations between the two populations, suggesting that HDL particle number may be important in determining serum levels of paraoxonase. Paraoxonase specific activities were also significantly different between the two groups of subjects (Geneva, 2.08 +/- 0.96 units/mg; Manchester, 3.08 +/- 1.73 units/mg: P < 0.001), which may reflect differences in HDL particle composition. The e.l.i.s.a. should furnish the necessary complement to studies of paraoxonase enzymic activity and has already provided evidence for differences with respect to serum levels of the protein both between populations and between phenotypes within populations.

Animals↗

Metabolism of apoB-100-containing lipoproteins in familial hyperchylomicronemia.

The metabolism of apolipoprotein B-100 was studied in three patients with familial hyperchylomicronemia (type I hyperlipoproteinemia) using a very low density lipoprotein (VLDL) dual-tracer technique. Radioiodinated VLDL1 (Sf 60-400) and VLDL2 (Sf 20-60) were injected and their catabolism and rate of the transfer of apoB into VLDL2, intermediate density lipoprotein (IDL) (Sf 12-20), and low density lipoprotein (LDL) (Sf 0-12) were compared in patients and in five normolipidemic controls. The rates of delipidation of large triglyceride-rich VLDL1 to VLDL2 (0.26-0.54 pools/day vs. 2.5-5.2 pools/day in controls) and VLDL1 direct catabolism (0.33-0.92 pools/day vs. 4.2-14.7 pools/day in controls) were found to be significantly reduced in type I patients resulting in a tenfold increase of VLDL1 pool size. ApoB synthesis into this density interval was, however, normal as was that into smaller VLDL2. the circulating apoB mass in VLDL2 was not increased. In fact, apart from a modest decrease in the rate of VLDL2 delipidation to IDL and LDL, the behavior of apoB in this density interval was similar in hyperchylomicronemic and normal subjects. Likewise, the transfer of apoB through the IDL and LDL density ranges was not significantly different from normal. Pool sizes of these fractions, however, were reduced, the latter significantly (354-491 mg vs. 1,160-2,505 mg in controls) due to increased direct catabolism in hyperchylomicronemic patients. The results of this study indicate that lipoprotein lipase deficiency primarily affects VLDL1 metabolism, both its delipidation and direct removal from plasma. Lipolysis further down the delipidation cascade is not dependent on this enzyme. Hypercatabolism rather than a failure of synthesis of IDL and LDL was responsible for the decreased pools for both lipoproteins.

Adult↗

An investigation of the role of lecithin:cholesterol acyltransferase and triglyceride-rich lipoproteins in the metabolism of pre-beta high density lipoproteins.

Small high density lipoproteins (HDL) with pre-beta electrophoretic mobility (pre-beta HDL) have recently been shown to be the primary acceptor of cholesterol from cultured cells. We studied the metabolism of these particles by incubating serum at 37 degrees C in the presence and absence of active lecithin: cholesterol acyltransferase (LCAT). We found that the serum pre-beta HDL concentration decreased in the presence of LCAT, but when LCAT was inhibited the concentration remained constant, or increased, depending on the method of inhibition. This suggests that pre-beta HDL are a substrate for LCAT. We also found a significant negative correlation between levels of LCAT activity and pre-beta HDL in 28 fasting healthy subjects, this provides evidence that the activity of LCAT regulates, at least in part the concentration of these particles in vivo. During the early phase of incubation there was a more rapid decrease in pre-beta HDL concentration which was greater in the post-prandial than fasting state. When we infused a triglyceride emulsion into 6 subjects or added this to serum in vitro we observed an immediate fall in pre-beta HDL concentration. These findings suggest that pre-beta HDL interact with triglyceride rich particles. We investigated the origin of pre-beta HDL from blood lipoproteins during their lipolysis, in vivo and in vitro and found that they were produced from both triglyceride-rich and high-density lipoproteins. Formation from triglyceride-rich lipoproteins was evident by the rise in pre-beta HDL concentration during heparin-induced lipolysis when fasting and post-prandially. The rise was greater post-prandially and particularly marked in 4 hypertriglyceridaemic patients following a fat load. Generation from alpha-HDL was evident when we prolonged the action of the heparin-released lipases by incubation of post-heparin sera at 37 degrees C. Continued formation of pre-beta HDL occurred at an equal rate in the fasting and post-prandial samples suggesting release by lipolysis of alpha-HDL. This was supported by the action of lipases on serum and isolated HDL in vitro, where triglyceride lipase rather than phospholipase activity appeared more effective at releasing pre-beta HDL. These findings suggest binding and release of pre-beta HDL by triglyceride-rich lipoproteins depending on the prandial state and production from alpha-HDL through the action of lipases.

Adolescent↗

Rapid screening for specific mutations in patients with a clinical diagnosis of familial hypercholesterolaemia.

We describe a rapid screening procedure to identify known DNA sequence changes in individuals diagnosed as having heterozygous familial hypercholesterolaemia (FH). The screening is made possible by combining a rapid DNA extraction protocol and small scale polymerase chain reaction DNA amplification, followed by oligonucleotide melting or restriction enzyme digestion. We have screened for two different mutations; firstly a mutation in the apolipoprotein B (apo B) gene that results in the substitution of glutamine (Gln) for arginine (Arg) at amino acid residue 3500 (apo B3500 mutation). Apo B is the principal component of the protein moiety of low density lipoprotein (LDL) and the mutation reduces the affinity for the LDL receptor (LDL-R). Secondly we have screened for a point mutation in the LDL-R gene itself that creates a new Pst I restriction enzyme site. This mutation in the LDL-R gene (LDL-R664 mutation) results in the substitution of leucine (Leu) for proline (Pro) at amino acid 664 and is known to slow processing of the LDL-R precursor to the mature form and to reduce the affinity of the receptor on the cell surface for LDL. In 77 unrelated patients with a clinical diagnosis of FH two out of 77 (2.6%) were positive for the apo B3500 mutation. Three (3.9%) were positive for the LDL-R664 mutation. Thus these two mutations might account for 5-6% of patients in the U.K. with a clinical diagnosis of FH (5000-6000 people).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗