Association between the NAT1 1095C > A polymorphism and homocysteine concentration.
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Adult↗
Biomedical subjects
Ian S Young
Publications and source records attributed to Ian S Young.
High density lipoprotein subfractions: isolation, composition, and their duplicitous role in oxidation.
The plasma HDLs represent a major class of cholesterol-transporting lipoprotein that can be divided into two distinct subfractions, HDL(2) and HDL(3), by ultracentrifugation. Existing methods for the subfractionation of HDL requires lengthy ultracentrifugations, making them unappealing for large-scale studies. We describe a method that subfractionates HDL from plasma in only 6 h, representing a substantial decrease in total isolation time. The subfractions so isolated were assessed for a variety of lipid and protein components, in addition to their susceptibility to oxidation, both alone and in combination with VLDL and LDL. We report for the first time a prooxidant role for HDL during VLDL oxidation, in which HDL donates preformed hydroperoxides to VLDL in a cholesteryl ester transfer protein (CETP)-dependent process. Examination of the participation of HDL in LDL oxidation has reinforced its classic role as a potent antioxidant. Furthermore, we have also implicated the second major HDL-associated enzyme, LCAT, in these processes, whereby it acts as a potent prooxidant during VLDL oxidation but as an antioxidant during LDL oxidation. Thus, we have identified a potentially duplicitous role for HDL in the pathogenesis of atherosclerosis, attributable to both CETP and LCAT.
Antioxidants↗
The LDLR variant T705I does not cause the typical phenotype of familial hypercholesterolaemia.
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Adolescent↗
Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE).
OBJECTIVE: To estimate the prevalence of age-related maculopathy in an older population from 7 European countries. METHODS: Randomly sampled people 65 years and older were invited to an eye examination in centers across 7 European countries (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain). Fundus images of each eye were graded at a single reading center. Prevalence rates were calculated for stage of age-related maculopathy with 95% confidence intervals (CIs) estimated for clustered data. RESULTS: Of 5040 participants (45% response rate), 4753 (2128 men and 2625 women) had gradable fundus images. The prevalences were grade 0, 47.59% (95% CI, 43.53%-51.65%); grade 1, 36.48% (95% CI, 32.66%-40.30%); grade 2, 10.14% (95% CI, 8.92% to 11.37%); grade 3, 2.46% (95% CI, 1.79%-3.13%); and grade 4 (age-related macular degeneration [AMD]), 3.32% (95% CI, 2.52%-4.13%) and large drusen only (> or = 125 microm), 15.41% (95% CI, 13.61%-17.21%). The prevalence of geographic atrophic AMD was 1.2% (95% CI, 0.8%-1.7%) and of neovascular AMD, 2.3% (95% CI, 1.7%-2.9%). The prevalence of bilateral AMD was 1.4% (95% CI, 1.0%-1.8%). CONCLUSION: Age-specific prevalences of age-related maculopathy in the European Eye Study (EUREYE) are similar to other population-based studies in Western populations.
Aged↗
Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache.
The present study combined molecular and neuroimaging techniques to examine if free radical-mediated damage to barrier function in hypoxia would result in extracellular edema, raise intracranial pressure (ICP) and account for the neurological symptoms typical of high-altitude headache (HAH) also known as acute mountain sickness (AMS). Twenty-two subjects were randomly exposed for 18 h to 12% (hypoxia) and 21% oxygen (O2 (normoxia)) for collection of venous blood (0 h, 8 h, 15 h, 18 h) and CSF (18 h) after lumbar puncture (LP). Electron paramagnetic resonance (EPR) spectroscopy identified a clear increase in the blood and CSF concentration of O2 and carbon-centered free radicals (P<0.05 versus normoxia) subsequently identified as lipid-derived alkoxyl (LO*) and alkyl (LC*) species. Magnetic resonance imaging (MRI) demonstrated a mild increase in brain volume (7.0+/-4.8 mL or 0.6%+/-0.4%, P<0.05 versus normoxia) that resolved within 6 h of normoxic recovery. However, there was no detectable evidence for gross barrier dysfunction, elevated lumbar pressures, T2 prolongation or associated neuronal and astroglial damage. Clinical AMS was diagnosed in 50% of subjects during the hypoxic trial and corresponding headache scores were markedly elevated (P<0.05 versus non-AMS). A greater increase in brain volume was observed, though this was slight, independent of oxidative stress, barrier dysfunction, raised lumbar pressure, vascular damage and measurable evidence of cerebral edema and only apparent in the most severe of cases. These findings suggest that free-radical-mediated vasogenic edema is not an important pathophysiological event that contributes to the mild brain swelling observed in HAH.
Adult↗
Manipulation of systemic oxygen flux by acute exercise and normobaric hypoxia: implications for reactive oxygen species generation.
Maximal exercise in normoxia results in oxidative stress due to an increase in free radical production. However, the effect of a single bout of moderate aerobic exercise performed in either relative or absolute normobaric hypoxia on free radical production and lipid peroxidation remains unknown. To examine this, we randomly matched {according to their normobaric normoxic VO2peak [peak VO2 (oxygen uptake)]} and assigned 30 male subjects to a normoxia (n = 10), a hypoxia relative (n = 10) or a hypoxia absolute (n = 10) group. Each group was required to exercise on a cycle ergometer at 55% of VO2peak for 2 h double-blinded to either a normoxic or hypoxic condition [FiO2 (inspired fraction of O2) = 0.21 and 0.16 respectively]. ESR (electron spin resonance) spectroscopy in conjunction with ex vivo spin trapping was utilized for the direct detection of free radical species. The main findings show that moderate intensity exercise increased plasma-volume-corrected free radical and lipid hydroperoxide concentration (pooled rest compared with exercise data, P < 0.05); however, there were no selective differences between groups (statexgroup interaction, P > 0.05). The delta change in free radical concentration was moderately correlated with systemic VO2 (r2 = 0.48, P < 0.05). The hyperfine coupling constants recorded from the ESR spectra [aN = 13.8 Gauss, and a(H)beta = 1.9 Gauss; where 1 Gauss = 10(-4) T (telsa)] are suggestive of oxygen-centred free radical species formed via the decomposition of lipid hydroperoxides. Peripheral leucocyte and neutrophil cells and total CK (creatine kinase) activity all increased following sustained exercise (pooled rest compared with exercise data, P < 0.05), but no selective differences were observed between groups (state x group interaction, P > 0.05). We conclude that a single bout of moderate aerobic exercise increases secondary free radical species. There is also evidence of exercise-induced muscle damage, possibly caused by the increase in free radical generation.
Adult↗
Methylprednisolone increases urinary nitrate concentrations and reduces subclinical renal injury during infrarenal aortic ischemia reperfusion.
OBJECTIVE: This study tests the hypothesis that methylprednisolone may influence eNOS activity in renal arterial and venous vascular beds and impede subclinical renal injury. SUMMARY BACKGROUND DATA: Acute renal failure is a major complication of cardiovascular surgery. Renal damage arises in part from excessive vasoconstriction mediated by an imbalance of vasoconstrictive ET-1 and vasodilatory NO produced by eNOS. While methylprednisolone may reduce subclinical renal injury as measured by urinary N-acetyl-beta-D-glucosaminidase (beta-NAG), its effects upon eNOS activity in renal arterial and venous vascular beds, reflected by urinary nitrate levels, is unclear. METHODS: A porcine model of normotensive, euvolemic infrarenal aortic ischaemia-reperfusion was used. Forty-two pigs underwent a 60-minute laparotomy followed by 150 minutes of infrarenal ischemia and 180 minutes of reperfusion. Animals were randomized to receive methylprednisolone 30 mg/kg or placebo after induction of general anesthesia. Urinary beta-NAG levels were assessed as an index of subclinical renal injury, whereas urinary nitrate was assessed as an indicator of eNOS activity in renal arterial and venous vascular beds. RESULTS: Methylprednisolone treatment did not influence mean arterial, central venous, or pulmonary artery wedge pressures but suppressed plasma IL-6 levels. After the ischemia-induced rise from preanaesthetic baseline levels, urinary beta-NAG levels declined to significantly lower values in the MP group, indicative of MP renal protection (P < 0.05). Conversely, urinary nitrate levels indicative of vascular e-NOS activity remained significantly and persistently higher in MP-treated animals (P < 0.05). CONCLUSION: This study, in a porcine model of renal ischaemia-reperfusion injury, shows the benefits of methylprednisolone pretreatment in enhancing urinary nitrate levels indicative of vascular eNOS activity and the reduction of urinary beta-NAG levels, which represent subclinical renal injury.
Acetylglucosaminidase↗
A few thoughts on reflective testing.
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Clinical Chemistry Tests↗
The pro-oxidant activity of high-dose vitamin E supplements in vivo.
BACKGROUND: A recent meta-analysis has demonstrated that the regular administration of high-dose vitamin E supplements may be associated with increased mortality. The biological mechanism for this effect is uncertain. METHODS: A ferrous oxidation xylenol assay was used to assess plasma oxidation activity levels in samples from a randomized, placebo-controlled, 6-week trial of daily vitamin E supplementation in adults with asthma (n = 72). RESULTS AND CONCLUSION: A 27% increase in plasma oxidation activity levels was observed in patients receiving vitamin E. We demonstrate a pro-oxidant effect of high-dose vitamin E supplementation that may explain the increase in mortality observed in intervention studies using this nutrient.
Adolescent↗
Effect of eucaloric high- and low-sucrose diets with identical macronutrient profile on insulin resistance and vascular risk: a randomized controlled trial.
The long-term impact of dietary carbohydrate type, in particular sucrose, on insulin resistance and the development of diabetes and atherosclerosis is not established. Current guidelines for the healthy population advise restriction of sucrose intake. We investigated the effect of high- versus low-sucrose diet (25 vs. 10%, respectively, of total energy intake) in 13 healthy subjects aged 33 +/- 3 years (mean +/- SE), BMI 26.6 +/- 0.9 kg/m(2), in a randomized crossover design with sequential 6-week dietary interventions separated by a 4-week washout. Weight maintenance, eucaloric diets with identical macronutrient profiles and fiber content were designed. All food was weighed and distributed. Insulin action was assessed using a two-step euglycemic clamp; glycemic profiles were assessed by the continuous glucose monitoring system and vascular compliance by pulse-wave analysis. There was no change in weight across the study. Peripheral glucose uptake and suppression of endogenous glucose production were similar after each diet. Glycemic profiles and measures of vascular compliance did not change. A rise in total and LDL cholesterol was observed. In this study, a high-sucrose intake as part of an eucaloric, weight-maintaining diet had no detrimental effect on insulin sensitivity, glycemic profiles, or measures of vascular compliance in healthy nondiabetic subjects.
Adult↗
Insulin sensitivity and clustering of coronary heart disease risk factors in young adults. The Northern Ireland Young Hearts Study.
BACKGROUND: Coronary heart disease (CHD) is usually associated with "clustering" of risk factors. Insulin resistance may cause deleterious changes in several CHD risk factors and is of potential interest in the aetiology of clustered risk. We analyzed how glucose and insulin variables were associated with clustered risk. METHODS: Participants were 489 young adults from Northern Ireland. Data were collected between October 1997 and October 1999. Nine risk factors were included in the clustered risk variable. Being "at risk" was defined as being in the upper quartile of risk for a particular risk factor. Subjects with clustered risk were defined as those displaying four or more risk factors. Blood glucose and insulin were measured in the fasting state and 2 h after ingestion of a 75 g glucose load. RESULTS: Fasting insulin and the homeostasis model assessment insulin resistance score (HOMA) were strong, graded predictors of clustered risk. The odds ratio (OR) for having clustered risk was 10.8 (95% CI: 3.6-32.4) for the upper quartile of fasting insulin compared to the lowest quartile, and the corresponding OR for HOMA was 23.2 (95% CI: 5.3-101.6). CONCLUSION: HOMA score predicts clustering of CHD risk factors. Fasting glucose alone did not predict clustering of risk factors, which may indicate that insulin resistance was compensated for by increased insulin secretion.
Adult↗
Vitamin C prophylaxis promotes oxidative lipid damage during surgical ischemia-reperfusion.
Reactive oxygen species (ROS) have been implicated in the cellular membrane damage and postoperative morbidity associated with obligatory ischemia-reperfusion (I-R) during vascular surgery. Thus, a clinical study was undertaken to evaluate the effects of ascorbate prophylaxis on ROS exchange kinetics in 22 patients scheduled for elective abdominal aortic aneurysm (AAA) or infra-inguinal bypass (IIB) repair. Patients were assigned double-blind to receive intravenous sodium ascorbate (2 g vitamin C, n=10) or placebo (0.9% saline, n=12) administered 2 h prior to surgery. Blood samples were obtained from the arterial and venous circulation proximal to the respective sites of surgical repair (local) and from an antecubital vein (peripheral) during cross-clamping (ischemia) and within 60 s of clamp release (reperfusion). Ascorbate supplementation increased the venoarterial concentration difference (v-adiff) of lipid hydroperoxides (LH), interleukin (IL)-6 and vascular endothelial growth factor (VEGF) protein during ischemia. This increased the peripheral concentration of LH, total creatine phosphokinase (CPK), and VEGF protein during reperfusion (P<0.05 vs placebo). Electron paramagnetic resonance (EPR) spectroscopy confirmed that free iron was available for oxidative catalysis in the local ischemic venous blood of supplemented patients. An increased concentration of the ascorbate radical (A.-) and alpha-phenyl-tert-butylnitrone (PBN) adducts assigned as lipid-derived alkoxyl (LO.) and alkyl (LC.) species were also detected in the peripheral blood of supplemented patients during reperfusion (P<0.05 vs ischemia). In conclusion, these findings suggest that ascorbate prophylaxis may have promoted iron-induced oxidative lipid damage via a Fenton-type reaction initiated during the ischemic phase of surgery. The subsequent release of LH into the systemic circulation may have catalyzed formation of second-generation radicals implicated in the regulation of vascular permeability and angiogenesis.
Aged↗
Short-term phytoestrogen supplementation alters insulin-like growth factor profile but not lipid or antioxidant status.
Phytoestrogens are plant compounds that have been proposed to have a variety of health benefits. The aim of this study was to assess the effects of these compounds on a number of physiological endpoints. Subjects were given a single intake of a phytoestrogen-rich (80 mg total phytoestrogens) supplement containing soy, rye and linseed (Phase 1), followed by a week-long intervention using the same supplement (Phase 2) (80 mg total phytoestrogens daily). A number of biochemical endpoints were assessed including urinary phytoestrogen metabolites, lipids, antioxidant status, DNA damage and insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) and -3 (IGFBP-3). Ten healthy female subjects took part in the study. Excretion of the isoflavones genistein, daidzein and equol in urine increased in both phases of the study. No other endpoint was altered in Phase 1. However, in Phase 2, concentrations of IGF-1 and IGFBP-3 were increased by phytoestrogen supplementation [IGF-1, median (IQ range), baseline 155 (123, 258), postweek 265 (228, 360) ng/ml, P<.05; IGFBP-3, baseline 3725 (3631, 4196), postweek 4420 (4192, 4935) ng/ml, P<.05]. There was no effect of supplementation on lipids or markers of antioxidant status. Short-term phytoestrogen supplementation increases urinary phytoestrogen excretion and increases IGF-1 and IGFBP-3. These results require elucidation in further controlled studies.
Adult↗
SNPs at the APOA5 gene account for the strong association with hypertriglyceridaemia at the APOA5/A4/C3/A1 locus on chromosome 11q23 in the Northern Irish population.
Serum triglyceride levels (TG) are important independent risk factors for coronary heart disease. The apolipoproteins C-III (apoCIII) and A-V (apoAV) are central to normal TG metabolism and the complete sequence analysis of these genes was carried out in severe cases (TG > 9 mmol/l) and controls (TG < 2 mmol/l). A total of 53 SNPs were identified in these genes with 17 being novel to this study. Further analysis defined four APOC3 SNPs and three APOA5 SNPs showing strong association with TG levels. Analysis of the two major SNPs from APOA5 [c.56C > G, c.-3A > G] and from APOC3 [c.102C > T, c.340C > G] using THESIAS has identified two major haplotypes relative to the most common CACC haplotype showing very strong association with hypertriglyceridaemia, CGTG and GATC (odds ratio 7.45 and 5.26). Logistic regression analysis of these four SNPs revealed that, carriage of the APOA5 c.56 G allele (odd ratios 4.49) and the APOA5 c.-3 G allele (odds ratio 3.23) were strong independent predictors of hypertriglyceridaemia (P < 0.001), whereas in contrast, carriage of the APOC3 c102 T allele (odds ratio 1.35) and the APOC3 c.340 G allele (odds ratio 1.37), did not show any significant effects that were independent of APOA5.
Apolipoprotein A-I↗
Diastereoselective synthesis of pyrrolidines using a nitrone/cyclopropane cycloaddition: synthesis of the tetracyclic core of nakadomarin A.
The synthesis of the tetracyclic core of nakadomarin A is described. The core contains all the heterocycles and the required stereocenters found in the natural product and provides a promising route to the target itself. The strategy utilizes a general, diastereoselective pyrrolidine synthesis that proceeds via a homo 3 + 2 dipolar cycloaddition. The scope of this methodology is also described. [structure: see text]
Carbolines↗
Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate.
Familial hypercholesterolemia (FH) is a common single gene disorder, which predisposes to coronary artery disease. In a previous study, we have shown that in patients with definite FH around 20% had no identifiable gene defect after screening the entire exon coding area of the low density lipoprotein receptor (LDLR) and testing for the common Apolipoprotein B (ApoB) R3500Q mutation. In this study, we have extended the screen to additional families and have included the non-coding intron splice regions of the gene. In families with definite FH (tendon xanthoma present, n=68) the improved genetic screening protocol increased the detection rate of mutations to 87%. This high detection rate greatly enhances the potential value of this test as part of a clinical screening program for FH. In contrast, the use of a limited screen in patients with possible FH (n=130) resulted in a detection rate of 26%, but this is still of significant benefit in diagnosis of this genetic condition. We have also shown that 14% of LDLR defects are due to splice site mutations and that the most frequent splice mutation in our series (c.1845+11 c>g) is expressed at the RNA level. In addition, DNA samples from the patients in whom no LDLR or ApoB gene mutations were found, were sequenced for the NARC-1 gene. No mutations were identified which suggests that the role of NARC-1 in causing FH is minor. In a small proportion of families (<10%) the genetic cause of the high cholesterol remains unknown, and other genes are still to be identified that could cause the clinical phenotype FH.
Apolipoproteins B↗
Micronutrients: dietary intake v. supplement use.
Whilst clinical deficiency of micronutrients is uncommon in the developed world, a suboptimal intake of certain micronutrients has been linked with an increased risk of chronic diseases such as CVD and cancer. Attention has therefore focused on increasing micronutrient status in order to theoretically reduce chronic disease risk. Increasing micronutrient status can involve a number of approaches: increasing dietary intake of micronutrient-rich foods; food fortification; use of supplements. Observational cohort studies have demonstrated an association between high intakes of micronutrients such as vitamin E, vitamin C, folic acid and beta-carotene, and lower risk of CHD, stroke and cancer at various sites. However, randomised intervention trials of micronutrient supplements have, to date, largely failed to show an improvement in clinical end points. The discordance between data from cohort studies and the results so far available from clinical trials remains to be explained. One reason may be that the complex mixture of micronutrients found, for example, in a diet high in fruit and vegetables may be more effective than large doses of a small number of micronutrients, and therefore that intervention studies that use single micronutrient supplements are unlikely to produce a lowering of disease risk. Studies concentrating on whole foods (e.g. fruit and vegetables) or diet pattern (e.g. Mediterranean diet pattern) may be more effective in demonstrating an effect on clinical end points. The present review will consider the clinical trial evidence for a beneficial effect of micronutrient supplements on health, and review the alternative approaches to the study of dietary intake of micronutrients.
Clinical Trials as Topic↗