Thorgeirsson T.E.,1deCODE Genetics |
Thorgeirsson T.E.,University of California at Santa Cruz |
Gudbjartsson D.F.,1deCODE Genetics |
Surakka I.,University of Helsinki |
And 105 more authors.
Nature Genetics | Year: 2010
Smoking is a common risk factor for many diseases1. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P 5 × 108), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 × 1069), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 × 1012) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 × 108), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006). © 2010 Nature America, Inc. All rights reserved.
Stead R.,Vascular Research Group |
Musa M.G.,Vascular Research Group |
Bryant C.L.,Vascular Research Group |
Lanham S.A.,Institute of Developmental science |
And 5 more authors.
Journal of Hypertension | Year: 2016
Objectives: The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDH:EDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease. Methods: Developmentally conditioned changes in EDH:EDRF signalling pathways were investigated in cremaster arterioles (18-32μm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age. Results: EDH via intermediate (IK Ca) and small (SK ca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with ∼60% in C/C (P<0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, P<0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDH:EDRF were associated with altered endothelial cell expression and localization of IK Ca channels. Conclusion: This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IK Ca signalling pathway. Conditioned offspring exposed to a 'second hit' (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function. © Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
Covic A.C.,Grigore T. Popa University of Medicine and Pharmacy |
Covic A.C.,rhon University Hospital |
Buimistriuc L.-D.,rhon University Hospital |
Green D.,Vascular Research Group |
And 5 more authors.
Annals of Noninvasive Electrocardiology | Year: 2013
Background Left ventricular hypertrophy (LVH) is associated with poor cardiovascular outcome in CKD. Electrocardiogram (ECG) is low-cost but infrequently used to assess presence of LVH in dialysis patients. The aim of this study was to establish which ECG-determined LVH method is most sensitive in dialysis patients, and also most predictive of death. Methods This was a longitudinal observational study in dialysis patients from a single center, undergoing interval ECGs. Fourteen methods of ECG LVH assessment were compared. Survival was also compared between four LVH evolutionary categories: persistent LVH; new LVH; LVH regression; and no LVH. Results The study included 418 dialysis patients (46.3% women, mean age 51 years, mean follow up 67 months, 76 deaths, 37 cardiovascular deaths). LVH prevalence varied according to method (range 13.4-41.9%). No measurement predicted all-cause mortality. After Cox regression, there was an independent association between LVH and cardiovascular mortality using Novacode (HR = 3.04; 95% [CI] = 1.11-8.28, P < 0.05), but not with other methods. Patients with persistent ECG changes of LVH had increased risk of cardiovascular mortality compared to other LVH evolutionary categories (P < 0.044). Conclusions ECG scoring of LVH can be predictive of cardiovascular mortality. The Novacode method, based on repolarization abnormalities, is a better predictor than standard ECG techniques that are based on voltage criteria. Novacode LVH estimation at dialysis initiation may prove to be a noninvasive and cost-effective bedside tool for cardiovascular risk stratification in patients receiving dialysis. ©2012, Wiley Periodicals, Inc.
Faint J.M.,The Binding Site Group |
Basu S.,Royal Wolverhampton Hospitals NHS Trust |
Sutton D.,Royal Wolverhampton Hospitals NHS Trust |
Showell P.J.,The Binding Site Group |
And 10 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2014
Background: Elevated polyclonal serum free light chain (FLC) levels have been associated with increased mortality and disease activity in many conditions. Currently, polyclonal FLC quantification requires summation of individual FLCκ and FLCλ assays. Here we present a single assay for combined FLC (cFLC, Combylite™) which reduces assay time and eliminates potential imprecision errors incurred by summating FLC assays (ΣFLC).Methods: Sheep FLCκ- and FLCλ-specific antibodies were conjugated to latex microparticles to quantify FLCκ and FLCλ in a single assay. Combylite results were compared to ΣFLC (Freelite®) in 132 healthy controls and 1127 patient samples. The utility of cFLC for predicting all-cause mortality in a haematological referral population was evaluated.Results: cFLC and ΣFLC results were highly concordant (Passing-Bablok equation y=0.98x-1.59 mg/L, R2=0.96). Combylite assay imprecision was low at concentrations around the upper normal range [coefficient of variation (CV) 5.5%, 54 mg/L] and the upper limit of the measuring range (CV 5.5%, 170 mg/L). cFLC levels were significantly raised in disease states compared with healthy controls. Additionally, cFLC >65 mg/L was associated with shorter overall survival in a haematological referral population (hazard ratio=4.5, p<0.001).Conclusions: cFLC values obtained using Combylite were comparable to ΣFLC results over a wide concentration range, were elevated in diseases characterised by B cell activation and were associated with increased mortality in a haematological referral population. These observations indicate the Combylite assay has value for investigating the role of B cell activation in disparate disease groups and could be considered as a surrogate indication of B cell function.
Apposite insulin-like growth factor (IGF) receptor glycosylation is critical to the maintenance of vascular smooth muscle phenotype in the presence of factors promoting osteogenic differentiation and mineralization
Siddals K.W.,University of Manchester |
Siddals K.W.,Vascular Research Group |
Allen J.,Vascular Research Group |
Sinha S.,University of Manchester |
And 6 more authors.
Journal of Biological Chemistry | Year: 2011
Vascular calcification is strongly linked with increased morbidity and mortality from cardiovascular disease. Vascular calcification is an active cell-mediated process that involves the differentiation of vascular smooth muscle cells (VSMCs) to an osteoblast-like phenotype. Several inhibitors of this process have been identified, including insulin-like growth factor-I (IGF-I). In this study, we examined the role of the IGF receptor (IGFR) and the importance of IGFR glycosylation in the maintenance of the VSMC phenotype in the face of factors known to promote osteogenic conversion. IGF-I (25 ng/ml) significantly protected VSMCs from β-glycerophosphate-induced osteogenic differentiation (p < 0.005) and mineral deposition (p < 0.01). Mevalonic acid depletion (induced by 100 nM cerivastatin) significantly inhibited these IGF protective effects (p < 0.01). Mevalonic acid depletion impaired IGFR processing, decreased the expression of mature IGFRs at the cell surface, and inhibited the downstream activation of Akt and MAPK. Inhibitors of N-linked glycosylation (tunicamycin, deoxymannojirimycin, and deoxynojirimycin) also markedly attenuated the inhibitory effect of IGF-I on β-glycerophosphate- induced mineralization (p < 0.05) and activation of Akt and MAPK. These results demonstrate that alterations in the glycosylation of the IGFR disrupt the ability of IGF-I to protect against the osteogenic differentiation and mineralization of VSMCs by several interrelated mechanisms: decreased IGFR processing, reduced IGFR cell-surface expression, and reduced downstream signaling via the Akt and MAPK pathways. IGF-I thus occupies a critical position in the maintenance of normal VSMC phenotype and protection from factors known to stimulate vascular calcification. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Khan A.S.A.,Vascular Research Group |
Gibson J.M.,Vascular Research Group |
Carlson G.L.,Injury Research Group |
Rooyackers O.,Karolinska Institutet |
And 2 more authors.
British Journal of Surgery | Year: 2015
Background Sepsis is associated with profound alterations in protein metabolism. The unpredictable time course of sepsis and the multiplicity of confounding factors prevent studies of temporal relations between the onset of endocrine and proinflammatory cytokine responses and the onset of protein catabolism. This study aimed to determine the time course of whole-body protein catabolism, and relate it to the endocrine, metabolic and cytokine responses in a human endotoxaemia model of early sepsis. Methods Six healthy male volunteers were studied twice in random order, before and for 600 min after administration of either an intravenous bolus of Escherichia coli lipopolysaccharide (LPS) or sterile saline. Whole-body protein synthesis, breakdown and net protein breakdown were measured by amino acid tracer infusion, and related to changes in plasma levels of growth hormone, glucagon, cortisol, insulin-like growth factor (IGF) 1, tumour necrosis factor (TNF) α and interleukin (IL) 6. Results Protein synthesis, breakdown and net protein breakdown increased and peaked 120 min after LPS administration (P < 0·001), the alterations persisting for up to 480 min. These peaks coincided with peaks in plasma growth hormone, TNF-α and IL-6 concentrations (P = 0·049, P < 0·001 and P < 0·001 for LPS versus saline), whereas plasma cortisol concentration peaked later. No alterations in plasma insulin or glucagon concentrations, or in the IGF axis were observed during the period of abnormalities of protein metabolism. Conclusion LPS administration induced an early protein catabolic response in young men and this coincided with changes in plasma growth hormone, TNF-α and IL-6 concentrations, rather than changes in cortisol, glucagon, insulin or the IGF axis. Surgical relevance Sepsis in surgical patients is common and remains associated with substantial mortality. Although sepsis is a heterogeneous condition and its pathophysiology therefore difficult to study, a universal and profound clinical problem is protein catabolism not responsive to nutritional support. Human experimental endotoxaemia is a promising model of clinical sepsis that can be used to elucidate underlying pathophysiology and explore novel therapeutic approaches. This study demonstrates that human experimental endotoxaemia replicates the changes in whole-body protein turnover seen in clinical sepsis. Frequent measurements allowed identification of tumour necrosis factor (TNF) α, interleukin (IL) 6 and growth hormone as putative mediators. Human experimental endotoxaemia is a valid model for further study of mechanisms and putative therapies of catabolism associated with sepsis. In particular, effects of TNF-α and IL-6 blockade should be evaluated. Interleukin 6 and tumour necrosis factor α potential treatment targets © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.
Tierney S.,University of Manchester |
Mamas M.,University of Manchester |
Skelton D.,Glasgow Caledonian University |
Woods S.,University of Manchester |
And 5 more authors.
Health Psychology | Year: 2011
Objectives: Keeping physically active has been shown to bring positive outcomes for patients diagnosed with heart failure (HF). However, a number of individuals with this health problem do not undertake regular exercise. A review of extant qualitative research was conducted to explore what it can tell us about barriers and enablers to physical activity among people with HF. Methods: A systematic search, involving electronic databases and endeavors to locate gray literature, was carried out to identify relevant qualitative studies published from 1980 onward. Data from retrieved papers were combined using framework analysis. Papers read in full numbered 32, and 20 were included in the review. Results: Synthesis of results from the 20 studies resulted in 4 main themes: Changing soma, negative emotional response, adjusting to altered status, and interpersonal influences. How individuals responded to their diagnosis and their altered physical status related to their activity levels, as did the degree of encouragement to exercise coming from family, friends, and professionals. These findings can be connected to the theory of behavioral change developed by Bandura, known as social cognitive theory (SCT). Conclusions: SCT may be a useful framework for developing interventions to support patients with HF in undertaking and maintaining regular exercise patterns. Specific components of SCT that practitioners may wish to consider include self-efficacy and outcome expectancies. These were issues referred to in papers for the systematic review that appear to be particularly related to exercise adherence. © 2011 American Psychological Association.
Eddington H.,Vascular Research Group |
Hoefield R.,Vascular Research Group |
Sinha S.,Vascular Research Group |
Chrysochou C.,Vascular Research Group |
And 7 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2010
Background and objectives: Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population. Design, setting, participants & measurements: Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets. Results: Mean (SD) eGFR was 32 (15) ml/min per 1.73 m2, age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality. Conclusions: In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival. Copyright © 2010 by the American Society of Nephrology.