Predicting Diabetes: Clinical, Biological, and Genetic Approaches: Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR)

OBJECTIVE—To provide a simple clinical diabetes risk score and to identify characteristics that predict later diabetes using variables available in the clinic setting as well as biological variables and polymorphisms

Adiposity has differing associations with incident coronary heart disease and mortality in the Scottish population: cross-sectional surveys with follow-up

Objective: Investigation of the association of excess adiposity with three different outcomes: all-cause mortality, coronary heart disease (CHD) mortality and incident CHD. Design: Cross-sectional surveys linked to hospital admissions and death records. Subjects: 19 329 adults (aged 18–86 years) from a representative sample of the Scottish population. Measurements: Gender-stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality, CHD mortality and incident CHD. Separate models incorporating the anthropometric measurements body mass index (BMI), waist circumference (WC) or waist–hip ratio (WHR) were created adjusted for age, year of survey, smoking status and alcohol consumption. Results: For both genders, BMI-defined obesity (greater than or equal to30 kg m−2) was not associated with either an increased risk of all-cause mortality or CHD mortality. However, there was an increased risk of incident CHD among the obese men (hazard ratio (HR)=1.78; 95% confidence interval=1.37–2.31) and obese women (HR=1.93; 95% confidence interval=1.44–2.59). There was a similar pattern for WC with regard to the three outcomes; for incident CHD, the HR=1.70 (1.35–2.14) for men and 1.71 (1.28–2.29) for women in the highest WC category (men greater than or equal to102 cm, women greater than or equal to88 cm), synonymous with abdominal obesity. For men, the highest category of WHR (greater than or equal to1.0) was associated with an increased risk of all-cause mortality (1.29; 1.04–1.60) and incident CHD (1.55; 1.19–2.01). Among women with a high WHR (greater than or equal to0.85) there was an increased risk of all outcomes: all-cause mortality (1.56; 1.26–1.94), CHD mortality (2.49; 1.36–4.56) and incident CHD (1.76; 1.31–2.38). Conclusions: In this study excess adiposity was associated with an increased risk of incident CHD but not necessarily death. One possibility is that modern medical intervention has contributed to improved survival of first CHD events. The future health burden of increased obesity levels may manifest as an increase in the prevalence of individuals living with CHD and its consequences

Weight change over five-year periods and number of components of the metabolic syndrome in a Dutch cohort

Overweight and obesity are associated with the metabolic syndrome (MetS). We studied the association of weight change over three consecutive 5-year periods with the number of MetS components in people aged 20–59 years. 5735 participants from the Doetinchem Cohort Study were included. Weight was measured in round 1 and at each 5-year interval follow-up (round 2, 3 and 4). Weight change was defined as the absolute weight change between two consecutive measurements. The number of MetS components (assessed in round 2, 3 and 4) was based on the presence of the following components of the MetS: central obesity, raised blood pressure, reduced high density lipoprotein cholesterol and elevated glucose. Associations of weight change and the number of components of the MetS were analyzed with Generalized Estimating Equations for Poisson regression, stratified for 10-year age groups. For each age group, 1 kg weight gain was positively associated with the number of components of the MetS, independent of sex and measurement round. The association was stronger in 30–39 years (adjusted rate ratio: 1.044; 95%CI: 1.040–1.049) and smaller in older age groups. Compared to stable weight (>−2.5 kg and < 2.5 kg), weight loss (≤−2.5 kg) and weight gain (≥2.5 kg) was associated with a lower and higher rate ratio respectively, for the number of components of the MetS. Our results support the independent association of weight change with the number of MetS components with a more pronounced association in younger people

Overweight status is associated with extensive signs of microvascular dysfunction and cardiovascular risk

The aim of this present study was to investigate if overweight individuals exhibit signs of vascular dysfunction associated with a high risk for cardiovascular disease (CVD). One hundred lean and 100 overweight participants were recruited for the present study. Retinal microvascular function was assessed using the Dynamic Retinal Vessel Analyser (DVA), and systemic macrovascular function by means of flow-mediated dilation (FMD). Investigations also included body composition, carotid intimal-media thickness (c-IMT), ambulatory blood pressure monitoring (BP), fasting plasma glucose, triglycerides (TG), cholesterol levels (HDL-C and LDL-C), and plasma von Willebrand factor (vWF). Overweight individuals presented with higher right and left c-IMT (p = 0.005 and p = 0.002, respectively), average 24-h BP values (all p <0.001), plasma glucose (p = 0.008), TG (p = 0.003), TG: HDL-C ratio (p = 0.010), and vWF levels (p = 0.004). Moreover, overweight individuals showed lower retinal arterial microvascular dilation (p = 0.039) and baseline-corrected flicker (bFR) responses (p = 0.022), as well as, prolonged dilation reaction time (RT, p = 0.047). These observations emphasise the importance of vascular screening and consideration of preventive interventions to decrease vascular risk in all individuals with adiposity above normal range

Genome wide association study identifies KCNMA1 contributing to human obesity

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity.</p> <p>Methods</p> <p>We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index > 40 kg/m²) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal <it>P</it>< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults.</p> <p>Results</p> <p>Potassium channel, calcium activated, large conductance, subfamily M, alpha member <it>(KCNMA1) </it>rs2116830*G and <it>BDNF </it>rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for <it>KCNMA1 </it>rs2116830*G with <it>P </it>= 2.82 × 10^-10and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for <it>BDNF </it>rs988712*G with <it>P </it>= 5.2 × 10^-17and an OR of 1.36 [95% C.I. 1.20-1.55]. <it>KCNMA1 </it>rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (<it>P </it>= 0.0001) and fat cell (<it>P </it>= 0.04) expression of <it>KCNMA1 </it>was increased in obesity.</p> <p>Conclusions</p> <p>We have identified <it>KCNMA1 </it>as a new susceptibility locus for obesity, and confirmed the association of the <it>BDNF </it>locus at the genome-wide significant level.</p

J-shaped relationship between habitual coffee consumption and 10-year (2002–2012) cardiovascular disease incidence:the ATTICA study

Purpose: The purpose of this work was to evaluate the association between coffee consumption and 10-year cardiovascular disease (CVD) incidence in the ATTICA study, and whether this is modified by the presence or absence of metabolic syndrome (MetS) at baseline. Methods: During 2001–2002, 3042 healthy adults (1514 men and 1528 women) living in the greater area of Athens were voluntarily recruited to the ATTICA study. In 2011–2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Coffee consumption was assessed by a validated food-frequency questionnaire at baseline (abstention, low, moderate, heavy). Incidence of fatal or non-fatal CVD event was recorded using WHO-ICD-10 criteria and MetS was defined by the National Cholesterol Education Program Adult Treatment panel III (revised) criteria. Results: Overall, after controlling for potential CVD risk factors, the multivariate analysis revealed a J-shaped association between daily coffee drinking and the risk for a first CVD event in a 10-year period. Particularly, the odds ratio for low (250 ml/day), compared to abstention, were 0.44 (95% CI 0.29–0.68), 0.49 (95% CI 0.27–0.92) and 2.48 (95% CI 1.56–1.93), respectively. This inverse association was also verified among participants without MetS at baseline, but not among participants with the MetS. Conclusions: These data support the protective effect of drinking moderate quantities of coffee (equivalent to approximately 1–2 cups daily) against CVD incidents. This protective effect was only significant for participants without MetS at baseline

Education as a Predictor of Chronic Periodontitis: A Systematic Review with Meta-Analysis Population-Based Studies

The impact of socioeconomic inequalities on health is well-documented. Despite the links of periodontal disease with cardiovascular diseases, adverse pregnancy outcomes and diabetes, no meta-analysis of socioeconomic variations in periodontal disease exists. This meta-analytic review was conducted to determine the extent to which education attainment influences risk of periodontitis in adults aged 35+ years in the general population.The authors searched studies published until November 2010 using EMBASE and MEDLINE databases. References listed were then scrutinised, our own files were checked, and, finally, we contacted experts in the field. The authors included only general population-based studies conducted in adults aged 35 years and more. All articles were blind reviewed by two investigators. In the case of disagreement, a third investigator arbitrated. Using PRISMA statement, two reviewers independently extracted papers of interest.Relative to the higher education group, people with low education attainment experience a greater risk of periodontitis (OR: 1.86 [1.66–2.10]; p<0.00001). The association was partially attenuated after adjustment for covariates (OR: 1.55 [1.30–1.86]; p<0.00001). Sensitivity analyses showed that methods used to assess periodontitis, definition of cases, study country and categorization of education are largely responsible for the heterogeneity between studies. No significant bias of publication was shown using both the Egger (p = 0.16) and rank correlation tests (p = 0.35).In the studies reviewed, low educational attainment was associated with an increased risk of periodontitis. Although this evidence should be cautiously interpreted due to methodological problems in selected studies, efforts to eliminate educational inequalities in periodontitis should focus on early life interventions

Epidemiology and cost of herpes zoster and postherpetic neuralgia among patients treated in primary care centres in the valencian community of Spain

<p>Abstract</p> <p>Background</p> <p>Data on the epidemiology and costs related to herpes zoster (HZ) and postherpetic neuralgia (PHN) in Spain are scarce; therefore, studies are needed to evaluate the epidemiological and economic impact of HZ and its most common complication, PHN. The present study aimed to estimate the clinical and economic burden of HZ and PHN in Valencia (Spain).</p> <p>Methods</p> <p>We prospectively analyzed the burden of HZ and PHN and their attributable costs in patients from 25 general practices in the Autonomous Community of Valencia serving 36,030 persons aged > 14 years. All patients with a clinical diagnosis of HZ who attended these centers between December 1^st2006 and November 30^th2007 were asked to participate. Patients included were followed for 1 year.</p> <p>Results</p> <p>Of the 130 cases of HZ followed up, continued pain was experienced by 47.6% (95% confidence interval (CI) = 35.6-56.7%) at 1 month after rash onset, by 14.5% (95% CI = 7.8-1.2%) at 3 months, by 9.0% (95% CI = 3.7-14.3%) at 6 months, and by 5.9% (95% CI = 1.5-10.3%) at 12 months. The percentage of patients with PHN increased with age, from 21.4% (95% CI = 8.3-40) in patients < 50 years to 59.2% (95% CI = 44.4-74) in patients ≥ 70 years. The estimated total cost for the 130 HZ cases during the follow-up period was €49,160 ($67,349). Mean cost per patient was €378 (range 53-2,830) ($517, range 73-3,877).</p> <p>Conclusions</p> <p>This study shows that PHN is a relatively common complication of HZ and that both conditions combined give rise to a significant clinical and economic burden for patients and providers.</p

A New Strategy to Generate Functional Insulin-Producing Cell Lines by Somatic Gene Transfer into Pancreatic Progenitors

BACKGROUND: There is increasing interest in developing human cell lines to be used to better understand cell biology, but also for drug screening, toxicology analysis and future cell therapy. In the endocrine pancreatic field, functional human beta cell lines are extremely scarce. On the other hand, rodent insulin producing beta cells have been generated during the past years with great success. Many of such cell lines were produced by using transgenic mice expressing SV40T antigen under the control of the insulin promoter, an approach clearly inadequate in human. Our objective was to develop and validate in rodent an alternative transgenic-like approach, applicable to human tissue, by performing somatic gene transfer into pancreatic progenitors that will develop into beta cells. METHODS AND FINDINGS: In this study, rat embryonic pancreases were transduced with recombinant lentiviral vector expressing the SV40T antigen under the control of the insulin promoter. Transduced tissues were next transplanted under the kidney capsule of immuno-incompetent mice allowing insulinoma development from which beta cell lines were established. Gene expression profile, insulin content and glucose dependent secretion, normalization of glycemia upon transplantation into diabetic mice validated the approach to generate beta cell lines. CONCLUSIONS: Somatic gene transfer into pancreatic progenitors represents an alternative strategy to generate functional beta cell lines in rodent. Moreover, this approach can be generalized to derive cells lines from various tissues and most importantly from tissues of human origin

Is blood pressure reduction a valid surrogate endpoint for stroke prevention? an analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the biomarker-surrogacy (BioSurrogate) evaluation schema (BSES)

<p>Abstract</p> <p>Background</p> <p>Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit.</p> <p>Methods</p> <p>We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3).</p> <p>Results</p> <p>In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure.</p> <p>Conclusions</p> <p>In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design.</p