Variabilité des concentrations plasmatiques de l'angiotensinogène et risque d'hypertension artérielle chez le rat transgénique [Variability of plasma angiotensinogen levels and risk of hypertension in a transgenic rat model].

AIM: Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors. METHODS: Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n=3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction). RESULTS: At baseline, transgenic rats had +18mmHg higher bood pressure and -8% lower body weight compared to non-transgenic rats (P<0.05) without significant changes for the vehicle groups throughout the study (P>0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P<0.05) in transgenic and +25%, +5.3% and +6.7% (P>0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P>0.05). CONCLUSION: Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.

Changes in the risk of death after HIV seroconversion compared with mortality in the general population.

CONTEXT: Mortality among human immunodeficiency virus (HIV)-infected individuals has decreased dramatically in countries with good access to treatment and may now be close to mortality in the general uninfected population. OBJECTIVE: To evaluate changes in the mortality gap between HIV-infected individuals and the general uninfected population. DESIGN, SETTING, AND POPULATION: Mortality following HIV seroconversion in a large multinational collaboration of HIV seroconverter cohorts (CASCADE) was compared with expected mortality, calculated by applying general population death rates matched on demographic factors. A Poisson-based model adjusted for duration of infection was constructed to assess changes over calendar time in the excess mortality among HIV-infected individuals. Data pooled in September 2007 were analyzed in March 2008, covering years at risk 1981-2006. MAIN OUTCOME MEASURE: Excess mortality among HIV-infected individuals compared with that of the general uninfected population. RESULTS: Of 16,534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1000 person-years) decreased from 40.8 (95% confidence interval [CI], 38.5-43.0; 1275.9 excess deaths in 31,302 person-years) before the introduction of highly active antiretroviral therapy (pre-1996) to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14,703 person-years) in 2004-2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03-0.09] for 2004-2006 vs pre-1996). By 2004-2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%-8.6%] in the first 10 years among those aged 15-24 years). CONCLUSIONS: Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of highly active antiretroviral therapy. In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.

BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD. DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(-8)) were tested for association with CAD in 31,400 cases and 92,927 controls. RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 Ã- 10(-9)), SLC17A3 (1.0 Ã- 10(-8)), GTPB10 (1.7 Ã- 10(-8)), CUBN (7.5 Ã- 10(-10)), HNF1A (1.2 Ã- 10(-12)), and FUT2 (6.6 Ã- 10(-9)), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 Ã- 10(-36)). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

Metabolic syndrome and the risk of cardiovascular disease in older adults.

OBJECTIVES: The purpose of this study was to assess whether metabolic syndrome (MetSyn) predicts a higher risk for cardiovascular events in older adults. BACKGROUND: The importance of MetSyn as a risk factor has not previously focused on older adults and deserves further study. METHODS: We studied the impact of MetSyn (38% prevalence) on outcomes in 3,035 participants in the Health, Aging, and Body Composition (Health ABC) study (51% women, 42% black, ages 70 to 79 years). RESULTS: During a 6-year follow-up, there were 434 deaths overall, 472 coronary events (CE), 213 myocardial infarctions (MI), and 231 heart failure (HF) hospital stays; 59% of the subjects had at least one hospital stay. Coronary events, MI, HF, and overall hospital stays occurred significantly more in subjects with MetSyn (19.9% vs. 12.9% for CE, 9.1% vs. 5.7% for MI, 10.0% vs. 6.1% for HF, and 63.1% vs. 56.1% for overall hospital stay; all p < 0.001). No significant differences in overall mortality was seen; however, there was a trend toward higher cardiovascular mortality (5.1% vs. 3.8%, p = 0.067) and coronary mortality (4.5% vs. 3.2%, p = 0.051) in patients with MetSyn. After adjusting for baseline characteristics, patients with MetSyn were at a significantly higher risk for CE (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.28 to 1.91), MI (HR 1.51, 95% CI 1.12 to 2.05), and HF hospital stay (HR 1.49, 95% CI 1.10 to 2.00). Women and whites with MetSyn had a higher coronary mortality rate. The CE rate was higher among subjects with diabetes and with MetSyn; those with both had the highest risk. CONCLUSIONS: Overall, subjects over 70 years are at high risk for cardiovascular events; MetSyn in this group is associated with a significantly greater risk.

Increased male offspring's risk of metabolic-neuroendocrine dysfunction and overweight after fructose-rich diet intake by the lactating mother.

An adverse endogenous environment during early life predisposes the organism to develop metabolic disorders. We evaluated the impact of intake of an iso-caloric fructose rich diet (FRD) by lactating mothers (LM) on several metabolic functions of their male offspring. On postnatal d 1, ad libitum eating, lactating Sprague-Dawley rats received either 10% F (wt/vol; FRD-LM) or tap water (controls, CTR-LM) to drink throughout lactation. Weaned male offspring were fed ad libitum a normal diet, and body weight (BW) and food intake were registered until experimentation (60 d of age). Basal circulating levels of metabolic markers were evaluated. Both iv glucose tolerance and hypothalamic leptin sensitivity tests were performed. The hypothalamus was dissected for isolation of total RNA and Western blot analysis. Retroperitoneal (RP) adipose tissue was dissected and either kept frozen for gene analysis or digested to isolate adipocytes or for histological studies. FRD rats showed increased BW and decreased hypothalamic sensitivity to exogenous leptin, enhanced food intake (between 49-60 d), and decreased hypothalamic expression of several anorexigenic signals. FRD rats developed increased insulin and leptin peripheral levels and decreased adiponectinemia; although FRD rats normally tolerated glucose excess, it was associated with enhanced insulin secretion. FRD RP adipocytes were enlarged and spontaneously released high leptin, although they were less sensitive to insulin-induced leptin release. Accordingly, RP fat leptin gene expression was high in FRD rats. Excessive fructose consumption by lactating mothers resulted in deep neuroendocrine-metabolic disorders of their male offspring, probably enhancing the susceptibility to develop overweight/obesity during adult life.

Estimation of forest canopy cover : a comparison of field measurement techniques

Abstract

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Risk of hypoglycemia in newborns from mothers with gestacional diabetes

There are not enough previous publications which are focused on mothers withwell-controlled gestational diabetes mellitus (GDM) as a risk factor that determines the occurrence of neonatal hypoglycemia. In addition, approaches to blood glucose monitoring have been inconsistent and poorly defined. Our objective is to determine if being a newborn from a mother with well-controlled gestational diabetes (regardless insulin treatment) have a higher risk to develop hypoglycemia than a healthy newborn, using a defined and strict protocol. The project will take place in a regional hospital of Girona. We will recruit from 2014 to 2015 a cohort of 623 infants born in this center without any malformation or any perinatal pathology or complication, selected with a consecutive sampling. We will record sex, ethnicity and gestational age information. We will measure blood glucose levels and anthropometric measurements in newborns always taking into account the presence of well-controlled maternal gestational diabetes or not. Patients will be followed up during 24 hours to determine the incidence of hypoglycemia. We will analyze the contribution between exposure factors that we have studied and the incidence of the outcome using a multivariate analysis

Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer.

BACKGROUND: Sex steroid hormones have been proposed to play a role in the development of non-epithelial ovarian cancers (NEOC) but so far no direct epidemiological data are available.METHODS: A case-control study was nested within the Finnish Maternity Cohort, the world's largest bio-repository of serum specimens from pregnant women. Study subjects were selected among women who donated a blood sample during a singleton pregnancy that led to the birth of their last child preceding diagnosis of NEOC. Case subjects were 41 women with sex-cord stromal tumors (SCST) and 21 with germ cell tumors (GCT). Three controls, matching the index case for age, parity at the index pregnancy, and date at blood donation were selected (n=171). Odds ratios (OR) and 95% confidence intervals (CI) associated with concentrations of testosterone, androstenedione, 17-OH-progesterone, progesterone, estradiol and sex hormone binding globulin (SHBG) were estimated through conditional logistic regression.RESULTS: For SCST, doubling of testosterone, androstenedione and 17-OH-progesterone concentrations were associated with about 2-fold higher risk of SCST [ORs and 95% CI of 2.16 (1.25-3.74), 2.16 (1.20-3.87), and 2.62 (1.27-5.38), respectively]. These associations remained largely unchanged after excluding women within 2, 4 or 6 years lag-time between blood donation and cancer diagnosis. Sex steroid hormones concentrations were not related to maternal risk of GCT.CONCLUSIONS: This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST. Impact: Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC.

Applying geostatistics for investigations of forest ecosystems using remote sensing imagery

Abstract

Type of alcoholic beverage and risk of head and neck cancer: a pooled analysis within the INHANCE Consortium

The authors pooled data from 15 case-control studies of head and neck cancer (9,107 cases, 14,219 controls) to investigate the independent associations with consumption of beer, wine, and liquor. In particular, they calculated associations with different measures of beverage consumption separately for subjects who drank beer only (858 cases, 986 controls), for liquor-only drinkers (499 cases, 527 controls), and for wine-only drinkers (1,021 cases, 2,460 controls), with alcohol never drinkers (1,124 cases, 3,487 controls) used as a common reference group. The authors observed similar associations with ethanol-standardized consumption frequency for beer-only drinkers (odds ratios (ORs) = 1.6, 1.9, 2.2, and 5.4 for < or =5, 6-15, 16-30, and >30 drinks per week, respectively; P(trend) < 0.0001) and liquor-only drinkers (ORs = 1.6, 1.5, 2.3, and 3.6; P < 0.0001). Among wine-only drinkers, the odds ratios for moderate levels of consumption frequency approached the null, whereas those for higher consumption levels were comparable to those of drinkers of other beverage types (ORs = 1.1, 1.2, 1.9, and 6.3; P < 0.0001). Study findings suggest that the relative risks of head and neck cancer for beer and liquor are comparable. The authors observed weaker associations with moderate wine consumption, although they cannot rule out confounding from diet and other lifestyle factors as an explanation for this finding. Given the presence of heterogeneity in study-specific results, their findings should be interpreted with caution.

Body mass index and risk of head and neck cancer in a pooled analysis of case-control studies in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium.

BACKGROUND: Head and neck cancer (HNC) risk is elevated among lean people and reduced among overweight or obese people in some studies; however, it is unknown whether these associations differ for certain subgroups or are influenced by residual confounding from the effects of alcohol and tobacco use or by other sources of biases. METHODS: We pooled data from 17 case-control studies including 12 716 cases and the 17 438 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for associations between body mass index (BMI) at different ages and HNC risk, adjusted for age, sex, centre, race, education, tobacco smoking and alcohol consumption. RESULTS: Adjusted ORs (95% CIs) were elevated for people with BMI at reference (date of diagnosis for cases and date of selection for controls) 25.0-30.0 kg/m(2) (0.52, 0.44-0.60) and BMI >/=30 kg/m(2) (0.43, 0.33-0.57), compared with BMI >18.5-25.0 kg/m(2). These associations did not differ by age, sex, tumour site or control source. Although the increased risk among people with BMI 25 kg/m(2) was present only in smokers and drinkers. CONCLUSIONS: In our large pooled analysis, leanness was associated with increased HNC risk regardless of smoking and drinking status, although reverse causality cannot be excluded. The reduced risk among overweight or obese people may indicate body size is a modifier of the risk associated with smoking and drinking. Further clarification may be provided by analyses of prospective cohort and mechanistic studies.

Bone mineral density (BMD), micro-architecture estimation (TBS) and vertebral fracture assessment (VFA) extracted from a single DXA device in combination with clinical risk factors improve significantly the identification of women at high risk of fracture.

Osteoporosis (OP) is a systemic skeletal disease characterized by a low bone mineral density (BMD) and a micro-architectural (MA) deterioration. Clinical risk factors (CRF) are often used as a MA approximation. MA is yet evaluable in daily practice by the trabecular bone score (TBS) measure. TBS is very simple to obtain, by reanalyzing a lumbar DXA-scan. TBS has proven to have diagnosis and prognosis values, partially independent of CRF and BMD. The aim of the OsteoLaus cohort is to combine in daily practice the CRF and the information given by DXA (BMD, TBS and vertebral fracture assessment (VFA)) to better identify women at high fracture risk. The OsteoLaus cohort (1400 women 50 to 80 years living in Lausanne, Switzerland) started in 2010. This study is derived from the cohort COLAUS who started in Lausanne in 2003. The main goal of COLAUS is to obtain information on the epidemiology and genetic determinants of cardiovascular risk in 6700 men and women. CRF for OP, bone ultrasound of the heel, lumbar spine and hip BMD, VFA by DXA and MA evaluation by TBS are recorded in OsteoLaus. Preliminary results are reported. We included 631 women: mean age 67.4 ± 6.7 years, BMI 26.1 ± 4.6, mean lumbar spine BMD 0.943 ± 0.168 (T-score − 1.4 SD), and TBS 1.271 ± 0.103. As expected, correlation between BMD and site matched TBS is low (r2 = 0.16). Prevalence of VFx grade 2/3, major OP Fx and all OP Fx is 8.4%, 17.0% and 26.0% respectively. Age- and BMI-adjusted ORs (per SD decrease) are 1.8 (1.2-2.5), 1.6 (1.2-2.1), and 1.3 (1.1-1.6) for BMD for the different categories of fractures and 2.0 (1.4-3.0), 1.9 (1.4-2.5), and 1.4 (1.1-1.7) for TBS respectively. Only 32 to 37% of women with OP Fx have a BMD < − 2.5 SD or a TBS < 1.200. If we combine a BMD < − 2.5 SD or a TBS < 1.200, 54 to 60% of women with an osteoporotic Fx are identified. As in the already published studies, these preliminary results confirm the partial independence between BMD and TBS. More importantly, a combination of TBS subsequent to BMD increases significantly the identification of women with prevalent OP Fx which would have been misclassified by BMD alone. For the first time we are able to have complementary information about fracture (VFA), density (BMD), micro- and macro architecture (TBS and HAS) from a simple, low ionizing radiation and cheap device: DXA. Such complementary information is very useful for the patient in the daily practice and moreover will likely have an impact on cost effectiveness analysis.