Essential role of GATA5 in the mammalian heart

réalisé en cotutelle avec le Dr. Marie Kmita et Dr. Marco Horb

Autosomal dominant polycystic kidney disease in hemodialysis patients in southern Brazil

Introduction: Autosomal dominant polycystic kidney disease is the most common hereditary renal disease in humans. Objective: To examine the prevalence, clinical and laboratory characteristics of patients with polycystic kidneys and relate disease manifestations by gender. Methods: This was an observational and retrospective study. All the medical records of patients with polycystic kidneys who initiated hemodialysis between 1995 and 2012, in four centers that treat patients of the coverage area of the 15th regional health Paraná (Brazil), were analyzed. Results: The study included 48 patients with polycystic kidneys, the primary cause of stage 5 CKD. Disease prevalence was one in 10,912 people. The average age of dialysis initiation was 50.7 years and the follow-up time on dialysis until transplantation (36.5 months) was lower among men. Hypertension was the most frequent diagnosis in 73% of patients, predominantly in women (51.4%). The liver cyst was the most frequent extrarenal manifestations in men (60.0%). The death occurred in 10.4% of patients using hemodialysis, and 60% of men. The class of antihypertensive drug used was that acts on the renin-angiotensin system with higher frequency of use among women (53.3%). The post-dialysis urea was significantly higher in men. Conclusion: The prevalence of the disease is low among hemodialysis patients in southern Brazil. The differences observed between genders, with the exception of the post-dialysis urea, were not significant. The findings are different from those reported in North America and Europe.

Coronary heart disease risk screening: the community pharmacy Healthy Heart Assessment Service

Objectives We examined the characteristics and CHD risks of people who accessed the free Healthy Heart Assessment (HHA) service operated by a large UK pharmacy chain from August 2004 to April 2006. Methods Associations between participants’ gender, age, and socioeconomics were explored in relation to calculated 10-year CHD risks by cross-tabulation of the data. Specific associations were tested by forming contingency tables and using Pearson chi-square (χ2). Results Data from 8,287 records were analysable; 5,377 were at low and 2,910 at moderate-to-high CHD risk. The likelihood of moderate-to-high risk for a male versus female participant was significantly higher with a relative risk ratio (RRR) 1.72 (P < 0.001). A higher percentage of those in socioeconomic categories ‘constrained by circumstances’ (RRR 1.15; P < 0.05) and ‘blue collar communities’ (RRR 1.13; P < 0.05) were assessed with moderate-to-high risk compared to those in ‘prospering suburbs’. Conclusions People from ‘hard-to-reach’ sectors of the population, men and people from less advantaged communities, accessed the HHA service and were more likely to return moderate-to-high CHD risk. Pharmacists prioritised provision of lifestyle information above the sale of a product. Our study supports the notion that pharmacies can serve as suitable environments for the delivery of similar screening services.

The gut microbiota and lipid metabolism: implications for human health and coronary heart disease

Coronary heart disease (CHD) is the leading cause of mortality in Western societies, affecting about one third of the population before their seventieth year. Over the past decades modifiable risk factors of CHD have been identified, including smoking and diet. These factors when altered can have a significant impact on an individuals' risk of developing CHD, their overall health and quality of life. There is strong evidence suggesting that dietary intake of plant foods rich in fibre and polyphenolic compounds, effectively lowers the risk of developing CHD. However, the efficacy of these foods often appears to be greater than the sum of their recognised biologically active parts. Here we discuss the hypothesis that beneficial metabolic and vascular effects of dietary fibre and plant polyphenols are due to an up regulation of the colon-systemic metabolic axis by these compounds. Fibres and many polyphenols are converted into biologically active compounds by the colonic microbiota. This microbiota imparts great metabolic versatility and dynamism, with many of their reductive or hydrolytic activities appearing complementary to oxidative or conjugative human metabolism. Understanding these microbial activities is central to determining the role of different dietary components in preventing or beneficially impacting on the impaired lipid metabolism and vascular dysfunction that typifies CHD and type 11 diabetes. This approach lays the foundation for rational selection of health promoting foods, rational target driven design of functional foods, and provides an essential thus-far, overlooked, dynamic to our understanding of how foods recognised as "healthy" impact on the human metabonome.

Obesity and health in Europeans aged 50 years and older

Background: Obesity is increasing globally across all population groups. Limited data are available on how obesity patterns differ across countries. Objective: To document the prevalence of obesity and related health conditions for Europeans aged 50 years and older, and to estimate the association between obesity and health outcomes across 10 European countries. Methods: Data were obtained from the 2004 Survey of Health, Ageing and Retirement in Europe, a cross-national survey of 22 777 Continental Europeans over the age of 50 years. The health outcomes included self-reported health, disability, doctor-diagnosed chronic health conditions and depression. Multivariate regression analysis was used to predict health outcomes across weight classes (defined by body mass index [BMI] from self-reported weight and height) in the pooled sample and individually in each country. Results: The prevalence of obesity (BMI >= 30) ranged from 12.8% in Sweden to 20.2% in Spain for men and from 12.3% in Switzerland to 25.6% in Spain for women. Adjusting for compositional differences across countries changed little in the observed large heterogeneity in obesity rates throughout Europe. Compared with normal weight individuals, men and women with greater BMI had significantly higher risks for all chronic health conditions examined except heart disease in overweight men. Depression was linked to obesity in women only. Particularly pronounced risks of impaired health and chronic health conditions were found among severely obese people. The effects of obesity on health did not vary significantly across countries. Conclusions: Cross-country differences in the prevalence of obesity in older Europeans are substantial and exceed socio-demographic differentials in excessive body weight. Obesity is associated with significantly poorer health outcomes among Europeans aged 50 years and over, with effects similar across countries. Large heterogeneity in obesity throughout Europe should be investigated further to identify areas for effective public policy. (C) 2007 Published by Elsevier Ltd on behalf of The Royal Institute of Public Health.

Marine omega-3 fatty acids and coronary heart disease

Purpose of review: To provide an overview of the key earlier intervention studies with marine omega-3 fatty acids and to review and comment on recent studies reporting on mortality outcomes and on selected underlying mechanisms of action. Recent findings: Studies relating marine omega-3 fatty acid status to current or future outcomes continue to indicate benefits, for example, on incident heart failure, congestive heart failure, acute coronary syndrome, and all-cause mortality. New mechanistic insights into the actions of marine omega-3 fatty acids have been gained. Three fairly large secondary prevention trials have not confirmed the previously reported benefit of marine omega-3 fatty acids towards mortality in survivors of myocardial infarction. Studies of marine omega-3 fatty acids in atrial fibrillation and in cardiac surgery-induced atrial fibrillation have produced inconsistent findings and meta-analyses demonstrate no benefit. A study confirmed that marine omega-3 fatty acids reduce the inflammatory burden with advanced atherosclerotic plaques, so inducing greater stability. Summary: Recent studies of marine omega-3 fatty acids on morbidity of, and mortality from, coronary and cardiovascular disease have produced mixed findings. These studies raise new issues to be addressed in future research.

Menopausal status: A possible predictive factor for recurrence in women with cancer of the uterine cervix without pelvic lymph node metastasis

Objectives: To evaluate risk factors for recurrence of carcinoma of the uterine cervix among women who had undergone radical hysterectomy without pelvic lymph node metastasis, while taking into consideration not only the classical histopathological factors but also sociodemographic, clinical and treatment-related factors. Study design: This was an exploratory analysis on 233 women with carcinoma of the uterine cervix (stages IB and IIA) who were treated by means of radical hysterectomy and pelvic lymphadenectomy, with free surgical margins and without lymph node metastases on conventional histopathological examination. Women with histologically normal lymph nodes but with micrometastases in the immunohistochemical analysis (AE1/AE3) were excluded. Disease-free survival for sociodemographic, clinical and histopathological variables was calculated using the Kaplan-Meier method. The Cox proportional hazards model was used to identify the independent risk factors for recurrence. Results: Twenty-seven recurrences were recorded (11.6%), of which 18 were pelvic, four were distant, four were pelvic + distant and one was of unknown location. The five-year disease-free survival rate among the study population was 88.4%. The independent risk factors for recurrence in the multivariate analysis were: postmenopausal status (HR 14.1; 95% CI: 3.7-53.6; P < 0.001), absence of or slight inflammatory reaction (HR 7.9; 95% CI: 1.7-36.5; P = 0.008) and invasion of the deepest third of the cervix (FIR 6.1; 95% CI: 1.3-29.1; P = 0.021). Postoperative radiotherapy was identified as a protective factor against recurrence (HR 0.02; 95% CI: 0.001-0.25; P = 0.003). Conclusion: Postmenopausal status is a possible independent risk factor for recurrence even when adjusted for classical prognostic factors (such as tumour size, depth of turnout invasion, capillary embolisation) and treatment-related factors (period of treatment and postoperative radiotherapy status). (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Copy number variants on the X chromosome in women with primary ovarian insufficiency

Objective: To investigate whether submicroscopic copy number variants (CNVs) on the X chromosome can be identified in women with primary ovarian insufficiency (POI), defined as spontaneous secondary amenorrhea before 40 years of age accompanied by follicle-stimulating hormone levels above 40 IU/L on at least two occasions. Design: Analysis of intensity data of single nucleotide polymorphism (SNP) probes generated by genomewide Illumina 370k CNV BeadChips, followed by the validation of identified loci using a custom designed ultra-high-density comparative genomic hybridization array containing 48,325 probes evenly distributed over the X chromosome. Setting: Multicenter genetic cohort study in the Netherlands. Patient(s): 108 Dutch Caucasian women with POI, 97 of whom passed quality control, who had a normal karyogram and absent fragile X premutation, and 235 healthy Dutch Caucasian women as controls. Intervention(s): None. Main Outcome Measure(s): Amount and locus of X chromosomal microdeletions or duplications. Result(s): Intensity differences between SNP probes identify microdeletions and duplications. The initial analysis identified an overrepresentation of deletions in POI patients. Moreover, CNVs in two genes on the Xq21.3 locus (i.e., PCDH11X and TGIF2LX) were statistically significantly associated with the POI phenotype. Mean size of identified CNVs was 262 kb. However, in the validation study the identified putative Xq21.3 deletions samples did not show deviations in intensities in consecutive probes. Conclusion(s): X chromosomal submicroscopic CNVs do not play a major role in Caucasian POI patients. We provide guidelines on how submicroscopic cytogenetic POI research should be conducted. (Fertil Steril (R) 2011;95:1584-8. (C) 2011 by American Society for Reproductive Medicine.)

Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease

Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.

Association between levels of pentraxin 3 and incidence of chronic kidney disease in the elderly

OBJECTIVE: Higher levels of the novel inflammatory marker pentraxin 3 (PTX3) predict cardiovascular mortality in patients with chronic kidney disease (CKD). Yet, whether PTX3 predicts worsening of kidney function has been less well studied. We therefore investigated the associations between PTX3 levels, kidney disease measures and CKD incidence. METHODS: Cross-sectional associations between serum PTX3 levels, urinary albumin/creatinine ratio (ACR) and cystatin C-estimated glomerular filtration rate (GFR) were assessed in two independent community-based cohorts of elderly subjects: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 768, 51% women, mean age 75 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 651, mean age 77 years). The longitudinal association between PTX3 level at baseline and incident CKD (GFR <60 mL( ) min(-1)  1.73 m(-) ²) was also analysed (number of events/number at risk: PIVUS 229/746, ULSAM 206/315). RESULTS: PTX3 levels were inversely associated with GFR [PIVUS: B-coefficient per 1 SD increase -0.16, 95% confidence interval (CI) -0.23 to -0.10, P < 0.001; ULSAM: B-coefficient per 1 SD increase -0.09, 95% CI -0.16 to -0.01, P < 0.05], but not ACR, after adjusting for age, gender, C-reactive protein and prevalent cardiovascular disease in cross-sectional analyses. In longitudinal analyses, PTX3 levels predicted incident CKD after 5 years in both cohorts [PIVUS: multivariable odds ratio (OR) 1.21, 95% CI 1.01-1.45, P < 0.05; ULSAM: multivariable OR 1.37, 95% CI 1.07-1.77, P < 0.05]. CONCLUSIONS: Higher PTX3 levels are associated with lower GFR and independently predict incident CKD in elderly men and women. Our data confirm and extend previous evidence suggesting that inflammatory processes are activated in the early stages of CKD and drive impairment of kidney function. Circulating PTX3 appears to be a promising biomarker of kidney disease.

TRAIL-R3-related apoptosis: Epigenetic and expression analyses in women with ovarian neoplasia

Objective. To assess the expression of TRAIL-R3 and the methylation of a CpG island within the TRAIL-R3 promoter both in cystadenoma tumors and primary and metastatic epithelial ovarian carcinoma (EOC).Methods. RNA was obtained from women with normal ovarian (NO) tissues (n = 18), ovarian serous cystadenoma tumors (n = 11) and EOC (n = 16) using Trizol (R). Quantitative PCR (gRT-PCR) was performed to quantify the relative levels of TRAIL-R3. The methylation frequency of the CpG island in the TRAIL-R3 promoter was assessed using the methylation-specific PCR (MSP) assay after DNA bisulfite conversion. The differences between the groups were evaluated using the chi-square, Student's t, ANOVA, Mann-Whitney U, Wilcoxon or Kruskal-Wallis tests as indicated. The survival rates were calculated using the Kaplan-Meier method.Results. Cystadenoma and metastatic EOC tumors expressed significantly more TRAIL-R3 mRNA than primary EOC tumors. Methylation of the TRAIL-R3 promoter was absent in NO tissues, while hemimethylation of the TRAIL-R3 promoter was frequently found in the neoplasia samples with 45.4% of the cystadenoma tumors, 8.3% of the primary EOC samples and 11.1% of the metastatic EOC samples showing at least partial methylation (p = 0.018). Neither the expression of TRAIL-R3 nor alterations in the methylation profile were associated to cumulative progression-free survival or the overall survival in EOC patients.Conclusions. Primary EOC is associated to a lower TRAIL-R3 expression, which leads to a better understanding of the complex disease and highlighting potential therapeutic targets. Promoter DNA methylation was not related to this finding, suggesting the presence of other mechanisms to transcriptional control. (C) 2012 Elsevier B.V. All rights reserved.

Frequency of coronary artery disease in patients with renal artery stenosis without clinical manifestations of coronary insufficiency

Atherosclerotic renal artery stenosis (RAS) and coronary artery disease (CAD) arise from the same multiple risk factors. The purpose of this study was to assess the frequency of previously undiagnosed CAD in patients with angiographically confirmed RAS, by conducting coronary arteriography in the same setting. of 57 consecutive patients referred for renal arteriography on clinical grounds during a 14-month period, 28 had no RAS and 6 had RAS, but previously documented CAD. of the remainder 23 patients. 17 (74%; CI 56%-92%) had both RAS and CAD (7 single vessel, 4 two-vessel, and 7 multivessel disease). The clinical characteristics, such as age, blood pressure (BP) levels, signs of heart failure, were no different between those with and without CAD, although the 4 diabetic patients, the 4 patients with fundoscopic findings of grade III retinopathy, 11 of 14 with peripheral arterial disease, and 7 of 8 patients with prior stroke belonged in the CAD group. None developed complications as a result of the two consecutive procedures. The data suggest that in patients with RAS the frequency of silent CAD is high and cannot be predicted on clinical grounds alone, therefore coronary angiography should be routinely recommended in the same setting.

Effect of total abdominal hysterectomy on ovarian blood supply in women of reproductive age

Objective. The purpose of this study was to evaluate the effect of total abdominal hysterectomy on ovarian blood supply using transvaginal color Doppler ultrasonography in women of reproductive age. Methods. This prospective study included 61 women aged 40 years or younger who were divided into 2 groups: group 1, comprising 31 patients who underwent total abdominal hysterectomy (TAH), and group 2, comprising 30 women with no abnormalities. Inclusion criteria included normal ovarian function at baseline, with basal follicle-stimulating hormone levels of less than 15 mUI/mL, normal body weight, no tobacco use, and no history of laparotomy or ovarian disease. Ovarian arterial blood supply by determination of the pulsatility index (PI) on Doppler analysis and ovarian volume on transvaginal ultrasonography were assessed at baseline and at 6 and 12 postoperative months. The Student t test, profile analysis, and Friedman and Mann-Whitney tests were used in the statistical analysis of data. Results. Statistical analysis of baseline data revealed that both groups were homogeneous. At months 6 and 12, greater ovarian volumes and lower PI values were observed in patients who underwent TAH (P < .05). By the end of the study, in 8 of the 31 patients who underwent TAH (25.5%), benign ovarian cysts were observed. in the control group, all the parameters studied remained unchanged. Conclusions. The reduced PI values observed on Doppler ultrasonography suggested a decrease in the resistance flow in the ovarian arteries in women of reproductive age who underwent TAH.

Pancreatic β-cell defects in women at risk of type 2 diabetes

We evaluated insulin release and insulin sensitivity in women with basal and/or postprandial hyperglycemia but normal oral glucose tolerance test (OGTT) in previous pregnancy (GHG). These women were individually matched with females without previous hyperglycemia (NGT). Both groups consisted of normal glucose-tolerant women at the time of this study. They underwent OGTT (75g; n= 32 pairs) and hyperglycemic clamp experiments (10mmoll-1; n=27 pairs) with plasma glucose, insulin, and C-peptide measurements and calculation of insulinogenic index, first- and second-phase insulin release, and insulin sensitivity index (ISI). The GHG group showed higher glycosylated hemoglobin levels (6.2±0.6% versus 5.8±0.8%; P<0.05); lower insulinogenic index at 30min (134.03±62.69pmolmmol-1 versus 181.59±70.26pmolmmoll-1; P<0.05) and diminished C-peptide response in relation to glucose (4.05±0.36nmolmmol-1 versus 4.23±0.36nmolmmol-1; P<0.05) at OGTT. Both groups did not show difference in insulin secretion and ISI by hyperglycemic clamp technique. We concluded that in up to 12 years from index pregnancy, women with previous GHG, presenting normal glucose tolerance and well-matched with their controls, showed β-cell dysfunction without change in ISI. As women with previous GHG are at risk of type 2 diabetes, β-cell dysfunction may be its primary defect. © 2003 Elsevier B.V. All rights reserved.