Adult Patients with Congenital Adrenal Hyperplasia Have Elevated Blood Pressure but Otherwise a Normal Cardiovascular Risk Profile

Contains fulltext : 96615.pdf (publisher's version ) (Open Access)OBJECTIVE: Treatment with glucocorticoids and mineralocorticoids has changed congenital adrenal hyperplasia (CAH) from a fatal to a chronic lifelong disease. Long-term treatment, in particular the chronic (over-)treatment with glucocorticoids, may have an adverse effect on the cardiovascular risk profile in adult CAH patients. The objective of this study was to evaluate the cardiovascular risk profile of adult CAH patients. DESIGN: Case-control study. PATIENTS AND MEASUREMENTS: In this case-control study the cardiovascular risk profile of 27 adult CAH patients and 27 controls, matched for age, sex and body mass index was evaluated by measuring ambulatory 24-hour blood pressure, insulin sensitivity (HOMA-IR), lipid profiles, albuminuria and circulating cardiovascular risk markers (PAI-1, tPA, uPA, tPA/PAI-1 complex, hsCRP, adiponectin, IL-6, IL-18 and leptin). RESULTS: 24-Hour systolic (126.3 mmHg+/-15.5 vs 124.8 mmHg+/-15.1 in controls, P = 0.019) and diastolic (76.4 mmHg+/-12.7 vs 73.5 mmHg+/-12.4 in controls, P<0.001) blood pressure was significantly elevated in CAH patients compared to the control population. CAH patients had higher HDL cholesterol levels (P<0.01), lower hsCRP levels (P = 0.03) and there was a trend toward elevated adiponectin levels compared to controls. Other cardiovascular risk factors were similar in both groups. CONCLUSION: Adult CAH patients have higher ambulatory blood pressure compared to healthy matched controls. Other cardiovascular risk markers did not differ, while HDL-cholesterol, hsCRP and adiponectin levels tended to be more favorable

An absolute sodium abundance for a cloud-free 'hot Saturn' exoplanet.

Broad absorption signatures from alkali metals, such as the sodium (Na I) and potassium (K I) resonance doublets, have long been predicted in the optical atmospheric spectra of cloud-free irradiated gas giant exoplanets1-3. However, observations have revealed only the narrow cores of these features rather than the full pressure-broadened profiles4-6. Cloud and haze opacity at the day-night planetary terminator are considered to be responsible for obscuring the absorption-line wings, which hinders constraints on absolute atmospheric abundances7-9. Here we report an optical transmission spectrum for the 'hot Saturn' exoplanet WASP-96b obtained with the Very Large Telescope, which exhibits the complete pressure-broadened profile of the sodium absorption feature. The spectrum is in excellent agreement with cloud-free, solar-abundance models assuming chemical equilibrium. We are able to measure a precise, absolute sodium abundance of logεNa = [Formula: see text], and use it as a proxy for the planet's atmospheric metallicity relative to the solar value (Zp/Zʘ = [Formula: see text]). This result is consistent with the mass-metallicity trend observed for Solar System planets and exoplanets10-12

Hippocampal Gene Expression Analysis Highlights Ly6a/Sca-1 as Candidate Gene for Previously Mapped Novelty Induced Behaviors in Mice

In this study, we show that the covariance between behavior and gene expression in the brain can help further unravel the determinants of neurobehavioral traits. Previously, a QTL for novelty induced motor activity levels was identified on murine chromosome 15 using consomic strains. With the goal of narrowing down the linked region and possibly identifying the gene underlying the quantitative trait, gene expression data from this F2-population was collected and used for expression QTL analysis. While genetic variation in these mice was limited to chromosome 15, eQTL analysis of gene expression showed strong cis-effects as well as trans-effects elsewhere in the genome. Using weighted gene co-expression network analysis, we were able to identify modules of co-expressed genes related to novelty induced motor activity levels. In eQTL analyses, the expression of Ly6a (a.k.a. Sca-1) was found to be cis-regulated by chromosome 15. Ly6a also surfaced in a group of genes resulting from the network analysis that was correlated with behavior. Behavioral analysis of Ly6a knock-out mice revealed reduced novelty induced motor activity levels when compared to wild type controls, confirming functional importance of Ly6a in this behavior, possibly through regulating other genes in a pathway. This study shows that gene expression profiling can be used to narrow down a previously identified behavioral QTL in mice, providing support for Ly6a as a candidate gene for functional involvement in novelty responsiveness

A survey on independence-based Markov networks learning

This work reports the most relevant technical aspects in the problem of learning the \emph{Markov network structure} from data. Such problem has become increasingly important in machine learning, and many other application fields of machine learning. Markov networks, together with Bayesian networks, are probabilistic graphical models, a widely used formalism for handling probability distributions in intelligent systems. Learning graphical models from data have been extensively applied for the case of Bayesian networks, but for Markov networks learning it is not tractable in practice. However, this situation is changing with time, given the exponential growth of computers capacity, the plethora of available digital data, and the researching on new learning technologies. This work stresses on a technology called independence-based learning, which allows the learning of the independence structure of those networks from data in an efficient and sound manner, whenever the dataset is sufficiently large, and data is a representative sampling of the target distribution. In the analysis of such technology, this work surveys the current state-of-the-art algorithms for learning Markov networks structure, discussing its current limitations, and proposing a series of open problems where future works may produce some advances in the area in terms of quality and efficiency. The paper concludes by opening a discussion about how to develop a general formalism for improving the quality of the structures learned, when data is scarce.Comment: 35 pages, 1 figur

National and firm-level drivers of the devolution of HRM decision making to line managers

Multinational companies must understand the influences on responsibility for managing people so that they can manage talent consistently thus ensuring that it is transferable across locations. We examine the impact of firm and national level characteristics on the devolution of HRM decision making to line managers. Our analysis draws on data from 2335 indigenous organizations in 21 countries. At the firm level, we found that where the HR function has higher power, devolution is less likely. At the national level, devolution of decision making to line management is more likely in societies with more stringent employment laws and lower power distance

Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms

Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug—yohimbine, and an anti-anxiety drug—diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain–blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders—notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.Peer reviewe