Implication of chromosome 13 on hypertension and associated disorders in Lyon hypertensive rats.

BACKGROUND: Hypertension and associated disorders are major risk factors for cardiovascular disease. The Lyon hypertensive rat (LH) is a genetically hypertensive strain that exhibits spontaneous and salt-sensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia, and elevated insulin-to-glucose ratio. Previous genetic mapping identified quantitative trait loci (QTLs) influencing blood pressure (BP) on rat chromosome 13 (RNO13) in several models of hypertension. METHODS: To study the effects of a single chromosome on the mapped traits, we generated consomic strains by substituting LH RNO13 with that of the normotensive Brown Norway (BN) strain (LH-13BN) and reciprocal consomics by substituting a BN RNO13 with that of LH (BN-13LH). These reciprocal consomic strains, as well as the two parental strains were characterized for BP, metabolic and morphological parameters. RESULTS: Compared with LH parents, LH-13BN rats showed decreased mean BP (up to -24 mmHg on 2% NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13LH and BN rats were much smaller than those observed between LH-13BN and LH rats, demonstrating the effects of the highly resistant BN genome background. Plasma renin activity was not affected by the substitution of RNO13, despite the significant BP differences. CONCLUSION: The present work demonstrates that RNO13 is a determinant of BP, proteinuria, and plasma lipids in the LH rat. The distinct phenotypic differences between the consomic LH-13BN and the LH make it a powerful model to determine genes and pathways leading to these risk factors for cardiovascular and renal disease.

Physical performance limitations in adolescent and adult survivors of childhood cancer and their siblings.

PURPOSE: This study investigates physical performance limitations for sports and daily activities in recently diagnosed childhood cancer survivors and siblings. METHODS: The Swiss Childhood Cancer Survivor Study sent a questionnaire to all survivors (≥ 16 years) registered in the Swiss Childhood Cancer Registry, who survived >5 years and were diagnosed 1976-2003 aged <16 years. Siblings received similar questionnaires. We assessed two types of physical performance limitations: 1) limitations in sports; 2) limitations in daily activities (using SF-36 physical function score). We compared results between survivors diagnosed before and after 1990 and determined predictors for both types of limitations by multivariable logistic regression. RESULTS: The sample included 1038 survivors and 534 siblings. Overall, 96 survivors (9.5%) and 7 siblings (1.1%) reported a limitation in sports (Odds ratio 5.5, 95%CI 2.9-10.4, p<0.001), mainly caused by musculoskeletal and neurological problems. Findings were even more pronounced for children diagnosed more recently (OR 4.8, CI 2.4-9.6 and 8.3, CI 3.7-18.8 for those diagnosed <1990 and ≥ 1990, respectively; p=0.025). Mean physical function score for limitations in daily activities was 49.6 (CI 48.9-50.4) in survivors and 53.1 (CI 52.5-53.7) in siblings (p<0.001). Again, differences tended to be larger in children diagnosed more recently. Survivors of bone tumors, CNS tumors and retinoblastoma and children treated with radiotherapy were most strongly affected. CONCLUSION: Survivors of childhood cancer, even those diagnosed recently and treated with modern protocols, remain at high risk for physical performance limitations. Treatment and follow-up care should include tailored interventions to mitigate these late effects in high-risk patients.

The clc element and related genomic islands in Proteobacteria

Genomic islands are large DNA segments, present in most bacterial genome, that are acquired via horizontal gene transfer and contribute to the rapid bacterial evolution and adaptation of the host cell. Here we focus on the clc element (or ICEclc), a 103‑kb genomic island first discovered in Pseudomonas knackmussii B13, as a model of this diverse group of mobile genetic elements. ICEclc is normally integrated in the host bacterial chromosome but can excise and transfer to a new host by conjugation. In this chapter we review the basic features of ICEclc, the mechanisms of its life‑style as well as evolutionary relationships with other known and unknown elements in a variety of Proteobacteria.

Genetic factors of obesity and eating disorders: Copy number variations (CNV) involving SH2B1

Context : It is now clearly shown that genetic factors in association with environment play a key role in obesity and eating disorders. This project studies the clinical symptoms and molecular abnormalities in patients carrying a strong hereditary predisposition to obesity and eating behavior disorders. We have previously published the association between the 16:29.5-30.1 deletion and a very penetrant form of morbid obesity and macrocephaly. We have also demonstrated the association between the reciprocal 16:29.5-30.1 duplication and underweight and small head circumference. These 2 studies demonstrate that gene dosage of one or several genes in this region regulates BMI as well as brain growth. At present, there are no data pointing towards particular candidate genes. We are currently investigating a second non-overlapping recurrent CNV encompassing SH2B1, upstream of the aforementioned rearrangement. SNPs in this gene have been associated with BMI in GWAS studies and mice models confirmed this association. Bokuchova et al have reported an association between deletions encompassing this gene and severe early onset obesity, as well as insulin resistance. We are currently collecting and analyzing data to fully characterize the phenotype and the transcriptional patterns associated with this rearrangement. Aims : 1. Identify carriers of any CNVs in the greater 16p11.2 region (between 16:28MB and 32MB) in the EGG consortium. 2. Perform association studies between SNPs in the greater 16p11.2 region (16:28-32MB) and anthropometric measures with adjusted "locus-wide significance", to identify or prioritize candidate genes potentially driving the association observed in patients with the CNVs (and thus worthy of further validation and sequencing). 3. Explore associations between GSV genome-wide and brain volume. 4. Explore relationship between brain volumes (whole brain and regional for those who underwent brain MRI), head circumference and BMI. 5. Extrapolate this procedure to other regions covered by the Metabochip. Methods : - Examine and collect clinical informations, as well as molecular informations in these patients. - Analysis of MRI data in children and adults with BMI > 2SD. Compare changes to MRI data obtained in patients with monogenic forms of obesity (data from Lausanne study) and to underweight (BMI<-2SD) individuals from EGG. - Test whether opposite extremes of the phenotypic distribution may be highly informative Expected results : This is a highly focused study, pertaining to approximately 1 0/00 of the human genome. Yet it is clear that if successful, the lessons learned from this study could be extrapolated to other segments of the genome and would need validation and replication by additional studies. Altogether they will contribute to further explore the missing heritability and point to etiologic genes and pathways underlying these important health burdens.

Personality and personality disorders in urban and rural Africa: results from a field trial in Burkina Faso

When conducting research in different cultural settings, assessing measurement equivalence is of prime importance to determine if constructs and scores can be compared across groups. Structural equivalence implies that constructs have the same meaning across groups, metric equivalence implies that the metric of the scales remains stable across groups, and full scale or scalar equivalence implies that the origin of the scales is the same across groups. Several studies have observed that the structure underlying both normal personality and personality disorders (PDs) is stable across cultures. Most of this cross-cultural research was conducted in Western and Asian cultures. In Africa, the few studies were conducted with well-educated participants using French or English instruments. No research was conducted in Africa with less privileged or preliterate samples. The aim of this research was to study the structure and expression of normal and abnormal personality in an urban and a rural sample in Burkina Faso. The sample included 1,750 participants, with a sub-sample from the urban area of Ouagadougou (n = 1,249) and another sub-sample from a rural village, Soumiaga (n = 501). Most participants answered an interview consisting of a Mooré language adaptation of the Revised NEO Personality Inventory and of the International Personality Disorders Examination. Mooré is the language of the Mossi ethnic group, and the most frequently spoken local language in Burkina Faso. A sub-sample completed the same self-report instruments in French. Demographic variables only had a small impact on normal and abnormal personality traits mean levels. The structure underlying normal personality was unstable across regions and languages, illustrating that translating a complex psychological inventory into a native African language is a very difficult task. The structure underlying abnormal personality and the metric of PDs scales were stable across regions. As scalar equivalence was not reached, mean differences cannot be interpreted. Nevertheless, these differences could be due to an exaggerated expression of abnormal traits valued in the two cultural settings. Our results suggest that studies using a different methodology should be conducted to understand what is considered, in different cultures, as deviating from the expectations of the individual's culture, and as a significant impairment in self and interpersonal functioning, as defined by the DSM-5.

Ruin and related quantities in some advanced insurance risk models

Risk theory has been a very active research area over the last decades. The main objectives of the theory are to find adequate stochastic processes which can model the surplus of a (non-life) insurance company and to analyze the risk related quantities such as ruin time, ruin probability, expected discounted penalty function and expected discounted dividend/tax payments. The study of these ruin related quantities provides crucial information for actuaries and decision makers. This thesis consists of the study of four different insurance risk models which are essentially related. The ruin and related quantities are investigated by using different techniques, resulting in explicit or asymptotic expressions for the ruin time, the ruin probability, the expected discounted penalty function and the expected discounted tax payments. - La recherche en théorie du risque a été très dynamique au cours des dernières décennies. D'un point de vue théorique, les principaux objectifs sont de trouver des processus stochastiques adéquats permettant de modéliser le surplus d'une compagnie d'assurance non vie et d'analyser les mesures de risque, notamment le temps de ruine, la probabilité de ruine, l'espérance de la valeur actuelle de la fonction de pénalité et l'espérance de la valeur actuelle des dividendes et taxes. L'étude de ces mesures associées à la ruine fournit des informations cruciales pour les actuaires et les décideurs. Cette thèse consiste en l'étude des quatre différents modèles de risque d'assurance qui sont essentiellement liés. La ruine et les mesures qui y sont associées sont examinées à l'aide de différentes techniques, ce qui permet d'induire des expressions explicites ou asymptotiques du temps de ruine, de la probabilité de ruine, de l'espérance de la valeur actuelle de la fonction de pénalité et l'espérance de la valeur actuelle des dividendes et taxes.

Durée et structure du sommeil et risques métaboliques et cardiovasculaires = [Sleep structure and cardiometabolic disorders]

Introduction : Plusieurs études épidémiologiques et de laboratoire basées sur des estimations subjectives de la durée et de la qualité du sommeil suggèrent que celles-ci pourraient être associées à une augmentation du risque de troubles métaboliques ou cardiovasculaires. Objectif : Dans cette étude nous avons examiné les associations entre les caractéristiques du sommeil évaluées objectivement par Polysomnographie (PSG) et le syndrome métabolique ainsi que ses composants (hypertension, diabète, obésité). Matériel et méthodes : Nous avons analysé les données de 2162 sujets de la population générale (dont le 51.2% étaient des femmes, âge moyen : 58.4±11.1 ans, fourchette d'âge: 40.5-84.4) qui ont participé à l'étude Hypnolaus. Tous les sujets ont eu une évaluation clinique et biologique et ils ont bénéficié d'une PSG complète à domicile. Résultats : Les analyses univariées ont montré que les sujets présentant un syndrome métabolique avaient une diminution du temps total de sommeil, du sommeil lent profond, du sommeil paradoxal et de l'efficacité du sommeil, ainsi qu'une augmentation de l'index de microéveils par rapport aux sujets qui n'avaient pas un syndrome métabolique. Nous avons aussi trouvé des différences significatives de la structure du sommeil en fonction de la présence ou de l'absence d'hypertension, de diabètes et de surpoids/obésité. Cependant, ces différences s'atténuent après ajustement pour des facteurs confondants (âge, genre, tabagisme, prise d'alcool, activité physique, médicaments qui affectent le sommeil, dépression, santé globale et indice de masse corporelle). Seules des différences marginales, non statistiquement significatives, persistaient dans le modèle multiajusté et après stratification en fonction de la présence de troubles respiratoires au cours du sommeil. Conclusions: Dans cet échantillon de la population générale nous avons mis en évidence des associations significatives entre la structure du sommeil et le syndrome métabolique ainsi que ses composants. Cependant, ces associations ne sont pas indépendantes des autres facteurs de risque cardiométabolique connus. Nous en concluons que les variations normales de la durée et de la structure du sommeil contribuent peu ou pas au syndrome métabolique et ses troubles associés.

Effectiveness of anti-psychotics and related drugs in the Huntington French-speaking group cohort.

PURPOSE: Huntington's disease is a rare condition. Patients are commonly treated with antipsychotics and tetrabenazine. The evidence of their effect on disease progression is limited and no comparative study between these drugs has been conducted. We therefore compared the effectiveness of antipsychotics on disease progression. METHODS: 956 patients from the Huntington French Speaking Group were followed for up to 8 years between 2002 and 2010. The effectiveness of treatments was assessed using Unified Huntington's Disease Rating Scale (UHDRS) scores and then compared using a mixed model adjusted on a multiple propensity score. RESULTS: 63% of patients were treated with antipsychotics during the survey period. The most commonly prescribed medications were dibenzodiazepines (38%), risperidone (13%), tetrabenazine (12%) and benzamides (12%). There was no difference between treatments on the motor and behavioural declines observed, after taking the patient profiles at the start of the drug prescription into account. In contrast, the functional decline was lower in the dibenzodiazepine group than the other antipsychotic groups (Total Functional Capacity: 0.41 ± 0.17 units per year vs. risperidone and 0.54 ± 0.19 vs. tetrabenazine, both p<0.05). Benzamides were less effective than other antipsychotics on cognitive evolution (Stroop interference, Stroop color and Literal fluency: p<0.05). CONCLUSIONS: Antipsychotics are widely used to treat patients with Huntington's disease. Although differences in motor or behavioural profiles between patients according to the antipsychotics used were small, there were differences in drug effectiveness on the evolution of functional and cognitive scores.

Childhood cancer and nuclear power plants in Switzerland: a census-based cohort study.

BACKGROUND: Previous studies on childhood cancer and nuclear power plants (NPPs) produced conflicting results. We used a cohort approach to examine whether residence near NPPs was associated with leukaemia or any childhood cancer in Switzerland. METHODS: We computed person-years at risk for children aged 0-15 years born in Switzerland from 1985 to 2009, based on the Swiss censuses 1990 and 2000 and identified cancer cases from the Swiss Childhood Cancer Registry. We geo-coded place of residence at birth and calculated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing the risk of cancer in children born <5 km, 5-10 km and 10-15 km from the nearest NPP with children born >15 km away, using Poisson regression models. RESULTS: We included 2925 children diagnosed with cancer during 21 117 524 person-years of follow-up; 953 (32.6%) had leukaemia. Eight and 12 children diagnosed with leukaemia at ages 0-4 and 0-15 years, and 18 and 31 children diagnosed with any cancer were born <5 km from a NPP. Compared with children born >15 km away, the IRRs (95% CI) for leukaemia in 0-4 and 0-15 year olds were 1.20 (0.60-2.41) and 1.05 (0.60-1.86), respectively. For any cancer, corresponding IRRs were 0.97 (0.61-1.54) and 0.89 (0.63-1.27). There was no evidence of a dose-response relationship with distance (P > 0.30). Results were similar for residence at diagnosis and at birth, and when adjusted for potential confounders. Results from sensitivity analyses were consistent with main results. CONCLUSIONS: This nationwide cohort study found little evidence of an association between residence near NPPs and the risk of leukaemia or any childhood cancer.

On solving fair exchange and related distributed problems in Byzantine environments

Abstract The solvability of the problem of fair exchange in a synchronous system subject to Byzantine failures is investigated in this work. The fair exchange problem arises when a group of processes are required to exchange digital items in a fair manner, which means that either each process obtains the item it was expecting or no process obtains any information on, the inputs of others. After introducing a novel specification of fair exchange that clearly separates safety and liveness, we give an overview of the difficulty of solving such a problem in the context of a fully-connected topology. On one hand, we show that no solution to fair exchange exists in the absence of an identified process that every process can trust a priori; on the other, a well-known solution to fair exchange relying on a trusted third party is recalled. These two results lead us to complete our system model with a flexible representation of the notion of trust. We then show that fair exchange is solvable if and only if a connectivity condition, named the reachable majority condition, is satisfied. The necessity of the condition is proven by an impossibility result and its sufficiency by presenting a general solution to fair exchange relying on a set of trusted processes. The focus is then turned towards a specific network topology in order to provide a fully decentralized, yet realistic, solution to fair exchange. The general solution mentioned above is optimized by reducing the computational load assumed by trusted processes as far as possible. Accordingly, our fair exchange protocol relies on trusted tamperproof modules that have limited communication abilities and are only required in key steps of the algorithm. This modular solution is then implemented in the context of a pedagogical application developed for illustrating and apprehending the complexity of fair exchange. This application, which also includes the implementation of a wide range of Byzantine behaviors, allows executions of the algorithm to be set up and monitored through a graphical display. Surprisingly, some of our results on fair exchange seem contradictory with those found in the literature of secure multiparty computation, a problem from the field of modern cryptography, although the two problems have much in common. Both problems are closely related to the notion of trusted third party, but their approaches and descriptions differ greatly. By introducing a common specification framework, a comparison is proposed in order to clarify their differences and the possible origins of the confusion between them. This leads us to introduce the problem of generalized fair computation, a generalization of fair exchange. Finally, a solution to this new problem is given by generalizing our modular solution to fair exchange

Interobserver agreement and validity of bedside 'positive signs' for functional weakness, sensory and gait disorders in conversion disorder: a pilot study.

BACKGROUND: Conversion disorder (CD) is no longer a diagnosis of exclusion. The new DSM-V criteria highlight the importance of 'positive signs' on neurological examination. Only few signs have been validated, and little is known about their reliability. OBJECTIVE: The aim was to examine the clinical value of bedside positive signs in the diagnosis of CD presenting with weakness, gait or sensory symptoms by assessing their specificity, sensitivity and their inter-rater reliability. PATIENTS AND METHODS: Standardised video recorded neurological examinations were performed in 20 consecutive patients with CD and 20 'organic' controls. Ten previously validated sensory and motor signs were grouped in a scale. Thirteen additional motor/sensory 'positive signs', 14 gait patterns and 1 general sign were assessed in a pilot validation study. In addition, two blinded independent neurologists rated the video recordings to assess the inter-rater reliability (Cohen's κ) of each sign. RESULTS: A score of ≥4/14 on the sensory motor scale showed a 100% specificity (CI 85 to 100) and a 95% sensitivity (CI 85 to 100). Among the additional tested signs, 10 were significantly more frequent in CD than controls. The interobserver agreement was acceptable for 23/38 signs (2 excellent, 10 good, 11 moderate). CONCLUSIONS: Our study confirms that six bedside 'positive signs' are highly specific for CD with good-excellent inter-rater reliability; we propose to consider them as 'highly reliable signs'. In addition 13 signs could be considered as 'reliable signs' and six further signs as 'suggestive signs' while all others should be used with caution until further validation is available.

Endometrial cancer and oral contraceptives : an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies.

BACKGROUND: Oral contraceptives are known to reduce the incidence rate of endometrial cancer, but it is uncertain how long this effect lasts after use ceases, or whether it is modified by other factors. METHODS: Individual participant datasets were sought from principal investigators and provided centrally for 27 276 women with endometrial cancer (cases) and 115 743 without endometrial cancer (controls) from 36 epidemiological studies. The relative risks (RRs) of endometrial cancer associated with oral contraceptive use were estimated using logistic regression, stratified by study, age, parity, body-mass index, smoking, and use of menopausal hormone therapy. FINDINGS: The median age of cases was 63 years (IQR 57-68) and the median year of cancer diagnosis was 2001 (IQR 1994-2005). 9459 (35%) of 27 276 cases and 45 625 (39%) of 115 743 controls had ever used oral contraceptives, for median durations of 3·0 years (IQR 1-7) and 4·4 years (IQR 2-9), respectively. The longer that women had used oral contraceptives, the greater the reduction in risk of endometrial cancer; every 5 years of use was associated with a risk ratio of 0·76 (95% CI 0·73-0·78; p<0·0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased, with no apparent decrease between the RRs for use during the 1960s, 1970s, and 1980s, despite higher oestrogen doses in pills used in the early years. However, the reduction in risk associated with ever having used oral contraceptives differed by tumour type, being stronger for carcinomas (RR 0·69, 95% CI 0·66-0·71) than sarcomas (0·83, 0·67-1·04; case-case comparison: p=0·02). In high-income countries, 10 years use of oral contraceptives was estimated to reduce the absolute risk of endometrial cancer arising before age 75 years from 2·3 to 1·3 per 100 women. INTERPRETATION: Use of oral contraceptives confers long-term protection against endometrial cancer. These results suggest that, in developed countries, about 400 000 cases of endometrial cancer before the age of 75 years have been prevented over the past 50 years (1965-2014) by oral contraceptives, including 200 000 in the past decade (2005-14). FUNDING: Medical Research Council, Cancer Research UK.

Clinically meaningful parameters of progression and long-term outcome of Parkinson disease: An international consensus statement.

Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs.