Parkinson"s disease DJ-1 L166P alters rRNA biogenesis by exclusion of TTRAP from the nucleolus and sequestration into cytoplasmic aggregates via TRAF6

Mutations in PARK7/DJ-1 gene are associated to autosomal recessive early onset forms of Parkinson"s disease (PD). Although large gene deletions have been linked to a loss-of-function phenotype, the pathogenic mechanism of missense mutations is less clear. The L166P mutation causes misfolding of DJ-1 protein and its degradation. L166P protein may also accumulate into insoluble cytoplasmic aggregates with a mechanism facilitated by the E3 ligase TNF receptor associated factor 6 (TRAF6). Upon proteasome impairment L166P activates the JNK/p38 MAPK apoptotic pathway by its interaction with TRAF and TNF Receptor Associated Protein (TTRAP). When proteasome activity is blocked in the presence of wild-type DJ-1, TTRAP forms aggregates that are localized to the cytoplasm or associated to nucleolar cavities, where it is required for a correct rRNA biogenesis. In this study we show that in post-mortem brains of sporadic PD patients TTRAP is associated to the nucleolus and to Lewy Bodies, cytoplasmic aggregates considered the hallmark of the disease. In SH-SY5Y neuroblastoma cells, misfolded mutant DJ-1 L166P alters rRNA biogenesis inhibiting TTRAP localization to the nucleolus and enhancing its recruitment into cytoplasmic aggregates with a mechanism that depends in part on TRAF6 activity. This work suggests that TTRAP plays a role in the molecular mechanisms of both sporadic and familial PD. Furthermore, it unveils the existence of an interplay between cytoplasmic and nucleolar aggregates that impacts rRNA biogenesis and involves TRAF6

Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.

PFAPA syndrome is the most common autoinflammatory syndrome in children from Western countries. In spite of its strong familial clustering, its genetic basis and inheritance pattern are still unknown. We performed a comprehensive genetic study on 68 individuals from 14 families. Linkage analysis suggested a susceptibility locus on chromosome 8, but direct molecular sequencing did not support this initial statistical finding. Exome sequencing revealed the absence of any gene that was mutated in all patients. Exhaustive screening of genes involved in other autoinflammatory syndromes or encoding components of the human inflammasome showed no DNA variants that could be linked to PFAPA molecular pathology. Among these, the previously-reported missense mutation V198M in the NLRP3 gene was clearly shown not to co-segregate with PFAPA. Our results on this relatively large cohort indicate that PFAPA syndrome is unlikely to be a monogenic condition. Moreover, none of the several genes known to be involved in inflammation or in autoinflammatory disorders seem to be relevant, alone, to its etiology, suggesting that PFAPA results from oligogenic or complex inheritance of variants in multiple disease genes and/or non-genetic factors.

Improving the Prediction of Spontaneous and Post-thrombolytic Recanalization in Ischemic Stroke Patients.

BACKGROUND: Endovascular treatment for acute ischemic stroke patients was recently shown to improve recanalization rates and clinical outcome in a well-defined study population. Intravenous thrombolysis (IVT) alone is insufficiently effective to recanalize in certain patients or of little value in others. Accordingly, we aimed at identifying predictors of recanalization in patients treated with or without IVT. METHODS: In the observational Acute Stroke Registry and Analysis of Lausanne (ASTRAL) registry, we selected those stroke patients (1) with an arterial occlusion on computed tomography angiography (CTA) imaging, (2) who had an arterial patency assessment at 24 hours (CTA/magnetic resonance angiography/transcranial Doppler), and (3) who were treated with IVT or had no revascularization treatment. Based on 2 separate logistic regression analyses, predictors of spontaneous and post-thrombolytic recanalization were generated. RESULTS: Partial or complete recanalization was achieved in 121 of 210 (58%) thrombolyzed patients. Recanalization was associated with atrial fibrillation (odds ratio , 1.6; 95% confidence interval, 1.2-3.0) and absence of early ischemic changes on CT (1.1, 1.1-1.2) and inversely correlated with the presence of a significant extracranial (EC) stenosis or occlusion (.6, .3-.9). In nonthrombolyzed patients, partial or complete recanalization was significantly less frequent (37%, P < .01). The recanalization was independently associated with a history of hypercholesterolemia (2.6, 1.2-5.6) and the proximal site of the intracranial occlusion (2.5, 1.2-5.4), and inversely correlated with a decreased level of consciousness (.3, .1-.8), and EC (.3, .1-.6) and basilar artery pathology (.1, .0-.6). CONCLUSIONS: Various clinical findings, cardiovascular risk factors, and arterial pathology on acute CTA-based imaging are moderately associated with spontaneous and post-thrombolytic arterial recanalization at 24 hours. If confirmed in other studies, this information may influence patient selection toward the most appropriate revascularization strategy.

Late careers and the transition to retirement in Switzerland

A substantial body of life-course research has considered occupational trajectories in Switzerland focusing either on early or middle adulthood careers. However, the issue of the last working period and the retirement transition is receiving increasing attention for several reasons: the permanence of low birth rates associated with an ageing population, a high proportion of active old workers, continuous changes in the timing of retirements, and active ageing policies aiming at keeping people working after the state pension age. Moving forward on this topic, the present doctoral thesis aimed to offer new insights on the dynamics of the final career phase and the transition to retirement in Switzerland through a life-course approach. Concerning the main results, this thesis provides consistent evidences on the great influence of longterm familial and employment trajectories as well as individual positional factors on (i) the vulnerability during the last working period, (ii) the timing of retirement, (iii) the voluntariness of late retirement, and (iv) the financial well-being of retirees. In this way, this thesis offers significant contributions to the life-course, gender, and social policy research focused on ageing processes. -- Un ensemble considérable de recherches sur les parcours de vie a examiné les trajectoires professionnelles en Suisse, en mettant l'accent sur la carrière professionnelle des jeunes et, plus tard, à l'âge adulte. Toutefois, l'étude de la fin de la carrière professionnelle (c'est-à-dire de 50 ans jusqu'à la retraite) reçoit une attention croissante pour plusieurs raisons: la persistance du faible taux de natalité associé à une population vieillissante, la forte proportion de travailleurs âgés actifs, des évolutions continues dans le moment du départ à la retraite, et des politiques visant à maintenir les personnes âgées au travail après l'âge légal de la retraite. Pour aller de l'avant sur ce sujet, la présente thèse de doctorat vise à offrir de nouvelles perspectives sur la fin de carrière et la transition à la retraite en Suisse, en mobilisant les outils de la sociologie des parcours de vie. En ce qui concerne les principaux résultats, cette thèse fournit des preuves cohérentes sur la grande influence des trajectoires professionnelles et familiales ainsi que des facteurs positionnels sur (i) la vulnérabilité au cours de la période de travail avant la retraite, (ii) le moment de départ à la retraite, (iii) le caractère volontaire de la retraite tardive, et (iv) le bien-être financier des retraités. Ainsi, cette thèse fournit d'importantes contributions à la recherche sur les parcours de vie, sur les étu es genre, et sur les politiques sociales, focalisées sur le processus de vieillissement.

Violences en famille : quelles réponses institutionnelles ?

Si la famille est en général synonyme d'intimité et de relations de confiance, elle peut également être un lieu d'abus, de contrôle ou de violences. Les diverses formes de violences qui se déroulent dans la sphère privée ont été dénoncées dès les années 1970 par les mouvements féministes. Elles ont alors fait l'objet d'une variété de politiques et d'actions publiques ayant pour vocation de défendre et d'accompagner les victimes, de punir et soigner les agresseurs ou de rétablir des liens familiaux distendus. En s'attachant à la façon dont ces violences ont été définies dans des contextes différents, en Europe, en Amérique du Nord et en Amérique latine, cet article a pour ambition de donner à voir les perspectives variées que recouvrent des catégories d'action publique aussi diverses que violences conjugales, violences domestiques, violences intrafamiliales ou encore féminicides ou fémicides, et les conséquences que ces différentes visions du problème ont sur sa prise en charge. Largement influencé par les études genre et la sociologie des problèmes publics, cet article, notamment à travers la présentation des contributions qui composent ce numéro de la revue Enfances Familles Générations, entend questionner les notions de violences de genre dans le cadre familial, dont les frontières sont fluctuantes et investies de façon variée, ainsi que les formes d'institutionnalisation du problème et les solutions qui sont envisagées.

Statines en prévention primaire: comment décider avec le patient [Statins in primary prevention: how to share the decision?].

Long-term treatment of hypercholesterolemia with statins diminishes the risk of cardiovascular events. Statins are recommended in secondary prevention of cardiovascular disease. In the absence of preexisting cardiovascular disease, the decision to start a statin or not is most often made by the general practitioner and his patient. An interactive decision aid, developed by the Mayo Clinic, has just been translated in French and adapted to the Swiss epidemiology of cardiovascular risk factors, with the aim of promoting shared decision-making. This paper reviews the conditions and potential benefits of shared decision-making about statin therapy in primary prevention.

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Birth Weight, Working Memory and Epigenetic Signatures in IGF2 and Related Genes: A MZ Twin Study.

Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.

Mesure de l'impact de l'implication des proches aidants de patients hospitalises dans une unité de soins psychiatriques aigus sur eux-mêmes

Le but de cette étude est de mesurer ainsi que de qualifier l'impact de l'implication des proches aidants de patients hospitalisés dans des unités de soins psychiatriques aigus sur eux-mêmes. Le cadre conceptuel utilisé est celui du fardeau des familles de Schene (1990). Il différencie les parties objectives et subjectives du fardeau familial. La récolte de données a été réalisée à l'aide de l'Involvement Evaluation Questionnaire (IEQ). Les résultats de cette étude montrent que les proches aidants souffrent d'un niveau d'inquiétude élevé, 3.8 sur une échelle de Likert à 5 questions, ainsi que d'un niveau de tension à 2.44 sur une échelle de Likert à 5 questions. Des associations ont été trouvées. L'augmentation de la durée du trouble diminue l'inquiétude, avec une valeur ρ de 0.048. Le fait d'être habitué à la situation a également un impact en diminuant la tension, avec une valeur ρ de 0.002. Plus on est « habitué à la situation », avec une valeur ρ de -0.021, moins le proche est inquiet par rapport à la situation du patient. Ainsi que, plus le patient est jeune, plus le proche aidant ressent de tension, avec une valeur ρ de 0.008. Ces résultats, peu généralisables au vu du petit échantillon (n=24), pourraient toutefois impliquer une réflexion approfondie sur l'accueil, la place et le soutien des proches aidants de patients souffrants de troubles psychiatriques hospitalisés dans une unité de soins aigus de la part des infirmières.

Potential blindness in children of patients with hereditary bone disease.

Mono- and bi-allelic mutations in the low-density lipoprotein receptor related protein 5 (LRP5) may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or persistent hyperplastic primary vitreous (PHPV). We report on a child affected with PHPV and carrying compound mutations. The father carried the splice mutation and suffered from severe bone fragility since childhood. The mother carried the missense mutation without any clinical manifestations. The genetic diagnosis of their child allowed for appropriate treatment in the father and for the detection of osteopenia in the mother. Mono- and bi-allelic mutations in LRP5 may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or PHPV. PHPV is a component of persistent fetal vasculature of the eye, characterized by highly variable expressivity and resulting in a wide spectrum of anterior and/or posterior congenital developmental defects, which may lead to blindness. We evaluated a family diagnosed with PHPV in their only child. The child presented photophobia during the first 3 weeks of life, followed by leukocoria at 2 months of age. Molecular resequencing of NDP, FZD4, and LRP5 was performed in the child and segregation of the observed mutations in the parents. At presentation, fundus examination of the child showed a retrolental mass in the right eye. Ultrasonography revealed retinal detachment in both eyes. Thorough familial analysis revealed that the father suffered from many fractures since childhood without specific fragility bone diagnosis, treatment, or management. The mother was asymptomatic. Molecular analysis in the proband identified two mutations: a c.[2091+2T>C] splice mutation and c.[1682C>T] missense mutation. We report the case of a child affected with PHPV and carrying compound heterozygous LRP5 mutations. This genetic diagnosis allowed the clinical diagnosis of the bone problem to be made in the father, resulting in better management of the family. It also enabled preventive treatment to be prescribed for the mother and accurate genetic counseling to be provided.

Surgical treatment for heart myxomas.

According to unselected autopsy data, primary cardiac tumours are a rare entity. About 80% of the tumours are benign and nearly half of these are myxomas. In clinical practice, when diagnosis of this pathological entity is ascertained, decision for surgical treatment is made in order to prevent thromboembolism and obstruction of the valvular apparatus. Surgical resection including total tumour removal is accompanied by low perioperative mortality. The recidive rate is low in sporadic cases. However, in familial syndrome groups, such as the Swiss-Carney syndrome, the recurrence rate is higher.

Smoking cessation and the incidence of pre-diabetes and type 2 diabetes: a cohort study.

AIMS: Smoking cessation has been suggested to increase the short-term risk of type 2 diabetes mellitus (T2DM). This study aimed at assessing the association between smoking cessation and incidence of T2DM and impaired fasting glucose (IFG). METHODS: Data from participants in the CoLaus study, Switzerland, aged 35-75 at baseline and followed for 5.5years were used. Participants were classified as smokers, recent (≤5years), long-term (>5years) quitters, and non-smokers at baseline. Outcomes were IFG (fasting serum glucose (FSG) 5.6-6.99mmol/l) and T2DM (FSG ≥7.0mmol/l and/or treatment) at follow up. RESULTS: 3,166 participants (63% women) had normal baseline FSG, of whom 26.7% were smokers, 6.5% recent quitters, and 23.5% long-term quitters. During follow-up 1,311 participants (41.4%) developed IFG (33.6% women, 54.7% men) and 47 (1.5%) developed T2DM (1.1% women, 2.1% men). Former smokers did not have statistically significant increased odds of IFG compared with smokers after adjustment for age, education, physical activity, hypercholesterolemia, hypertension and alcohol intake, with OR of 1.29 [95% confidence interval 0.94-1.76] for recent quitters and 1.03 [0.84-1.27] for long-term quitters. Former smokers did not have significant increased odds of T2DM compared with smokers with multivariable-adjusted OR of 1.53 [0.58-4.00] for recent quitters and 0.64 [0.27-1.48] for long-term quitters. Adjustment for body-mass index and waist circumference attenuated the association between recent quitting and IFG (OR 1.07 [0.78-1.48]) and T2DM (OR 1.28 [0.48-3.40]. CONCLUSION: In this middle-aged population, smoking cessation was not associated with an increased risk of IFG or T2DM.

Gli altri noi : Rom e residenti nella Svizzera italiana : etnografia e mediazione

Cette recherche porte sur les roms (vlach) qui séjournent périodiquement en Suisse italienne, en camping-cars ou en caravanes, pratiquant un semi- nomadisme lié à des motivations principalement économiques, mais également familiales et religieuses. Elle poursuit simultanément deux objectifs. Le premier est lié à un souci de médiation culturelle, qui rejoint les réflexions sur la façon de gérer au mieux les conflits entre les diverses composantes du vivre ensemble. Le second vise à approfondir la connaissance des populations roms concernées (lovara, éurara ou kalderasa, de nationalités italienne, française et espagnole). Les deux objectifs sont évidemment reliés, car comprendre les dynamiques conflictuelles exige la connaissance approfondie des acteurs en interaction. Les relations entre résidents tessinois et roms ont évolué dans le temps, avec des oscillations entre le pôle du refus et celui de l'attraction, entre rejet et reconnaissance, méfiance et confiance. Ces variations historiques renvoient à un fondement commun, à une dynamique des oppositions réciproques. L'analyse anthropologique a fait apparaître le rôle ambivalent du conflit dans la production et la reproduction de la relation d'altérité. L'exclusion des roms fournit à certaines tendances politiques locales l'occasion d'apparaître comme les protecteurs des résidents contre les étrangers ; inversement, l'opposition des roms aux gaiés leur permet de resserrer leur communauté et de prévenir l'assimilation. La médiation culturelle peut espérer gérer cette dynamique relationnelle, certainement pas la faire disparaître. Le modèle intégratif traditionnel de l'État- nation se révèle trop étroit pour accueillir la culture rom. Casser la résistance des roms envers le travail salarié et envers la scolarisation obligatoire, entraver leur semi-nomadisme (qui incite aussi leurs rencontres familiales et religieuses), refuser de reconnaître leur organe de justice interne et leur langue, tout cela ne ferait que concourir à leur disparition culturelle. Les roms sont conscients de ces possibilités, raison pour laquelle ils maintiennent une ambivalence relationnelle avec les ga£és, quitte à apparaître comme des « tsiganes indésirables ». Abstract : This research focuses on the Roma people (Vlach) who periodically stay in Italian Switzerland in caravans or camper vans, practising a semi-nomadic lifestyle - a choice based mainly on economic imperatives but also on familial and religious grounds. This study will address two objectives at the same time. The first involves cultural mediation, and considers the best way to manage the existing conflicts between the cultural components of the social environment. The second aims to increase knowledge of the Roma populations under examination - the Italian, French and Spanish Lovara, Éurara or Kalderasa. The two objectives are clearly linked, as a deeper understanding of the people involved is vital if we are to increase understanding of the dynamics of confrontation. The relationships between the residents of the Ticino area and the Roma people have evolved over time, oscillating in varying degrees between rejection and attraction, confrontation and recognition, suspicion and trust. These variations spring from a common base, a dynamic shaped by mutual opposition. The anthropological analysis highlights the ambivalent role of conflict in the production and reproduction of relations of otherness. Excluding the Roma has given some local politicians the opportunity to position themselves as protectors of residents against foreigners. Inversely, the Roma people's opposition to the Gazé strengthens links within their community and prevents assimilation. Cultural mediation may aspire to manage this relational dynamic, but not abolish it. The traditional integrative model of the nation-state has shown itself to be too restrictive to accommodate the Romani culture. Rejecting the Roma's resistance to salaried work and obligatory schooling, obstructing their semi-nomadic lifestyle (one that also involves family and religious assemblies) and refusing to recognise their traditional courts and mother tongue, all that can only contribute to the dilution of their cultural heritage. The Roma are fully aware of these possibilities, which is why they retain a relational ambivalence in their dealings with the Gazé, at the cost of appearing to be "undesirable gypsies".

Prognostic value of PCSK9 levels in patients with acute coronary syndromes.

AIMS: Proprotein convertase subtilisin kexin 9 (PCSK9) is an emerging target for the treatment of hypercholesterolaemia, but the clinical utility of PCSK9 levels to guide treatment is unknown. We aimed to prospectively assess the prognostic value of plasma PCSK9 levels in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Plasma PCSK9 levels were measured in 2030 ACS patients undergoing coronary angiography in a Swiss prospective cohort. At 1 year, the association between PCSK9 tertiles and all-cause death was assessed adjusting for the Global Registry of Acute Coronary Events (GRACE) variables, as well as the achievement of LDL cholesterol targets of <1.8 mmol/L. Patients with higher PCSK9 levels at angiography were more likely to have clinical familial hypercholesterolaemia (rate ratio, RR 1.21, 95% confidence interval, CI 1.09-1.53), be treated with lipid-lowering therapy (RR 1.46, 95% CI 1.30-1.63), present with longer time interval of chest pain (RR 1.29, 95% CI 1.09-1.53) and higher C-reactive protein levels (RR 1.22, 95% CI 1.16-1.30). PCSK9 increased 12-24 h after ACS (374 ± 149 vs. 323 ± 134 ng/mL, P < 0.001). At 1 year follow-up, HRs for upper vs. lower PCSK9-level tertiles were 1.13 (95% CI 0.69-1.85) for all-cause death and remained similar after adjustment for the GRACE score. Patients with higher PCSK9 levels were less likely to reach the recommended LDL cholesterol targets (RR 0.81, 95% CI 0.66-0.99). CONCLUSION: In ACS patients, high initial PCSK9 plasma levels were associated with inflammation in the acute phase and hypercholesterolaemia, but did not predict mortality at 1 year.

Rétinome révélé par des myodésopsies

Un homme, âgé de 56 ans, sans antécédent oculaire ni familial, se plaint de myodésopsies récentes. L'acuité visuelle est de 1.0 avec un segment antérieur calme et une tension normale des 2 côtés. Le fond d'oeil (FO) gauche est sans particularité, alors que le droit révèle une masse grisâtre avec des éclats calcifiés flottant dans le vitré. À l'angiographie fluorescéinique, la masse est quasiment avasculaire.