Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.

La coordination des dirigeants économiques face à la financiarisation : gouvernance d'entreprise, relations industrielles et élites dirigeantes dans l'industrie suisse des machines, de l'électrotechnique et de la métallurgie (1970-2008)

Résumé Cette recherche analyse les transformations de la gouvernance d'entreprise et des relations industrielles entre 1970 et 2008 dans le contexte suisse, en mettant l'accent sur les changements survenus depuis les années 1990. Elle se centre sur le secteur de l'industrie des machines, de l'électrotechnique et de la métallurgie -noyau historique du capitalisme helvétique et principal employeur et exportateur industriel du pays - et discute l'hypothèse de la convergence des économies coordonnées vers le modèle libéral. Elle examine d'abord les formes de coordination hors-marché qui se sont consolidées entre les élites économiques suisses au cours de la période d'après-guerre. Les stratégies d'innovation incrémentale des grandes sociétés étaient soutenues par une gouvernance marquée par la faible pression des marchés des capitaux, en raison notamment de la forte concentration de l'actionnariat, de mécanismes protectionnistes en matière d'accès au contrôle des sociétés, ainsi que d'une grande interdépendance entre banques et entreprises. Cette interdépendance apparaît dans la forte densité du réseau d'interconnexions des Conseils d'administration, où les principales banques tiennent une place centrale. Le réseau met également en relation les sociétés du secteur entre elles, ainsi qu'avec des firmes actives sur d'autres marchés, ce qui témoigne de l'irréductibilité des stratégies industrielles à une pure logique de compétition centrée sur les marchés. Les stratégies à long terme du management peuvent également s'appuyer sur un système pacifié de relations industrielles, caractérisé par l'autorégulation des acteurs privés dans le cadre d'un partenariat social de branche entre des associations aux stratégies modérées, « néocorporatistes ». Nous analysons alors l'impact de la libéralisation et de la financiarisation de l'économie suisse sur la coordination des élites économiques durant les années 1990. Nous montrons que l'affirmation des fonds d'investissement a déstabilisé le système traditionnel de gouvernance d'entreprise. Ce dernier a ainsi été marqué par l'émergence d'un marché pour le contrôle de l'entreprise -fin du «capital patient » -, la dissolution de l'interdépendance entre banques et industries et plus globalement des formes de coordination hors-marché reposant sur le réseau d'interconnexions des Conseils d'administration, ainsi que par de profondes restructurations des grandes sociétés orientées vers la création de richesse pour les actionnaires. La recherche explore alors les logiques d'interactions entre la sphère de la gouvernance d'entreprise et celle des relations industrielles, l'affirmation du capital financier faisant pression sur le partenariat social dans le sens d'une flexibilisation et déréglementation du marché du travail. Par ailleurs, nous mettons en perspective le rôle central des élites dans le changement institutionnel. Loin de subir la pression des actionnaires, les préférences d'une nouvelle élite managériale au profil financier ont convergé avec les intérêts des investisseurs dans le processus de financiarisation. Ces préférences ont également participé à l'érosion du partenariat social de branche. Du côté syndical, l'émergence -ici aussi - d'une nouvelle élite, académique et issue de la gauche politique, au cours des années 1990, a remis en cause les recettes de l'ancienne génération de syndicalistes ouvriers. La principale association du secteur a ainsi diversifié ses registres d'action en investissant la sphère politique et en relativisant la paix absolue du travail, deux stratégies activement rejetées par le syndicat au cours du régime de croissance d'après-guerre. Tout en mettant la sociologie des élites au service d'une meilleure compréhension des processus de changement institutionnel dans les capitalismes contemporains, cette recherche souligne des logiques de changement différentes dans les sphères sous revue :changement disruptif dans la gouvernance d'entreprise, incrémentai dans les relations industrielles. L'analyse s'est appuyée sur le croisement de différentes méthodes : analyse documentaire, entretiens semi-directifs, analyse du parcours et profil des élites, analyse de réseau, études de cas.

Depressive disorder moderates the effect of the FTO gene on body mass index.

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.

Anterior cingulate cortex pathology in schizophrenia and bipolar disorder.

To explore possible morphological abnormalities in the dorsal and subgenual parts of anterior cingulate cortex in mood disorders and schizophrenia, we performed a quantitative postmortem study of 44 schizophrenic patients, 21 patients with sporadic bipolar disorder, 20 patients with sporadic major depression, and 55 age- and sex-matched control cases. All individuals were drug naïve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Neuron densities and size were estimated on cresyl violet-stained sections using a stereological counting approach. The distribution and density of microtubule-associated (MAP2, MAP1b) and tau proteins were assessed by immunocytochemistry and quantitative immunodot assay. Mean total and laminar cortical thicknesses as well as mean pyramidal neuron size were significantly decreased in the dorsal and subgenual parts of areas 24 (24sg) in schizophrenic cases. Patients with bipolar disorder showed a substantial decrease in laminar thickness and neuron densities in layers III, V, and VI of the subgenual part of area 24, whereas patients with major depression were comparable to controls. Immunodot assay showed a significant decrease of both MAP2 and MAP1b proteins in bipolar patients but not in patients with schizophrenia and major depression. The neuroanatomical and functional significance of these findings are discussed in the light of current hypotheses regarding the role of areas 24 and 24sg in schizophrenia and bipolar disorder.

DSM-IV and DSM-5 alcohol use disorder among young Swiss men.

BACKGROUND AND AIMS: Previous studies suggest that the new DSM-5 criteria for alcohol use disorder (AUD) will increase the apparent prevalence of AUD. This study estimates the 12-month prevalence of AUD using both DSM-IV and DSM-5 criteria and compares the characteristics of men in a high risk sample who meet both, only one and neither sets of diagnostic criteria. DESIGN, SETTING AND PARTICIPANTS: 5943 Swiss men aged 18-25 years who participated in the Cohort Study on Substance Use Risk Factors (C-SURF), a population-based cohort study recruited from three of the six military recruitment centres in Switzerland (response rate = 79.2%). MEASUREMENTS: DSM-IV and DSM-5 criteria, alcohol use patterns, and other substance use were assessed. FINDINGS: Approximately 31.7% (30.5-32.8) of individuals met DSM-5 AUD criteria [21.2% mild (20.1-22.2); 10.5% moderate/severe (9.7-11.3)], which was less than the total rate when DSM-IV criteria for alcohol abuse (AA) and alcohol dependence (AD) were combined [36.8% overall (35.5-37.9); 26.6% AA (25.4-27.7); 10.2% AD (9.4-10.9)]. Of 2479 respondents meeting criteria for either diagnoses, 1585 (63.9%) met criteria for both. For those meeting DSM-IV criteria only (n = 598, 24.1%), hazardous use was most prevalent, whereas the criteria larger/longer use than intended and tolerance to alcohol were most prevalent for respondents meeting DSM-5 criteria only (n = 296, 11.9%). Two in five DSM-IV alcohol abuse cases and one-third of DSM-5 mild AUD individuals fulfilled the diagnostic criteria due to the hazardous use criterion. The addition of the craving and excluding of legal criterion, respectively, did not affect estimated AUD prevalence. CONCLUSIONS: In a high-risk sample of young Swiss males, prevalence of alcohol use disorder as diagnosed by DSM-5 was slightly lower than prevalence of DSM-IV diagnosis of dependence plus abuse; 63.9% of those who met either criterion met criteria for both.

Multiple roles of mouse Numb in tuning developmental cell fates.

BACKGROUND: Notch signaling regulates multiple differentiation processes and cell fate decisions during both invertebrate and vertebrate development. Numb encodes an intracellular protein that was shown in Drosophila to antagonize Notch signaling at binary cell fate decisions of certain cell lineages. Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates, the developmental processes in which Numb is involved remained elusive. RESULTS: We generated mice with a homozygous inactivation of Numb. These mice died before embryonic day E11.5, probably because of defects in angiogenic remodeling and placental dysfunction. Mutant embryos had an open anterior neural tube and impaired neuronal differentiation within the developing cranial central nervous system (CNS). In the developing spinal cord, the number of differentiated motoneurons was reduced. Within the peripheral nervous system (PNS), ganglia of cranial sensory neurons were formed. Trunk neural crest cells migrated and differentiated into sympathetic neurons. In contrast, a selective differentiation anomaly was observed in dorsal root ganglia, where neural crest--derived progenitor cells had migrated normally to form ganglionic structures, but failed to differentiate into sensory neurons. CONCLUSIONS: Mouse Numb is involved in multiple developmental processes and required for cell fate tuning in a variety of lineages. In the nervous system, Numb is required for the generation of a large subset of neuronal lineages. The restricted requirement of Numb during neural development in the mouse suggests that in some neuronal lineages, Notch signaling may be regulated independently of Numb.

Disorder-induced critical phenomena in magnetically glassy Cu-Al-Mn alloys

Measurements of magnetic hysteresis loops in Cu-Al-Mn alloys of different Mn content at low temperatures are presented. The loops are smooth and continuous above a certain temperature, but exhibit a magnetization discontinuity below that temperature. Scaling analysis suggest that this system displays a disorder-induced phase transition line. Measurements allow one to determine the critical exponents ß=0.03±0.01 and ß¿=0.4±0.1, which coincide with those reported recently in a different system, thus supporting the existence of universality for disorder-induced critical points.

Observer-rated Coping Associated with Borderline Personality Disorder: An Exploratory Study.

BACKGROUND: Little is known about coping specificities, as operationalization of the concept of affect regulation, in borderline personality disorder (BPD). It is most important to take into account methodological criticisms addressed to the self-report questionnaire approach and to compare BPD coping specificities to the ones of neighbouring diagnostic categories, such as bipolar disorder (BD). SAMPLING AND METHODS: The present exploratory study compared the coping profiles of N = 25 patients presenting BPD to those of N = 25 patients presenting BD and to those of N = 25 healthy controls. All participants underwent a clinical interview that was transcribed and rated using the Coping Patterns observer-rater system. RESULTS: Results partially confirmed study hypotheses and showed differences between BPD patients and healthy controls in all coping domains (competence, resources and autonomy), whereas the only coping domain presenting a BPD-specific lack of skills, compared with the BD patients, was autonomy, a set of coping strategies facing stress appraised as challenge. These coping processes were linked to general and BPD symptomatology. CONCLUSIONS: These results extend conclusions of earlier studies on affect regulation processes in BPD and bear important clinical implications, in the context of dialectical behavior therapy and other therapeutic approaches. Limitations of this exploratory study, such as the small sample size, are acknowledged. Copyright © 2012 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Coping can be reliably assessed in the narrative process in an non-structured interview frame. Patients with borderline personality disorder present with a specific lack of skills in affect regulation related to autonomy issues, compared to patients with bipolar disorder and healthy controls. Lack of skills in accommodation to distressing emotions in borderline personality disorder is related to symptom gravity and may be treated using radical acceptance strategies.

Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice.

Cleft palate is a common congenital disorder that affects up to 1 in 2,500 live human births and results in considerable morbidity to affected individuals and their families. The etiology of cleft palate is complex, with both genetic and environmental factors implicated. Mutations in the transcription factor-encoding genes p63 and interferon regulatory factor 6 (IRF6) have individually been identified as causes of cleft palate; however, a relationship between the key transcription factors p63 and IRF6 has not been determined. Here, we used both mouse models and human primary keratinocytes from patients with cleft palate to demonstrate that IRF6 and p63 interact epistatically during development of the secondary palate. Mice simultaneously carrying a heterozygous deletion of p63 and the Irf6 knockin mutation R84C, which causes cleft palate in humans, displayed ectodermal abnormalities that led to cleft palate. Furthermore, we showed that p63 transactivated IRF6 by binding to an upstream enhancer element; genetic variation within this enhancer element is associated with increased susceptibility to cleft lip. Our findings therefore identify p63 as a key regulatory molecule during palate development and provide a mechanism for the cooperative role of p63 and IRF6 in orofacial development in mice and humans.

Cognitive errors assessed by observer ratings in bipolar affective disorder: relationship with symptoms and therapeutic alliance

The construct of cognitive errors is clinically relevant for cognitive therapy of mood disorders. Beck's universality hypothesis postulates the relevance of negative cognitions in all subtypes of mood disorders, as well as positive cognitions for manic states. This hypothesis has rarely been empirically addressed for patients presenting bipolar affective disorder (BD). In-patients (n = 30) presenting with BD were interviewed, as were 30 participants of a matched control group. Valid and reliable observer-rater methodology for cognitive errors was applied to the session transcripts. Overall, patients make more cognitive errors than controls. When manic and depressive patients were compared, parts of the universality hypothesis were confirmed. Manic symptoms are related to positive and negative cognitive errors. These results are discussed with regard to the main assumptions of the cognitive model for depression; thus adding an argument for extending it to the BD diagnostic group, taking into consideration specificities in terms of cognitive errors. Clinical implications for cognitive therapy of BD are suggested.