Delinquency in male adolescents: the role of alexithymia and family structure

The purpose of this study was to examine the linkages between alexithymia and delinquency in male adolescents (age ranging from 14 to 18 years), and to investigate whether alexithymia was a good discriminatory factor for juvenile delinquency. Thirty-six offender adolescents and 46 non-offender control adolescents participated in the study and completed the 20-item Toronto Alexithymia Scale (TAS-20) (alexithymia), the Revised Children's Manifest Anxiety Scale (R-CMAS) (anxiety), the Liste d'Adjectifs Bipolaires et en Echelles de Likert (LABEL) (personality-Big Five) and demographic data. Findings revealed that the adolescents of the offender group scored high on alexithymia and that proportion of disrupted family structure in the offender group is higher than in the control group. Logistic regressions confirmed that alexithymia and family structure are the strongest discriminatory factors for juvenile delinquency. Limitations and clinical implications are discussed, and recommendations for future research are provided

Sleep structure and cardiometabolic disorders in the general population : the Hypnolaus study

Objectives: Previous studies using subjective assessments have reported associations between sleep quantity and quality and cardiometabolic disorders, but little is known regarding the associ-ations with objective sleep characteristics. The purpose of this study was to evaluate the association between objective sleep measure sand metabolic syndrome (MS), hypertension, diabetes and obesity. Methods: 2162 subjects (51.2% women, mean age 58,11.1) from the general population were evaluated for hypertension,diabetes, overweight/obesity and MS, and underwent a full polysom-nography (PSG). PSG measured variables included: Total sleep time(TST), percentage and time spent in slow wave sleep (SWS) and in rapid eye movement (REM) sleep, sleep efficiency and arousal index(ArI) Results: In univariate analyses, MS was associated with decreased TST, SWS, REM sleep, sleep efficiency and increased ArI. After adjustment for age, gender, smoking, alcohol, physical activity, drugsthat affect sleep and depression, the ArI remained significantly higher, but the difference disappeared in subjects without significant sleep disordered breathing (SDB). Differences in sleep structure were also found according to the presence or absence of hypertension, diabetes and overweight/obesity in univariate analysis. However, these differences were attenuated after multivariate adjustment and after excluding subjects with significant SDB. Conclusions: In this population-based sample we found significant associations between sleep structure and MS, hypertension, diabetes and obesity. However, these associations were cancelled after multivariate adjustment. We conclude that normal variations in sleep contribute little if any to MS and associated disorders.

Towards the validation of "in silico" models and physicochemical filters to identify and characterize new chemical entities

Summary: Lipophilicity plays an important role in the determination and the comprehension of the pharmacokinetic behavior of drugs. It is usually expressed by the partition coefficient (log P) in the n-octanol/water system. The use of an additional solvent system (1,2-dichlorethane/water) is necessary to obtain complementary information, as the log Poct values alone are not sufficient to explain ail biological properties. The aim of this thesis is to develop tools allowing to predict lipophilicity of new drugs and to analyze the information yielded by those log P values. Part I presents the development of theoretical models used to predict lipophilicity. Chapter 2 shows the necessity to extend the existing solvatochromic analyses in order to predict correctly the lipophilicity of new and complex neutral compounds. In Chapter 3, solvatochromic analyses are used to develop a model for the prediction of the lipophilicity of ions. A global model was obtained allowing to estimate the lipophilicity of neutral, anionic and cationic solutes. Part II presents the detailed study of two physicochemical filters. Chapter 4 shows that the Discovery RP Amide C16 stationary phase allows to estimate lipophilicity of the neutral form of basic and acidic solutes, except of lipophilic acidic solutes. Those solutes present additional interactions with this particular stationary phase. In Chapter 5, 4 different IANI stationary phases are investigated. For neutral solutes, linear data are obtained whatever the IANI column used. For the ionized solutes, their retention is due to a balance of electrostatic and hydrophobie interactions. Thus no discrimination is observed between different series of solutes bearing the same charge, from one column to an other. Part III presents two examples illustrating the information obtained thanks to Structure-Properties Relationships (SPR). Comparing graphically lipophilicity values obtained in two different solvent systems allows to reveal the presence of intramolecular effects .such as internai H-bond (Chapter 6). SPR is used to study the partitioning of ionizable groups encountered in Medicinal Chemistry (Chapter7). Résumé La lipophilie joue un .rôle important dans la détermination et la compréhension du comportement pharmacocinétique des médicaments. Elle est généralement exprimée par le coefficient de partage (log P) d'un composé dans le système de solvants n-octanol/eau. L'utilisation d'un deuxième système de solvants (1,2-dichloroéthane/eau) s'est avérée nécessaire afin d'obtenir des informations complémentaires, les valeurs de log Poct seules n'étant pas suffisantes pour expliquer toutes les propriétés biologiques. Le but de cette thèse est de développer des outils permettant de prédire la lipophilie de nouveaux candidats médicaments et d'analyser l'information fournie par les valeurs de log P. La Partie I présente le développement de modèles théoriques utilisés pour prédire la lipophilie. Le chapitre 2 montre la nécessité de mettre à jour les analyses solvatochromiques existantes mais inadaptées à la prédiction de la lipophilie de nouveaux composés neutres. Dans le chapitre 3, la même méthodologie des analyses solvatochromiques est utilisée pour développer un modèle permettant de prédire la lipophilie des ions. Le modèle global obtenu permet la prédiction de la lipophilie de composés neutres, anioniques et cationiques. La Partie II présente l'étude approfondie de deux filtres physicochimiques. Le Chapitre 4 montre que la phase stationnaire Discovery RP Amide C16 permet la détermination de la lipophilie de la forme neutre de composés basiques et acides, à l'exception des acides très lipophiles. Ces derniers présentent des interactions supplémentaires avec cette phase stationnaire. Dans le Chapitre 5, 4 phases stationnaires IAM sont étudiées. Pour les composés neutres étudiés, des valeurs de rétention linéaires sont obtenues, quelque que soit la colonne IAM utilisée. Pour les composés ionisables, leur rétention est due à une balance entre des interactions électrostatiques et hydrophobes. Donc aucune discrimination n'est observée entre les différentes séries de composés portant la même charge d'une colonne à l'autre. La Partie III présente deux exemples illustrant les informations obtenues par l'utilisation des relations structures-propriétés. Comparer graphiquement la lipophilie mesurée dans deux différents systèmes de solvants permet de mettre en évidence la présence d'effets intramoléculaires tels que les liaisons hydrogène intramoléculaires (Chapitre 6). Cette approche des relations structures-propriétés est aussi appliquée à l'étude du partage de fonctions ionisables rencontrées en Chimie Thérapeutique (Chapitre 7) Résumé large public Pour exercer son effet thérapeutique, un médicament doit atteindre son site d'action en quantité suffisante. La quantité effective de médicament atteignant le site d'action dépend du nombre d'interactions entre le médicament et de nombreux constituants de l'organisme comme, par exemple, les enzymes du métabolisme ou les membranes biologiques. Le passage du médicament à travers ces membranes, appelé perméation, est un paramètre important à optimiser pour développer des médicaments plus puissants. La lipophilie joue un rôle clé dans la compréhension de la perméation passive des médicaments. La lipophilie est généralement exprimée par le coefficient de partage (log P) dans le système de solvants (non miscibles) n-octanol/eau. Les valeurs de log Poct seules se sont avérées insuffisantes pour expliquer la perméation à travers toutes les différentes membranes biologiques du corps humain. L'utilisation d'un système de solvants additionnel (le système 1,2-dichloroéthane/eau) a permis d'obtenir les informations complémentaires indispensables à une bonne compréhension du processus de perméation. Un grand nombre d'outils expérimentaux et théoriques sont à disposition pour étudier la lipophilie. Ce travail de thèse se focalise principalement sur le développement ou l'amélioration de certains de ces outils pour permettre leur application à un champ plus large de composés. Voici une brève description de deux de ces outils: 1)La factorisation de la lipophilie en fonction de certaines propriétés structurelles (telle que le volume) propres aux composés permet de développer des modèles théoriques utilisables pour la prédiction de la lipophilie de nouveaux composés ou médicaments. Cette approche est appliquée à l'analyse de la lipophilie de composés neutres ainsi qu'à la lipophilie de composés chargés. 2)La chromatographie liquide à haute pression sur phase inverse (RP-HPLC) est une méthode couramment utilisée pour la détermination expérimentale des valeurs de log Poct.

Long-term effects of cannabis on brain structure.

The dose-dependent toxicity of the main psychoactive component of cannabis in brain regions rich in cannabinoid CB1 receptors is well known in animal studies. However, research in humans does not show common findings across studies regarding the brain regions that are affected after long-term exposure to cannabis. In the present study, we investigate (using Voxel-based Morphometry) gray matter changes in a group of regular cannabis smokers in comparison with a group of occasional smokers matched by the years of cannabis use. We provide evidence that regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex; these regions are rich in cannabinoid CB1 receptors and functionally associated with motivational, emotional, and affective processing. Furthermore, these changes correlate with the frequency of cannabis use in the 3 months before inclusion in the study. The age of onset of drug use also influences the magnitude of these changes. Significant gray matter volume reduction could result either from heavy consumption unrelated to the age of onset or instead from recreational cannabis use initiated at an adolescent age. In contrast, the larger gray matter volume detected in the cerebellum of regular smokers without any correlation with the monthly consumption of cannabis may be related to developmental (ontogenic) processes that occur in adolescence.

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.

Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL.

Unlike other tumor necrosis factor family members, the cytotoxic ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L contains an unpaired cysteine residue (Cys(230)) in its receptor-binding domain. Here we show that the biological activity of both soluble recombinant TRAIL and cell-associated, full-length TRAIL is critically dependent on the presence of Cys(230). Mutation of Cys(230) to alanine or serine strongly affected its ability to kill target cells. Binding to its receptors was decreased by at least 200-fold, and the stability of its trimeric structure was reduced. In recombinant TRAIL, Cys(230) was found engaged either in interchain disulfide bridge formation, resulting in poorly active TRAIL, or in the chelation of one zinc atom per TRAIL trimer in the active, pro-apoptotic form of TRAIL.

Modelling the distribution of bats in relation to landscape structure in a temperate mountain environment

1. Landscape modification is often considered the principal cause of population decline in many bat species. Thus, schemes for bat conservation rely heavily on knowledge about species-landscape relationships. So far, however, few studies have quantified the possible influence of landscape structure on large-scale spatial patterns in bat communities. 2. This study presents quantitative models that use landscape structure to predict (i) spatial patterns in overall community composition and (ii) individual species' distributions through canonical correspondence analysis and generalized linear models, respectively. A geographical information system (GIS) was then used to draw up maps of (i) overall community patterns and (ii) distribution of potential species' habitats. These models relied on field data from the Swiss Jura mountains. 3. Fight descriptors of landscape structure accounted for 30% of the variation in bat community composition. For some species, more than 60% of the variance in distribution could be explained by landscape structure. Elevation, forest or woodland cover, lakes and suburbs, were the most frequent predictors. 4. This study shows that community composition in bats is related to landscape structure through species-specific relationships to resources. Due to their nocturnal activities and the difficulties of remote identification, a comprehensive bat census is rarely possible, and we suggest that predictive modelling of the type described here provides an indispensable conservation tool.

The Maggia cross-fold: An enigmatic structure of the lower Penninic nappes of the Lepontine Alps

The geometry and kinematics of the map scale Maggia cross-fold structure has been studied by several generations of geologists over seventy years and different models have been proposed for its formation. New observations indicate that the Maggia structure is a SW-verging cross-fold created after earlier NW-directed overthrusting of the Maggia nappe onto the deeper Simano and Antigorio recumbent fold nappes. The nappe emplacement and later cross-folding occurred under amphibolite facies conditions by detachment of the upper European crust during its SE-directed underthrusting below the Adriatic plate.