Risk factors of obesity and their determinants in preschool children (the Swiss Ballabeina study)

This thesis has been conducted in the context of a lifestyle intervention in 40 Swiss kindergarten classes in the cantons St. Gallen and Vaud, in areas with a high migrant prevalence (Ballabeina study). The main objective of this work was to fill certain gaps of the literature and to bring a better understanding of the risk factors of overweight and obesity and their determinants in preschool children. Our data show that parental migrant status and educational level influence independently of each other adiposity and/or eating habits in these children. In addition, sports club participation at this young age seems to be a better indicator of healthy lifestyle characteristics in terms of physical activity, sedentary behaviour and eating habits than weight status. Finally, we found that in this population higher scores of hyperactivity/inattention are associated with lower adiposity and with both healthy (more physical activity and less sedentary activity) and unhealthy (more television viewing and more unhealthy eating habits) lifestyle characteristics. Thus, our findings can be used by different actors of health and education system to better target their preventive actions and can serve as a basis for future complementary researches. - Cette thèse a été réalisée dans le cadre d'un projet de promotion de la santé mené dans 40 classes enfantines suisses issues de régions à forte prévalence migrante des cantons de St. Gall et de Vaud (étude Ballabeina). L'objectif principal de ce travail était de combler certaines lacunes de la littérature et d'approfondir nos connaissances sur les facteurs de risque du surpoids et de l'obésité et de leurs déterminants chez les enfants d'âge préscolaire. Nos analyses montrent que le statut de migrant des parents et leur niveau d'éducation influencent indépendamment l'un de l'autres l'adiposité et les habitudes alimentaires chez ces enfants. De plus, à ce jeune âge la participation dans un club de sport semble être un meilleur indicateur de style de vie sain en termes d'activité physique, de comportements sédentaires et d'habitudes alimentaires que le statut pondéral. Nous avons également trouvé que dans cette population, un score plus élevé d'hyperactivité/inattention est associé aussi bien à des caractéristiques de style de vie saines (plus d'activité physique, moins d'activité sédentaire) que malsaines (plus de consommation de télévision et moins bonnes habitudes alimentaire. Ainsi, nos résultats peuvent aider les différents acteurs de la santé et de l'éducation à mieux cibler leurs actions de prévention et servir de base à de futures recherches complémentaires.

Determinants of persistence in hypertensive patients treated with irbesartan: results of a postmarketing survey.

BACKGROUND: Persistence is a key factor for long-term blood pressure control, which is of high prognostic importance for patients at increased cardiovascular risk. Here we present the results of a post-marketing survey including 4769 hypertensive patients treated with irbesartan in 886 general practices in Switzerland. The goal of this survey was to evaluate the tolerance and the blood pressure lowering effect of irbesartan as well as the factors affecting persistence in a large unselected population. METHODS: Prospective observational survey conducted in general practices in all regions of Switzerland. Previously untreated and uncontrolled pre-treated patients were started with a daily dose of 150 mg irbesartan and followed up to 6 months. RESULTS: After an observation time slightly exceeding 4 months, the average reduction in systolic and diastolic blood pressure was 20 (95% confidence interval (CI) -19.6 to -20.7 mmHg) and 12 mmHg (95% CI -11.4 to -12.1 mmHg), respectively. At this time, 26% of patients had a blood pressure < 140/90 mmHg and 60% had a diastolic blood pressure < 90 mmHg. The drug was well tolerated with an incidence of adverse events (dizziness, headaches,...) of 8.0%. In this survey more than 80% of patients were still on irbesartan at 4 month. The most important factors predictive of persistence were the tolerability profile and the ability to achieve a blood pressure target < or = 140/90 mmHg before visit 2. Patients who switched from a fixed combination treatment tended to discontinue irbesartan more often whereas those who abandoned the previous treatment because of cough (a class side effect of ACE-Inhibitors) were more persistent with irbesartan. CONCLUSION: The results of this survey confirm that irbesartan is effective, well tolerated and well accepted by patients, as indicated by the good persistence. This post-marketing survey also emphasizes the importance of the tolerability profile and of achieving an early control of blood pressure as positive predictors of persistence.

The Lausanne cohort Lc65+: a population-based prospective study of the manifestations, determinants and outcomes of frailty

BACKGROUND: Frailty is a relatively new geriatric concept referring to an increased vulnerability to stressors. Various definitions have been proposed, as well as a range of multidimensional instruments for its measurement. More recently, a frailty phenotype that predicts a range of adverse outcomes has been described. Understanding frailty is a particular challenge both from a clinical and a public health perspective because it may be a reversible precursor of functional dependence. The Lausanne cohort Lc65+ is a longitudinal study specifically designed to investigate the manifestations of frailty from its first signs in the youngest old, identify medical and psychosocial determinants, and describe its evolution and related outcomes. METHODS/DESIGN: The Lc65+ cohort was launched in 2004 with the random selection of 3054 eligible individuals aged 65 to 70 (birth year 1934-1938) in the non-institutionalized population of Lausanne (Switzerland). The baseline data collection was completed among 1422 participants in 2004-2005 through questionnaires, examination and performance tests. It comprised a wide range of medical and psychosocial dimensions, including a life course history of adverse events. Outcomes measures comprise subjective health, limitations in activities of daily living, mobility impairments, development of medical conditions or chronic health problems, falls, institutionalization, health services utilization, and death. Two additional random samples of 65-70 years old subjects will be surveyed in 2009 (birth year 1939-1943) and in 2014 (birth year 1944-1948). DISCUSSION: The Lc65+ study focuses on the sequence "Determinants --> Components --> Consequences" of frailty. It currently provides information on health in the youngest old and will allow comparisons to be made between the profiles of aging individuals born before, during and at the end of the Second World War.

Determinants of smoking and cessation in older women

Résumé Introduction : Le tabagisme est le facteur de risque le plus important dans 7 des 14 premières causes de décès chez les personnes de plus de 65 ans. De nombreuses études ont démontré les bénéfices sur la santé d'un arrêt du tabagisme même à un âge avancé. Malgré cela, peu d'actions préventives sont entreprises dans cette population. Le but de ce travail est d'analyser les caractéristiques du tabagisme et de l'arrêt du tabagisme spécifiquement chez les fumeuses d'âge avancé afin de mieux les aider dans leur désir d'arrêter. Méthode : Nous avons évalué les caractéristiques tabagiques au sein d'une étude prospective de 7'609 femmes vivant en Suisse, âgées de plus de 70 ans et physiquement autonomes (étude Semof s'intéressant à la mesure de l'ostéoporose par ultrason osseux). Un questionnaire sur les habitudes tabagiques a été envoyé aux 486 fumeuses éligibles de la cohorte. Leurs stades de dépendance nicotinique et de motivation ont été évalués à l'aide respectivement des scores «Heavy Smoking Index» et « Prochaska ». Les participantes ayant cessé de fumer pendant le suivi ont été questionnées sur, les motivations, les raisons et les méthodes de leur arrêt. Résultats : 424 femmes ont retourné le questionnaire (taux de réponse de 87%) parmi lesquelles 372 ont répondu de façon complète permettant leur inclusion. L'âge moyen s'élevait à 74,5 ans. La consommation moyenne était de 12 cigarettes par jour, sur une moyenne de 51 ans avec une préférence pour les cigarettes dites « légères » ou « light ». Un peu plus de la moitié des participantes avait une consommation entre 1 et 10 cigarettes par jour et la grande majorité (78%) présentait un score de dépendance faible. Les raisons du tabagisme les plus fréquemment évoquées étaient la relaxation, le plaisir et l'habitude. Les principaux obstacles mentionnés : arrêter à un âge avancé n'a pas de bénéfice, fumer peu ou des cigarettes dites light n'a pas d'impact sur la santé et fumer n'augmente pas le risque d'ostéoporose. Le désir d'arrêter était positivement associé avec un début tardif du tabagisme, une éducation plutôt modeste et la considération que d'arrêter est difficile. Durant le suivi de 3 ans, 57 femmes sur 372 (15%) ont arrêté de-fumer avec succès. Le fait d'être une fumeuse occasionnelle (moins de 1 cigarette par jour) et de considérer que d'arrêter de fumer n'est pas difficile était associés à un meilleur taux d'arrêt du tabagisme. Seuls 11% des femmes ayant stoppé la cigarette signalaient avoir reçu des conseils de leur médecin. Conclusion : ces données illustrent le comportement tabagique spécifique des fumeuses d'âge avancé (consommation et dépendance plutôt faibles) et suggèrent que les interventions médicales pour l'aide à l'arrêt du tabagisme devraient intégrer ces caractéristiques. La volonté d'arrêter est associée à un niveau d'éducation plutôt modeste. Les obstacles les plus fréquemment mentionnés sont basés sur des appréciations erronées de l'impact du tabagisme sur la santé.

Sequence determinants of a microtubule tip localization signal (MtLS).

Microtubule plus-end-tracking proteins (+TIPs) specifically localize to the growing plus-ends of microtubules to regulate microtubule dynamics and functions. A large group of +TIPs contain a short linear motif, SXIP, which is essential for them to bind to end-binding proteins (EBs) and target microtubule ends. The SXIP sequence site thus acts as a widespread microtubule tip localization signal (MtLS). Here we have analyzed the sequence-function relationship of a canonical MtLS. Using synthetic peptide arrays on membrane supports, we identified the residue preferences at each amino acid position of the SXIP motif and its surrounding sequence with respect to EB binding. We further developed an assay based on fluorescence polarization to assess the mechanism of the EB-SXIP interaction and to correlate EB binding and microtubule tip tracking of MtLS sequences from different +TIPs. Finally, we investigated the role of phosphorylation in regulating the EB-SXIP interaction. Together, our results define the sequence determinants of a canonical MtLS and provide the experimental data for bioinformatics approaches to carry out genome-wide predictions of novel +TIPs in multiple organisms.

The CoLaus study : a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome

Rapport de synthèse : Les maladies cardio-vasculaires constituent les causes principales causes de morbidité et de mortalité dans les pays industrialisés. Des études épidémiologiques ont démontré l'implication de facteurs de risques comme l'hypertension, l'hypercholestérolémie, l'obésité abdominale, le diabète et le tabagisme dans le développement des affections cardiovasculaires comme l'infarctus du myocarde ou l'accident vasculaire cérébral. De larges études génétiques cas-contrôle ont contribué modestement à l'identification de gènes de susceptibilité au développement de ces FRCV. Une étude populationnelle offre par contre l'avantage d'effectuer des études associatives pour des traits phénotypiques continus correctement mesurés et aussi pour des traits de catégories utilisant des protocoles d'étude cas-contrôle très discordants. ~ Elle permet l'exploration des déterminants génétiques comme par exemple le syndrome métabolique. Cette approche permet également de procéder à des analyses de séquençage sur l'ADN des participants chez qui un trait phénotypique spécifique est étudié mais distribué de manière opposée. A titre d'exemple, le séquençage de l'ADN de participants à taux très élevé d'HDL-cholestérol versus très bas de ce marqueur lipidique permet d'identifier des variants génétiques rares localisés sur les parties codantes de gènes spécifiques associés aux dyslipidémies. Pour ce faire, nous avons recruté 6'188 personnes âgées de 35 à 75 ans, d'origine caucasienne et résidant en ville de Lausanne (3251 femmes et 2937 hommes). L'obtention d'un tel collectif a nécessité l'échantillonnage aléatoire de quelque 19'830 personnes de cette tranche d'âge. Les participants ont fait l'objet d'une anamnèse approfondie et d'un examen clinique. Le bilan était complété par une prise de sang pour le dosage de paramètres biologiques ainsi qu'une analyse .génétique. Cette dernière a été effectuée après extraction d'ADN au moyen d'une puce Affimetrix qui évalue la présence de quelques 500'000 SNPs. Les données récoltées lors de cette étude dévoilent que l'obésité (index de masse corporelle > 30 kg/m2), le tabagisme, l'hypertension (pression artérielle >_ 140/90 mmHg et/ou hypertension traitée), une dyslipidémie (LDL cholestérol élevé et/ou HDL cholestérol bas et/ou triglycéride élevé) et le diabète (glucose à jeun >_ 7 mmol/l et/ou traitement) affectent respectivement 947 (15,7%), 1673 (27%), 2268 (36,7%), 2113 (34,2%) et 407 (6,6%) participants. La prévalence de ces FRCV est plus marquée chez les hommes que chez les femmes. Dans les deux genres les prévalences de l'obésité, de l'hypertension et du diabète augmentent drastiquement avec l'âge. En conclusion la prévalence des FRCV est élevée au sein d'une population représentative de Lausanne âgée de 35 à 75 ans. A l'avenir, l'étude CoLaus constituera par la richesse de ses données phénotypiques et génétiques, une source unique pour investiguer l'épidémiologie et l'identification de gènes associés à ces FRCV.

Socio-cultural determinants of adiposity and physical activity in preschool children: a cross-sectional study.

Both individual socio-cultural determinants such as selected parental characteristics (migrant background, low educational level and workload) as well as the regional environment are related to childhood overweight and physical activity (PA). The purpose of the study was to compare the impact of distinct socio-cultural determinants such as the regional environment and selected parental characteristics on adiposity, PA and motor skills in preschool children. Forty preschools (N = 542 children) of two culturally different urban regions (German and French speaking part of Switzerland) participated in the study (Ballabeina Study). Outcome measures included adiposity (BMI and skinfold thickness), objectively measured sedentary activities and PA (accelerometers) and agility performance (obstacle course). Parental characteristics (migrant status, educational level and workload) were assessed by questionnaire. Children from the French speaking areas had higher adiposity, lower levels of total and of more intense PA, were more sedentary and less agile than children from the German speaking regions (percent differences for all outcome parameters except for BMI ≥10%; all p ≤ 0.04). Differences in skinfold thickness, sedentary activities and agility, but not in PA, were also found between children of Swiss and migrant parents, though they were ≤8% (p ≤ 0.02). While paternal workload had no effect, maternal workload and parental education resulted in differences in some PA measures and/or agility performance (percent differences in both: ≤9%, p ≤ 0.008), but not in adiposity or sedentary activities (p = NS). Regional differences in skinfold thickness, PA, sedentary activities and agility performance persisted after adjustment for parental socio-cultural characteristics, parental BMI and, where applicable, children's skinfolds (all p ≤ 0.01). The regional environment, especially the broader social environment, plays a prominent role in determining adiposity, PA and motor skills of young children and should be implicated in the prevention of obesity and promotion of PA in children. clinicaltrials.gov NCT00674544.

Molecular determinants of vesicular storage and release of the gliotransmitter D-serine from cortical astrocytes

Neuron-astrocyte reciprocal communication at synapses has emerged as a novel signalling pathway in brain function. Astrocytes sense the level of synaptic activity and, in turn, influence its efficacy through the regulated release of 'gliotransmitters' such as glutamate, ATP or D-serine. A calcium-dependent exocytosis is proposed to drive the release of gliotransmitters but its existence is still debated. Over the last years, we have been studying the molecular determinants governing D-serine release from glia using different approaches. Using a novel bioassay for D-serine, we have been able to show that D-serine release occurs mainly through a calcium- and SNARE proteindependent mechanism just supporting the idea that this amino acid is released by exocytosis from glia. We next have pursued our exploration by confocal imaging and tracking of the exocytotic routes for Dserine- mediated gliotransmission and have shown that D-serine releasable pools are confined to synaptobrevin2/cellubrevin-bearing vesicles. To shed light onto the mechanisms controlling the storage and the release of gliotransmitters and namely D-serine, we have developed a new method for the immunoisolation of synaptobrevin 2- positive vesicles from rat cortical astrocytes in culture while preserving their content in gliotransmitters. The purified organelles are clear round shape vesicles of excellent purity with homogeneous size (40 nm) as judged by electron microscopy. Immunoblotting analysis revealed that isolated vesicles contain most of the major proteins already described for neuron-derived vesicles like synaptic vesicle protein 2 (SV2) and the proton pump H?-ATPase. In addition, we have analyzed the content for various amino acids of these vesicles by means of chiral capillary electrophoresis coupled to laser-induced fluorescence detection. The purified vesicles contain large amount of D-serine. We also detect peaks corresponding to unidentified compounds that may correspond to others amino acids. Postembedding immunogold labelling of the rat neocortex further revealed the expression of D-serine in astrocytes processes contacting excitatory synapses. Finally, we have examined the uptake properties for Dserine and glutamate inside the isolated glial vesicles. Our results provide significant support for the existence of an uptake system for D-serine in secretory glial vesicles and for the storage of chemical substances like D-serine and glutamate. 11th International Congress on Amino Acids, Peptides and Proteins 763 123

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Molecular determinants of desensitization in an ENaC/degenerin channel.

Epithelial Na(+) channel (ENaC)/degenerin family members are involved in mechanosensation, blood pressure control, pain sensation, and the expression of fear. Several of these channel types display a form of desensitization that allows the channel to limit Na(+) influx during prolonged stimulation. We used site-directed mutagenesis and chemical modification, functional analysis, and molecular dynamics simulations to investigate the role of the lower palm domain of the acid-sensing ion channel 1, a member of the ENaC/degenerin family. The lower palm domains of this trimeric channel are arranged around a central vestibule, at ∼20 Å above the plasma membrane and are covalently linked to the transmembrane channel parts. We show that the lower palm domains approach one another during desensitization. Residues in the palm co-determine the pH dependence of desensitization, its kinetics, and the stability of the desensitized state. Mutations of palm residues impair desensitization by preventing the closing movement of the palm. Overexpression of desensitization-impaired channel mutants in central neurons allowed--in contrast to overexpression of wild type--a sustained signaling response to rapid pH fluctuations. We identify and describe here the function of an important regulatory domain that most likely has a conserved role in ENaC/degenerin channels.

Multiscale determinants of tree frog (Hyla arborea L.) calling ponds in western Switzerland

A tree frog (Hyla arborea L., 1758) metapopulation in western Switzerland was studied during spring 2001. All potential calling ponds in an area of 350 km(2) were searched for tree frog calling males. Twenty-nine out of 111 ponds sheltered between 1 and 250 callers. Most ponds were occupied by less than 12 males. Pond parameters were measured at three different levels using field analysis and a Geographical Information System (GIS). The first level was water chemistry and pond-associated measures. The second level was the surrounding land use in a 30 m buffer around the pond. The third level consisted of landscape indices on a broader scale (up to 2 km). Logistic regression was applied to identify parameters that can predict the presence of calling males in a pond. Response variable was the presence or absence of callers. Four significant parameters allowed us to explain about 40% of the total deviance of the observed occupational pattern. Urbanization around the pond had a highly negative impact on the probability of presence of calling males. Hours of direct sunlight on the pond was positively correlated with callers. Higher water conductivity was associated with a lesser probability of species presence. Finally, the further the closest two-lane road, the higher the probability of callers presence. Our results show that presence or absence of callers is influenced by factors acting at various geographical scales.