LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases.

BACKGROUND: Niemann-Pick type C (NP-C) is a rare progressive neurodegenerative lipid storage disorder with heterogeneous clinical presentation and challenging diagnostic procedures. Recently oxysterols have been reported to be specific biomarkers for NP-C but knowledge on the intra-individual variation and on reference intervals in children and adolescents are lacking. METHODS: We established a LC-MS/MS assay to measure Cholestane-3β, 5α, 6β-triol (C-triol) and 7-Ketocholesterol (7-KC) following Steglich esterification. To assess reference intervals and intra-individual variation we determined oxysterols in 148 children and adolescents from 0 to 18 years and repeat measurements in 19 of them. RESULTS: The reported method is linear (r>0.99), sensitive (detection limit of 0.03 ng/mL [0.07 nM] for C-triol, and 0.54 ng/mL [1.35 nM] for 7-KC) and precise, with an intra-day imprecision of 4.8% and 4.1%, and an inter-day imprecision of 7.0% and 11.0% for C-triol (28 ng/ml, 67 nM) and 7-KC (32 ng/ml, 80 nM), respectively. Recoveries for 7-KC and C-triol range between 93% and 107%. The upper reference limit obtained for C-triol is 40.4 ng/mL (95% CI: 26.4-61.7 ng/mL, 96.0 nM, 95% CI: 62.8-146.7 nM) and 75.0 ng/mL for 7-KC (95% CI: 55.5-102.5 ng/mL, 187.2 nM, 95% CI: 138.53-255.8 nM), with no age or gender dependency. Both oxysterols have a broad intra-individual variation of 46%±23% for C-triol and 52%±29% for 7-KC. Nevertheless, all Niemann-Pick patients showed increased C-triol levels including Niemann-Pick type A and B patients. CONCLUSIONS: The LC-MS/MS assay is a robust assay to quantify C-triol and 7-KC in plasma with well documented reference intervals in children and adolescents to screen for NP-C in the pediatric population. In addition our results suggest that especially the C-triol is a biomarker for all three Niemann-Pick diseases.

Social trust : a public good?

Combining theories on social trust and social capital with sociopsychological approaches and applying contextual analyses to Swiss and European survey data, this thesis examines under what circumstances generalised trust, often understood as public good, may not benefit everyone, but instead amplify inequality. The empirical investigation focuses on the Swiss context, but considers different scales of analysis. Two broader questions are addressed. First, might generalised trust imply more or less narrow visions of community and solidarity in different contexts? Applying nonlinear principal component analysis to aggregate indicators, Study 1 explores inclusive and exclusive types of social capital in Europe, measured as regional configurations of generalised trust, civic participation and attitudes towards diversity. Study 2 employs multilevel models to examine how generalised trust, as an individual predisposition and an aggregate climate at the level of Swiss cantons, is linked to equality- directed collective action intention versus radical right support. Second, might high-trust climates impact negatively on disadvantaged members of society, precisely because they reflect a normative discourse of social harmony that impedes recognition of inequality? Study 3 compares how climates of generalised trust at the level of Swiss micro-regions and subjective perceptions of neighbourhood cohesion moderate the negative relationship between socio-economic disadvantage and mental health. Overall, demonstrating beneficial, as well as counterintuitive effects of social trust, this thesis proposes a critical and contextualised approach to the sources and dynamics of social cohesion in democratic societies. -- Cette thèse combine des théories sur le capital social et la confiance sociale avec des approches psychosociales et s'appuie sur des analyses contextuelles de données d'enquêtes suisses et européennes, afin d'étudier dans quelles circonstances la confiance généralisée, souvent présentée comme un bien public, pourrait ne pas bénéficier à tout le monde, mais amplifier les inégalités. Les études empiriques, centrées sur le contexte suisse, intègrent différentes échelles d'analyse et investiguent deux questions principales. Premièrement, la confiance généralisée implique-t-elle des visions plus ou moins restrictives de la communauté et de la solidarité selon le contexte? Dans l'étude 1, une analyse à composantes principales non-linéaire sur des indicateurs agrégés permet d'explorer des types de capital social inclusif et exclusif en Europe, mesurés par des configurations régionales de confiance généralisée, de participation civique, et d'attitudes envers la diversité. L'étude 2 utilise des modèles multiniveaux afin d'analyser comment la confiance généralisée, en tant que prédisposition individuelle et climat agrégé au niveau des cantons suisses, est associée à l'intention de participer à des actions collectives en faveur de l'égalité ou, au contraire, à l'intention de voter pour la droite radicale. Deuxièmement, des climats de haute confiance peuvent-ils avoir un impact négatif sur des membres désavantagés de la société, précisément parce qu'ils reflètent un discours normatif d'harmonie sociale qui empêche la reconnaissance des inégalités? L'étude 3 analyse comment des climats de confiance au niveau des micro-régions suisses et la perception subjective de faire partie d'un environnement cohésif modèrent la relation négative entre le désavantage socio-économique et la santé mentale. En démontrant des effets bénéfiques mais aussi contre-intuitifs de la confiance sociale, cette thèse propose une approche critique et contextualisée des sources et dynamiques de la cohésion sociale dans les sociétés démocratiques.

Preoperative assessment and classification of benign laryngotracheal stenosis: a consensus paper of the European Laryngological Society.

Adult and pediatric laryngotracheal stenoses (LTS) comprise a wide array of various conditions that require precise preoperative assessment and classification to improve comparison of different therapeutic modalities in a matched series of patients. This consensus paper of the European Laryngological Society proposes a five-step endoscopic airway assessment and a standardized reporting system to better differentiate fresh, incipient from mature, cicatricial LTSs, simple one-level from complex multilevel LTSs and finally "healthy" from "severely morbid" patients. The proposed scoring system, which integrates all of these parameters, may be used to help define different groups of LTS patients, choose the best treatment modality for each individual patient and assess distinct post-treatment outcomes accordingly.

ß2-adrenergic agonists actions on the human skeletal muscle

Les ß2-agonistes sont des bronchodilatateurs qui sont prescrits pour traiter l'asthme et l'asthme induite par l'exercice (AIE). Il est relevant de comprendre s'il y a une utilisation adéquate de ces médicaments pour traiter l'AIE chez les athlètes de haut niveau, ou s'ils sont utilisés pour leur potentiel effet ergogénique sur la performance physique. Ce travail examine les actions centrales et périphériques sur la fonction contractile du muscle squelettique humain in vivo induits par l'ingestion d'une dose thérapeutique de ß2- agonistes. Le premier but était d'évaluer si les ß2-agonistes exerçaient une potentialisation de la contractilité du muscle humain et/ou un effet "anti¬fatigue" comme observé dans le modèle animal. Les résultats n'ont fournit aucune évidence d'une potentialisation sur le muscle squelettique humain in vivo non-fatigué et fatigué induit par l'administration orale de ß2-agonistes. Tout effet excitateur exercé par ce traitement sur le système nerveux central a été aussi exclu. Le deuxième but était de déterminer si les ß2-agonistes affaiblissaient la contractilité du muscle squelettique humain à contraction lente, et d'évaluer si ce changement pouvait interférer avec le contrôle moteur au muscle. Les résultats ont montré que les ß2-agonistes affaiblissent la contractilité des fibres lentes, comme conséquence de l'effet lusitrope positif se produisant dans ces fibres. La capacité de développer une force maximale n'est pas réduite par le traitement, même si une augmentation de la commande centrale au muscle est requise pour produire la même force lors de contractions sous-maximales. Le but final était d'examiner si une adaptation du contrôle moteur était re¬quis pour compenser l'affaiblissement des fibres lentes exercée par les ß2- agonistes pendant un exercice volontaire, et de déterminer si cette adaptation centrale pouvait accroître la fatigue musculaire. Malgré le fait que les résultats confirment l'effet affaiblissant induit par les ß2-agonistes, ce changement contractile n'influence pas le contrôle moteur au muscle pendant les contractions sous-maximales de l'exercice fatiguant, et n'accroît pas le degré de fatigue. Ce travail éclaircit les actions spécifiques des ß2-agonistes sur la fonction contractile du muscle squelettique humain in vivo et leurs influence sur le contrôle moteur. Les mécanismes sous-jacents de l'action ergogénique sur la performance physique produit par les ß2-agonistes sont aussi élucidés. -- ß2-Agonists are bronchodilators that are widely prescribed for the treatment of asthma and exercise-induced asthma (EIA). The extensive use of ß2-agonists by competitive athletes has raised the question as to whether there is a valid need for this class of drugs because of EIA or a misuse because of their potential ergogenic effect on exercise performance. This work investigated the central and peripheral actions that were elicited by the ingestion of a therapeutic dose of ß2-agonists on the contractility of human skeletal muscle in vivo. The first objective was to investigate whether ß2-agonists would potentiate muscle contractility and/or exert the "anti-fatigue" effect observed in animal models. The findings did not provide any evidence for the ß2-agonist-induced potentiation of in vivo human non-fatigued and fatigued skeletal muscle. Moreover, the findings exclude any excitatory action of this treatment on the central nervous system. The second objective was to explore whether the weakening action on the contractile function would occur after ß2-agonist intake in human slow-twitch skeletal muscle and to ascertain whether this contractile change may interfere with muscle motor control. The results showed that ß2-agonists weaken the contractility of slow-twitch muscle fibres as a result of the lusitropic effect occurring in these fibres. The maximal force-generating capacity of the skeletal muscle is not reduced by ß2-agonists, even though an augmented neural drive to muscle is required to develop the same force during submaximal contractions. The final objective was to examine whether a motor control adjustment is needed to compensate for the ß2-agonist-induced weakening effect on slow- twitch fibres during a voluntary exercise and to also assess whether this central adaptation could exaggerate muscle fatigue. Despite the findings confirming the occurrence of the weakening action that is exerted by ß2- agonists, this contractile change did not interfere with muscle motor control during the submaximal contractions of the fatiguing exercise and did not augment the degree of the muscle fatigue. This work contributes to a better understanding of the specific actions of ß2-agonists on the contractile function of in vivo human skeletal muscles and their influence on motor control. In addition, the findings elucidate mechanisms that could underlie the ergogenic effect that is exerted by ß2- agonists on physical performance.

Screening and overdiagnosis : public health implications

Overdiagnosis is the diagnosis of an abnormality that bears no substantial health hazard and no benefit for patients to be aware of. Resulting mainly from the use of increasingly sensitive screening and diagnostic tests, as well as broadened definitions of conditions requiring an intervention, overdiagnosis is a growing but still largely misunderstood public health issue. Fear of missing a diagnosis or of litigation, financial incentives or patient's need of reassurance are further causes of overdiagnosis. The main consequence of overdiagnosis is overtreatment. Treating an overdiagnosed condition bears no benefit but can cause harms and generates costs. Overtreatment also diverts health professionals from caring for those most severely ill. Recognition of overdiagnosis due to screening is challenging since it is rarely identifiable at the individual level and difficult to quantify precisely at the population level. Overdiagnosis exists even for screening of proven efficacy and efficiency. Measures to reduce overdiagnosis due to screening include heightened sensitization of health professionals and patients, active surveillance and deferred treatment until early signs of disease progression and prognosis estimation through biomarkers (including molecular) profiling. Targeted screening and balanced information on its risk and benefits would also help limit overdiagnosis. Research is needed to assess the the public health burden and implications of overdiagnosis due to screening activity.

CT attenuation values of blood and myocardium: rationale for accurate coronary artery calcifications detection with multi-detector CT.

OBJECTIVES: To determine inter-session and intra/inter-individual variations of the attenuations of aortic blood/myocardium with MDCT in the context of calcium scoring. To evaluate whether these variations are dependent on patients' characteristics. METHODS: Fifty-four volunteers were evaluated with calcium scoring non-enhanced CT. We measured attenuations (inter-individual variation) and standard deviations (SD, intra-individual variation) of the blood in the ascending aorta and of the myocardium of left ventricle. Every volunteer was examined twice to study the inter-session variation. The fat pad thickness at the sternum and noise (SD of air) were measured too. These values were correlated with the measured aortic/ventricular attenuations and their SDs (Pearson). Historically fixed thresholds (90 and 130 HU) were tested against different models based on attenuations of blood/ventricle. RESULTS: The mean attenuation was 46 HU (range, 17-84 HU) with mean SD 23 HU for the blood, and 39 HU (10-82 HU) with mean SD 18 HU for the myocardium. The attenuation/SD of the blood were significantly higher than those of the myocardium (p < 0.01). The inter-session variation was not significant. There was a poor correlation between SD of aortic blood/ventricle with fat thickness/noise. Based on existing models, 90 HU threshold offers a confidence interval of approximately 95% and 130 HU more than 99%. CONCLUSIONS: Historical thresholds offer high confidence intervals for exclusion of aortic blood/myocardium and by the way for detecting calcifications. Nevertheless, considering the large variations of blood/myocardium CT values and the influence of patient's characteristics, a better approach might be an adaptive threshold.

Regional differences of physical activity and sedentary behaviour in Swiss children are not explained by socio-demographics or the built environment.

OBJECTIVE: We evaluated whether regional differences in physical activity (PA) and sedentary behaviour (SB) existed along language boundaries within Switzerland and whether potential differences would be explained by socio-demographics or environmental characteristics. METHODS: We combined data of 611 children aged 4 to 7 years from four regional studies. PA and SB were assessed by accelerometers. Information about the socio-demographic background was obtained by questionnaires. Objective neighbourhood attributes could be linked to home addresses. Multivariate regression models were used to test associations between PA and SB and socio-demographic characteristics and neighbourhood attributes. RESULTS: Children from the German compared to the French-speaking region were more physically active and less sedentary (by 10-15 %, p < 0.01). Although German-speaking children lived in a more favourable environment and a higher socioeconomic neighbourhood (differences p < 0.001), these characteristics did not explain the differences in PA behaviour between French and German speaking. CONCLUSIONS: Factors related to the language region, which might be culturally rooted were among the strongest correlates of PA and SB among Swiss children, independent of individual, social and environmental factors.

No Evidence for moral reward and punishment in an anonymous context.

Human social interactions are regulated by moral norms that define individual obligations and rights. These norms are enforced by punishment of transgressors and reward of followers. Yet, the generality and strength of this drive to punish or reward is unclear, especially when people are not personally involved in the situation and when the actual impact of their sanction is only indirect, i.e., when it diminishes or promotes the social status of the punished or rewarded individual. In a real-life study, we investigated if people are inclined to anonymously punish or reward a person for her past deeds in a different social context. Participants from three socio-professional categories voted anonymously for early career violinists in an important violin competition. We found that participants did not punish an immoral violin candidate, nor did they reward another hyper-moral candidate. On the contrary, one socio-professional category sanctioned hyper-morality. Hence, salient moral information about past behavior did not elicit punishment or reward in an impersonal situation where the impact of the sanction was indirect. We conclude that contextual features play an important role in human motivation to enforce moral norms.

Keeping the balance? Management of oxidative stress, body mass and reproduction under energetic constraints by dispersing and philopatric collared flycatchers.

Dispersal, i.e. individual movement between breeding sites, is a key process for metapopulation dynamics and gene flow. Its success can be modulated by phenotypic differences between dispersing and philopatric individuals, or dispersal syndromes. However, the environmental (external) and physiological (internal) constraints underlying such syndromes remain poorly known. This project aimed at clarifying the impact of environmental variation and oxidative constraints, linked to the reactive oxygen species produced during respiration, on phenotypes associated to dispersal in a passerine bird, the collared flycatcher Ficedula albicollis. Energetic demand was experimentally (i) increased through a wing load manipulation or (ii) relieved through food supplementation. The oxidative balance of breeding flycatchers was influenced by complex interactions of dispersal status and extrinsic factors (breeding density, year, experimental treatments). Interestingly, antioxidant capacity was influenced both by permanent individual differences and by food availability, whereas measures of pro-oxidants were highly variables within individuals. Environmental variation and energetic constraints also modulated the differences in reproduction associated with dispersal: dispersing and philopatric birds differ in their management of the oxidative balance when it is competing with reproductive investment. This thesis highlights that reaction norms, rather than fixed differences, often shape traits associated to dispersal. ----- Le déplacement d'un individu entre sites de reproduction, ou dispersion, est un processus clé pour la dynamique des métapopulations et les flux de gènes. Son succès peut être modulé par des différences de phénotype, ou syndromes de dispersion. Cependant, les contraintes environnementales et physiologiques qui sous-tendent ces syndromes restent mal connues. Ce projet vise à clarifier l'impact des variations environnementales et des contraintes oxydatives (liées aux espèces réactives de l'oxygène produites durant la respiration) sur les phénotypes associés à la dispersion chez un passereau, le gobemouche à collier Ficedula albicollis. La demande énergétique a été expérimentalement (i) augmentée en manipulant la surface alaire ou (ii) diminuée par une supplémentation en nourriture. L'équilibre oxydo-réducteur des gobemouches en reproduction est influencé par des interactions complexes entre statut de dispersion et facteurs extrinsèques (densité de couples reproducteurs, année, traitement expérimental). La capacité antioxydante dépend principalement de différences permanentes entre individus, alors que les pro-oxydants présentent de grandes variations intra-individu. Environnement et contraintes énergétiques modulent aussi les différences de reproduction liées à la dispersion : les oiseaux dispersants et philopatriques diffèrent dans leur gestion de l'équilibre oxydo-réducteur lorsqu'il est en compétition avec l'investissement reproducteur. Ce travail souligne que les traits associés à la dispersion sont souvent déterminés par des normes de réaction à l'environnement et non des différences fixées entre individus.