Introduction La randomisation mendélienne (RM) est une approche de plus en plus populaire dans les études observationnelles qui utilise des variants génétiques (habituellement des polymorphismes mononucléotidiques ou single-nucleotide polymorphisms, SNPs) associés à une exposition (hypothèse 1 ou pertinence) comme instruments pour estimer l’effet causal de cette exposition sur une issue, en assumant l’absence de confusion entre l’instrument et l’issue (hypothèse 2 ou indépendance) et l’absence d’un effet de l’instrument sur l’issue en dehors de l’exposition (hypothèse 3 ou restriction d’exclusion). Cependant, la validité des résultats de la RM est menacée par la pléiotropie, phénomène biologique par lequel un SNP affecte distinctement l’exposition et l’issue, qui est l’une des principales causes de violation de la restriction d’exclusion. Cette thèse examine certains défis méthodologiques pratiques de la RM relatifs à la vérification de la restriction d’exclusion et à la validité des résultats à travers trois principaux objectifs : 1) cartographier comment les chercheurs en RM préviennent, détectent et/ou contrôlent, et discutent des violations potentielles de la restriction d'exclusion dues notamment à la pléiotropie ; 2) évaluer la performance de la méthode basée sur la confusion positive, qui compare les estimés ponctuels de l’effet de l’exposition sur l’issue obtenus par la RM et par la régression conventionnelle, dans la détection des instruments invalides dans plusieurs contextes pratiques d’études de RM ; et 3) examiner l’impact des méthodes courantes de gestion de la médication antihypertensive dans les études de RM modélisant la pression artérielle (PA) sur l'estimation de l’effet causal et la détection des violations potentielles de la restriction d'exclusion. Méthodes Pour l’objectif 1, une revue de littérature de 128 études de RM ayant utilisé au moins un SNP sur le gène FTO (fat mass and obesity-associated) comme instrument de l’indice de masse corporelle (IMC) a été réalisée. La façon dont les auteurs préviennent, évaluent ou contrôlent, et discutent des violations potentielles de la restriction d’exclusion dues notamment à la pléiotropie a été examinée. Pour l’objectif 2, une étude de simulation statistique considérant des contextes d’études de RM utilisant comme instrument un SNP ou un score de risque génétique (genetic risk score, GRS), une issue continue ou binaire, dans des scénarios évaluant l’impact de la taille de l’échantillon et du type de pléiotropie (indirect ou direct), a été réalisée. La performance de la méthode basée sur la confusion positive a été définie comme le pourcentage de jeux de données simulés dans lesquels la méthode détectait des instruments invalides. Pour l’objectif 3, une étude de RM de l’association entre l’IMC et la PA systolique (PAS) a été réalisée. Les méthodes de gestion de la médication antihypertensive examinées étaient : (i) pas de correction, (ii) inclure la médication dans les modèles comme une covariable d’ajustement, (iii) exclure de l’analyse les sujets traités aux antihypertenseurs, (iv) ajouter une valeur constante de 15 mm Hg aux valeurs mesurées de la PAS chez les sujets traités aux antihypertenseurs, et (v) utiliser comme issue un indicateur binaire de l'hypertension. Résultats Il existe une pléthore de méthodes utilisées dans les études de RM dont certaines peuvent être sous-optimales à prévenir, détecter ou contrôler le biais dû à l’inclusion des SNPs pléiotropiques. Les simulations statistiques montrent qu’en RM utilisant un SNP comme instrument, la méthode basée sur la confusion positive est performante à détecter l’invalidité de l’instrument lorsque la pléiotropie est directe plutôt qu’indirecte, indépendamment de l’issue, mais la performance de la méthode s’améliore avec l’augmentation de taille de l’échantillon. En revanche, la méthode est moins performante à détecter l’invalidité lorsque l’instrument est un GRS, mais sa performance augmente avec la proportion des SNPs invalides inclus dans le GRS. Enfin, les estimations de la RM varient énormément selon la stratégie de gestion de la médication antihypertensive choisie, contrairement à la détection des violations de la restriction d’exclusion qui n’en est pas affectée. Conclusion Cette thèse met de l’avant certaines difficultés méthodologiques dans les applications de la RM et l’importance de la triangulation de plusieurs méthodes dans la vérification des hypothèses de RM. Le champ de la RM est en plein essor, et des nouvelles méthodes sont souvent proposées. Il devient important non seulement de les évaluer, mais aussi d’en détailler l’utilisation et les hypothèses sous-jacentes pour une utilisation optimale en complément aux méthodes existantes. / Introduction Mendelian randomization (MR) is an increasingly popular technique in observational studies that uses genetic variants (usually single-nucleotide polymorphisms, SNPs) associated with an exposure (Assumption 1 or relevance) as instruments to estimate the causal effect of that exposure on an outcome, assuming no confounding between the instrument and the outcome (Assumption 2 or independence) and no effect of the instrument on the outcome outside of its association with the exposure (Assumption 3 or exclusion restriction). However, the validity of the MR results is challenged by pleiotropy, the biological phenomenon whereby a SNP distinctly affects the exposure and the outcome, which is one of the leading causes of violation of the exclusion restriction assumption. This thesis examines some practical MR methodological challenges related to the assessment of the exclusion restriction and the validity of MR results through three main objectives: 1) to examine how MR researchers prevent, detect, and/or control for, and discuss potential violations of the exclusion restriction due especially to pleiotropy; 2) to evaluate the performance of the leveraging positive confounding (LPC) method that compares the MR and the conventional point estimates in detecting invalid instruments in several practical MR settings; and 3) to examine the impact of commonly used methods of accounting for antihypertensive medication in MR studies modeling blood pressure (BP) on the estimation of the causal effect and the detection of potential violations of the exclusion restriction. Methods For Objective 1, a literature review of 128 MR studies that used at least one SNP in the fat mass and obesity-associated (FTO) gene as an instrument for body mass index (BMI) was conducted to examined how the authors prevent, detect, or control, and discuss potential violations of the exclusion restriction, especially due to pleiotropy. For Objective 2, a simulation study considering MR analyse settings using single SNP or genetic risk score (GRS) as an instrument, continuous or binary outcome, in scenarios evaluating the impact of sample size and type of pleiotropy (indirect vs. direct) was performed. The performance of the LPC method was assessed as the percentage of simulated datasets in which the LPC method detected invalid instruments. For Objective 3, an MR study of the association between BMI and systolic BP (SBP) was performed. The methods for accounting for antihypertensive medication examined were: (i) no adjustment, (ii) include medication in the models as an adjustment covariate, (iii) exclude from the analysis subjects treated with antihypertensive medication, (iv) add a constant value of 15 mm Hg to the measured values of SBP in subjects using antihypertensive medication, and (v) use as outcome a binary indicator of hypertension. Results There exists a plethora of methods used in MR studies, some of which may be suboptimal for preventing, detecting, or controlling for bias due to the inclusion of pleiotropic SNPs. Statistical simulations show that in MR using single SNP as an instrument, the LPC method performs better at detecting invalidity of the instrument when the pleiotropy is direct than indirect, regardless of the outcome, although the performance of the method improves with increasing sample size. In contrast, the method performs less well in detecting invalidity when the instrument is a GRS, but its performance increases with the proportion of invalid SNPs included in the GRS. Finally, MR estimates change greatly depending on the chosen strategy of accounting for antihypertensive medication in contrast to the detection of exclusion restriction violations which is not impacted. Conclusion This present thesis highlights some of the methodological challenges in MR applications and the importance of triangulating multiple methods when assessing the MR assumptions. The MR field is booming, and new methods are often proposed. Therefore, it is important to evaluate these methods as well as to detail their application and underlying assumptions for optimal use as a complement to existing methods.

Obesity is a risk factor for development of cardiovascular disease, diabetes type 2 and some cancers. Newly detected genetic risk factor for body weight is the FTO gene ("fat mass and obesity associated"). The aim of this thesis was determine 1) whether the presence of risk alleles correlate with BMI in Czech population and to determine 2) whether there is an association between variants in the FTO gene and risk of myocardial infarction/ acute coronary syndrome (MI/ ACS), 3) renal failure (ESRD), or 4) incidence of colorectal cancer (CRC). We analyzed polymorphisms rs17817449 (first intron) and rs17818902 (3rd intron) using by PCR-RFLP and then also RT PCR. We found an association of the first intron variant (but not the 3rd one) and BMI in Czech control population. We have detected an association of 1st intron SNP and BMI changes during the intervention study in obese children, but not in obese females. We found a correlation between the risk allele and increased risk of ACS (OR 1.49) in patients with MI. In patients with ESRD was detected association between the risk allele and the risk of disease (OR 1.37). We didn't confirmed the association between rs17817449 and the development of CRC. Representative selected groups of the Czech populations "MONICA" and "HAPPIE" were used as controls. One...

The central nervous system (CNS) melanocortin signaling pathway plays a critical role in the regulation of metabolism. However, the regulatory effects of CNS melanocortin signaling on hepatic lipid metabolism and fatty liver disease have not been well established. Although the activity of the CNS melanocortin system is regulated by metabolic signals, the mechanism for this regulation is not fully understood. Variants of the FTO (fat mass and obesity-associated) gene are associated with obesity and FTO is expressed in the hypothalamic neurons including proopiomelanocortin (POMC) neurons. Therefore, it is hypothesized that hypothalamic FTO plays a role in the regulation of metabolism by mediating the effect of metabolic signals on hypothalamic melanocortinergic neurons, and that impairments in this regulation may cause metabolic impairments including obesity and fatty liver disease. Intracerebroventricular (i.c.v.) treatment with SHU9119, a melanocortin antagonist, increased hepatic lipid accumulation and the expression of genes encoding lipogenic enzymes in lean mice. Conversely, i.c.v. treatment with MTII, a melanocortin agonist, reduced the expression of hepatic lipogenic genes in association with reduction in body weight in ob/ob mice, a mouse model of fatty liver disease. Immunohistochemical analysis demonstrated that Fto is co-expressed in both POMC and agouti-related protein (AgRP) neurons in the mouse hypothalamus. Fto mRNA and protein expression was reduced by fasting and increased by glucose treatment in nutritionally important hypothalamic nuclei. Fasting-induced reduction in hypothalamic Fto expression was observed in both lean wild-type and obese ob/ob mice, while the stimulatory effect of glucose on hypothalamic Fto expression was absent in ob/ob mice. These findings support the hypothesis that central melanocortin signaling regulates hepatic lipid metabolism in part by regulating de novo lipogenesis. Impairments in the central melanocortin signaling lead to the development of hepatic steatosis, while enhanced melanocortin signaling may be beneficial in reversing abnormal hepatic lipid metabolism in fatty liver disease (Poritsanos et al., 2008). These findings also support the hypothesis that Fto is expressed in the hypothalamic melanocortinergic neurons and is regulated by metabolic signals involving changes in CNS glucose availability and/or glucose action. Impairments in this regulation may cause metabolic impairments including obesity and fatty liver disease.

The central nervous system (CNS) melanocortin signaling pathway plays a critical role in the regulation of metabolism. However, the regulatory effects of CNS melanocortin signaling on hepatic lipid metabolism and fatty liver disease have not been well established. Although the activity of the CNS melanocortin system is regulated by metabolic signals, the mechanism for this regulation is not fully understood. Variants of the FTO (fat mass and obesity-associated) gene are associated with obesity and FTO is expressed in the hypothalamic neurons including proopiomelanocortin (POMC) neurons. Therefore, it is hypothesized that hypothalamic FTO plays a role in the regulation of metabolism by mediating the effect of metabolic signals on hypothalamic melanocortinergic neurons, and that impairments in this regulation may cause metabolic impairments including obesity and fatty liver disease. Intracerebroventricular (i.c.v.) treatment with SHU9119, a melanocortin antagonist, increased hepatic lipid accumulation and the expression of genes encoding lipogenic enzymes in lean mice. Conversely, i.c.v. treatment with MTII, a melanocortin agonist, reduced the expression of hepatic lipogenic genes in association with reduction in body weight in ob/ob mice, a mouse model of fatty liver disease. Immunohistochemical analysis demonstrated that Fto is co-expressed in both POMC and agouti-related protein (AgRP) neurons in the mouse hypothalamus. Fto mRNA and protein expression was reduced by fasting and increased by glucose treatment in nutritionally important hypothalamic nuclei. Fasting-induced reduction in hypothalamic Fto expression was observed in both lean wild-type and obese ob/ob mice, while the stimulatory effect of glucose on hypothalamic Fto expression was absent in ob/ob mice. These findings support the hypothesis that central melanocortin signaling regulates hepatic lipid metabolism in part by regulating de novo lipogenesis. Impairments in the central melanocortin signaling lead to the development of hepatic steatosis, while enhanced melanocortin signaling may be beneficial in reversing abnormal hepatic lipid metabolism in fatty liver disease (Poritsanos et al., 2008). These findings also support the hypothesis that Fto is expressed in the hypothalamic melanocortinergic neurons and is regulated by metabolic signals involving changes in CNS glucose availability and/or glucose action. Impairments in this regulation may cause metabolic impairments including obesity and fatty liver disease.

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Surface texturization of Transparent Conductive Oxides (TCOs) is a well-known strategy to enhance the light-trapping capabilities of thin-film solar cells and thus, to increase their power conversion efficiency. Herein, the surface modification of fluorine-doped tin oxide (FTO) using picosecond infrared direct laser interference patterning (DLIP) is presented. The surface characterization exhibits periodic microchannels, which act as diffraction gratings yielding an increase in the average diffuse transmittance up to 870% in the spectral range of 400–1000 nm. Despite the one dimensionality of the microstructures, the films did not acquire a significant anisotropic electrical behavior, but a partial deterioration of their conductivity is observed as a result of the removal of conductive material. This work proposes the feasibility of trading off a portion of the electrical conductivity to obtain a substantial improvement in the optical performance.

<p>Detta arbete, inom ämnet Kristendomens historia, presenterar en svenskkyrklig orden, ”Franciskus Tredje Orden inom Svenska kyrkan” (F.T.O.), som tillhör den ”Tredje Orden” (TSSF) inom ”The Society of Saint Francis” (SSF), en ordensgemenskap inom den Anglikanska kyrkan, Church of England. Orden är öppen för kvinnor och män, vigda (biskopar, präster och diakoner) och lekfolk som lever vanliga liv i familj och samhälle, med en vilja att leva sina liv utifrån en tydlig inspiration av den helige Franciskus och hans liv.</p><p>Syftet med arbetet är att undersöka och redogöra för de primärkällor som finns från tiden av F.T.O.: s grundande för att svara på frågan om huruvida Ordens uppkomst var förenlig eller ej med den Svenska kyrkan, dess tro, lära och bekännelse.</p><p>Undersökningen inleds med en deskriptiv del gällande bakgrunden till frågeställningen där jag redogör något för reformationen och vad detta medförde för Svenska kyrkan gällande klosterliv. Sedan följer en redogörelse och en hermeneutiskt och dogmatisk analys av de, för tiden av Ordens grundande, aktuella källorna.</p><p>En sammanfattning av resultatet som framkommit är det att grundandet av F.T.O. i början av 1970-talet var förenligt med den Svenska kyrkan. Vi kan se i källorna att Ordens syfte och annat typiskt för Orden, korresponderar väl med vad som uttrycks gällande tro, lära och bekännelse i Kyrkolagen 1686 och de, förutom Bibeln, samlade bekännelseskrifterna för den Svenska kyrkan. Genom detta arbete konstaterar vi att ett ordensliv likt F.T.O. kan tillämpas inom ett evangeliskt-lutherskt kyrkosamfund och att det på intet sätt är synonymt med den gärningsfromhet inom klosterväsendet som reformatorerna så tydligt vände sig mot under medeltiden.</p> / <p>This study, in the subject the history of Christianity, present an order in the Church of Sweden, “Saint Francis Third Order within the Church of Sweden” (F.T.O.), which is a part of the “Third Order” (TSSF) within “The Society of Saint Francis” (SSF), a community within the Anglican Church, Church of England. The order is open for women and men, ordained (bishops, priests and deacons) and lay people who live ordinary lives in family and society, with a desire to live their lives inspired by Saint Francis and his life.</p><p>My purpose with this study is to examine and describe the prime sources from the time of the foundation of the F.T.O. to answer the question about whether the foundation of the Order was compatible or not with the Church of Sweden, their faith, doctrine and confession.</p><p>The examination starts with a descriptive part about the background to the study problem where I give some facts about the reformation and what that brings for the Church of Sweden in relation to monastery life. Then comes a description and a hermeneutics and a dogmatic analysis of the, for the time of the foundation of the Order, current sources.</p><p>A summery of the upcoming results of this study is that at the foundation of F.T.O. in 1970ths was compatible with the Church of Sweden. In the sources we can see that the Orders purpose and other typical for the Order corresponds well with what they say about faith, doctrine and confession in the church law from 1686 and the, except the holy Bible, confession scripts for the Church of Sweden. Through this work we establish the fact that an order life like that we see in F.T.O. could practices in an evangelical-Lutheran church and it is not in any way synonymic with that phenomena called “action piety” within the monastery life that the men’s of the reformation so clearly said no to under the middle age.</p>

Background: Type 2 diabetes is thought to result from interactions between genetic and lifestyle factors, but few robust examples exist. The overarching aim of this thesis was to discover such interactions by studying cohorts of white youth and adults from northern Europe in which physical activity, genotypes, and diabetes-related traits or diabetes incidence had been ascertained.   Methods: The thesis includes four papers. In Paper I, we investigated associations and interactions between 35 common PPARGC1A polymorphisms and cardiovascular and metabolic disease traits in 2,101 Danish and Estonian children from the European Youth Heart Study (EYHS). Paper II used the same cohort to test associations and interactions on cardiometabolic traits for the diabetes-predisposing TCF7L2 polymorphism. In Paper III, we assessed associations for 17 type 2 diabetes gene polymorphisms on impaired glucose regulation (IGR) or incident type 2 diabetes, and tested whether these effects are modified by physical activity in a prospective cohort study of ~16,000 initially non-diabetic Swedish adults – the Malmö Preventive Project (MPP). Paper IV aimed to replicate main genetic effects and gene x physical activity interactions for an FTO polymorphism on obesity in 18,435 primarily non-diabetic Swedish (MPP) and Finnish (Prevalence, Prediction and Prevention of Diabetes in Botnia) adults. Results: In Paper I, nominally significant associations were observed for BMI (rs10018239, P=0.039), waist circumference (rs7656250, P=0.012; rs8192678 [Gly482Ser], P=0.015; rs3755863, P=0.02; rs10018239, P=0.043), systolic blood pressure (rs2970869, P=0.018) and fasting glucose concentrations (rs11724368, P=0.045). Stronger associations were observed for aerobic fitness (rs7656250, P=0.005; rs13117172, P=0.008) and fasting glucose concentrations (rs7657071, P=0.002). None remained significant after correcting for multiple statistical comparisons. We proceeded by testing for gene × physical activity interactions for the polymorphisms that showed statistical evidence of association (P&lt;0.05) in the main effect models, but none was statistically significant. In Paper II, the minor T allele at the rs7903146 variant was associated with higher glucose levels in older (beta=–0.098 mmol/l per minor allele copy, P=0.029) but not in younger children (beta=–0.001 mmol/l per minor allele copy, P=0.972). A significant inverse association between the minor allele at rs7903146 and height was evident in boys (beta=–1.073 cm per minor allele copy, P=0.001), but not in girls. The test of interaction between the TCF7L2 rs7903146 variant and physical activity on HOMA-B was nominally statistically significant (beta=0.022, Pinteraction=0.015), whereby physical activity reduced the effect of the risk allele on estimated beta-cell function. In Paper III, tests of gene x physical activity interactions on IGR-risk for three polymorphisms were nominally statistically significant: CDKN2A/B rs10811661 (Pinteraction=0.015); HNF1B rs4430796 (Pinteraction=0.026); PPARG rs1801282 (Pinteraction=0.04). Consistent interactions were observed for the CDKN2A/B (Pinteraction=0.013) and HNF1B (Pinteraction=0.0009) variants on 2 hr glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed and this was for the HNF1B rs4430796 variant (Pinteraction=0.0004). The interaction effects for HNF1B on 2 hr glucose and incident diabetes remained significant after correction for multiple testing (Pinteraction=0.015 and 0.0068, respectively). In Paper IV, the minor A allele at rs9939609 was associated with higher BMI (P&lt;0.0001). The tests of gene x physical activity interaction on BMI were not statistically significant in either cohort (Sweden: P=0.71, Finland: P=0.18). Conclusions: Variation at PPARGC1A is unlikely to have a major impact on cardiometabolic health in European children, but physical activity may modify the effect of the TFC7L2 variants on beta-cell function in this cohort. In Swedish adults, physical activity modifies the effects of common HNF1B and CDKN2A/B variants on risk of IGR and also modifies the effect of the HNF1B on type 2 diabetes risk. In Swedish and Finnish adults, we were unable to confirm previous reports of an interaction between FTO gene variation and physical activity on obesity predisposition.

Detta arbete, inom ämnet Kristendomens historia, presenterar en svenskkyrklig orden, ”Franciskus Tredje Orden inom Svenska kyrkan” (F.T.O.), som tillhör den ”Tredje Orden” (TSSF) inom ”The Society of Saint Francis” (SSF), en ordensgemenskap inom den Anglikanska kyrkan, Church of England. Orden är öppen för kvinnor och män, vigda (biskopar, präster och diakoner) och lekfolk som lever vanliga liv i familj och samhälle, med en vilja att leva sina liv utifrån en tydlig inspiration av den helige Franciskus och hans liv. Syftet med arbetet är att undersöka och redogöra för de primärkällor som finns från tiden av F.T.O.: s grundande för att svara på frågan om huruvida Ordens uppkomst var förenlig eller ej med den Svenska kyrkan, dess tro, lära och bekännelse. Undersökningen inleds med en deskriptiv del gällande bakgrunden till frågeställningen där jag redogör något för reformationen och vad detta medförde för Svenska kyrkan gällande klosterliv. Sedan följer en redogörelse och en hermeneutiskt och dogmatisk analys av de, för tiden av Ordens grundande, aktuella källorna. En sammanfattning av resultatet som framkommit är det att grundandet av F.T.O. i början av 1970-talet var förenligt med den Svenska kyrkan. Vi kan se i källorna att Ordens syfte och annat typiskt för Orden, korresponderar väl med vad som uttrycks gällande tro, lära och bekännelse i Kyrkolagen 1686 och de, förutom Bibeln, samlade bekännelseskrifterna för den Svenska kyrkan. Genom detta arbete konstaterar vi att ett ordensliv likt F.T.O. kan tillämpas inom ett evangeliskt-lutherskt kyrkosamfund och att det på intet sätt är synonymt med den gärningsfromhet inom klosterväsendet som reformatorerna så tydligt vände sig mot under medeltiden. / This study, in the subject the history of Christianity, present an order in the Church of Sweden, “Saint Francis Third Order within the Church of Sweden” (F.T.O.), which is a part of the “Third Order” (TSSF) within “The Society of Saint Francis” (SSF), a community within the Anglican Church, Church of England. The order is open for women and men, ordained (bishops, priests and deacons) and lay people who live ordinary lives in family and society, with a desire to live their lives inspired by Saint Francis and his life. My purpose with this study is to examine and describe the prime sources from the time of the foundation of the F.T.O. to answer the question about whether the foundation of the Order was compatible or not with the Church of Sweden, their faith, doctrine and confession. The examination starts with a descriptive part about the background to the study problem where I give some facts about the reformation and what that brings for the Church of Sweden in relation to monastery life. Then comes a description and a hermeneutics and a dogmatic analysis of the, for the time of the foundation of the Order, current sources. A summery of the upcoming results of this study is that at the foundation of F.T.O. in 1970ths was compatible with the Church of Sweden. In the sources we can see that the Orders purpose and other typical for the Order corresponds well with what they say about faith, doctrine and confession in the church law from 1686 and the, except the holy Bible, confession scripts for the Church of Sweden. Through this work we establish the fact that an order life like that we see in F.T.O. could practices in an evangelical-Lutheran church and it is not in any way synonymic with that phenomena called “action piety” within the monastery life that the men’s of the reformation so clearly said no to under the middle age.