La pandémie de l'obésité entraine une augmentation de la prévalence des maladies chroniques du foie ou stéatopathies métaboliques (NAFLD). Le spectre des NAFLD va de la stéatose caractérisée par une accumulation de lipides dans le foie à la stéatohépatite (NASH) associant une inflammation, de la mort hépatocytaire et de la fibrose. Lors de l'obésité, l'élévation de signaux de dangers métaboliques perturbe les fonctions du réticulum endoplasmique (RE) essentielles pour l’homéostasie cellulaire. Les perturbations sont transmises par 3 senseurs : IRE1α, ATF6 et PERK pour activer une réponse adaptative. Si ce stress est sévère ou devient chronique, la cellule enclenchera une réponse terminale apoptotique. La protéine Bax Inhibitor-1 (BI-1) pourrait jouer un rôle hépatoprotecteur en inhibant l’hyperactivation de la voie de signalisation IRE1α.En combinant des études chez l’homme et dans des modèles animaux, l’objectif de cette étude était de mieux caractériser l'activation chronique du stress du RE dans les NAFLD. Ce travail a émis l’hypothèse qu’une déficience en BI-1 entrainerait l’activation soutenue de la voie IRE1α qui serait responsable de la transition de la stéatose à la NASH. Cette étude s'intéresse au dialogue potentiel entre le stress du RE et l’activation de l'inflammasome NLRP3, qui induit la sécrétion des cytokines pro-inflammatoires (IL-1β, IL-18) grâce aux caspases pro-inflammatoires (caspase-1, caspase-4/11). L’utilisation d’un inhibiteur global du stress du RE ou des inhibiteurs pharmacologiques spécifiques à la voie IRE1α améliorerait les caractéristiques pathophysiologiques de la NASH et pourrait ouvrir de nouvelles perspectives thérapeutiques. / Due to the obesity pandemic, the last decades have been marked by a constantly increasing prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD covers a spectrum of hepatic disorders ranging from steatosis, characterized by the ectopic accumulation of lipids in the liver, to steatohepatitis (NASH), featuring inflammation, hepatocellular death and fibrosis. During obesity, an increase in metabolic danger signals leads to disrupted endoplasmic reticulum (ER) function, essential for cellular homeostasis. The resulting ER stress activates a signaling network involving three sensors: IRE1α, ATF6 and PERK to enforce adaptive programs. If this stress is severe or becomes chronic, the cell will trigger a terminal apoptotic response. The protein Bax Inhibitor-1 (BI-1), as a negative endogenous regulator of the IRE1α signaling pathway in the liver, may play a hepatoprotective role.By combining data from obese patients with liver complications and experimental approaches in mice, this thesis aimed to better characterize the chronic activation of ER stress in NAFLD pathogenesis. This work also emitted the hypothesis that a deficiency in BI-1 leads to unrestrained IRE1α signaling that may be responsible for the steatosis to NASH transition. This study further investigated the potential dialogue between ER stress and the activation the NLRP3 inflammasome, which induces the secretion of pro-inflammatory cytokines (IL-1β, IL-18) by activating pro-inflammatory caspases (caspase-1, caspase-4/11). The administration of a broad spectrum ER stress inhibitor or specific inhibitors of IRE1α improved the pathophysiological features of NASH and may open novel therapeutic perspectives.

Bakgrund: Sömnstörningar är ett vanligt fenomen hos personer med demenssjukdom. Störningarna yttrar sig ofta genom upplevd trötthet under dagtid och osammanhängande sömn under natten. Sömnen är betydelsefull för återhämtningen och bidrar till en ökad livskvalitet.  Problem: Personer med demenssjukdom lider ofta av flera symtom som kan förvärras vid sömnbrist. Omvårdnadsåtgärder som sjuksköterskan kan använda för att främja sömnen för personer med demenssjukdom är bristande och behöver tydliggöras samt lyftas fram. Syfte: Syftet är att skapa en översikt av omvårdnadsåtgärder för att främja sömnen hos personer med demenssjukdom. Metod: En litteraturöversikt med kvalitativa-, mixade- samt kvantitativa artiklar. Resultat: Resultatet visade flera olika omvårdnadsåtgärder som kan tillämpas vid sömnstörningar för att främja sömnen hos personer med demenssjukdom. De olika kategorierna som presenteras under resultatet är: Miljöns betydelse, kvalitetssäkra rutiner för sömn och vikten av beröring. Slutsats: Några generella slutsatser kunde inte dras då evidensen för omvårdnadsåtgärderna är låg och kräver mer forskning. Sömnen kunde dock främjas genom de omvårdnadsåtgärder som presenteras i resultatet. / Background: Sleep disorders are a common phenomenon in people with dementia. The disorders are often manifested by perceived fatigue during the day and incoherent sleep during the night. Sleep is important for recovery and contributes to an increased quality of life. Problem: People with dementia can suffer from several symptoms that can be worsened by a lack of sleep. Nursing interventions that can be used to promote sleep in people with dementia are deficient therefore, they need to be clarified and highlighted. Aim: The aim is to create an overview of nursing measures to promote sleep in people with dementia. Method: A literature review with qualitative-, mixed-and quantitative articles. Results: The results showed several different nursing interventions that can be applied in sleep disorders to promote sleep in people with dementia. The importance of the environment, quality-assured routines for sleep and the importance of touch. Conclusion: No general conclusions could be drawn as the evidence for nursing measures is low and needs more research. However, sleep could be promoted through the nursing measures presented in the development.

Bakgrund: Fysisk aktivitet har flera positiva effekter på hälsan. Fysisk aktivitet på recept är en behandlingsmetod mot olika ohälsotillstånd, samt i preventivt syfte. Fysisk aktivitet på recept kan förskrivas av legitimerad vårdpersonal, exempelvis sjuksköterskor.  Syfte: Att beskriva patienters upplevelser av följsamhet till fysisk aktivitet på recept. Metod: Kvalitativ litteraturöversikt med induktiv ansats där tio vetenskapliga artiklar sammanställdes efter analys av materialet enligt Fribergs femstegsanalys.  Resultat: Tre kategorier formades: individuella påverkansfaktorer, sociala påverkansfaktorer och yttre påverkansfaktorer. Individuella påverkansfaktorer berörde exempelvis symtom och tidigare erfarenheter. Sociala faktorer var till exempel stöd från familj och närstående samt vårdpersonal. Yttre påverkansfaktorer handlade bland annat om tid och ekonomi. Slutsats: Både yttre och inre faktorer påverkade följsamheten till receptet. Orsakerna till följsamhet/icke följsamhet var ofta multifaktoriella och komplexa. Vårdpersonalen som förskriver receptet behöver vara lyhörda för patientens behov och förutsättningar. Som förskrivande vårdpersonal är det även viktigt att erbjuda stöd och uppföljningar. / Background: Physical activity (PA) has several beneficial effects on health. Physical activity on prescription (PAP) is a non-medical treatment method and is also used to prevent future illness. Health care practioners with a legitimation – e.g. nurses - can prescribe PAP. Aim: To describe patients experiences of compliance to physical activity on prescription.  Method: A qualitative literature review with inductive approach. Ten articles with qualitative design were analyzed and compiled through Friberg’s analyze in five steps.  Results: The result was organized in three main categories: individual factors, social influential factors and external factors. Individual factors was for example symptoms and previous experience. Social factors was for example support from family, friends and healthcare staff. External factors was for example time and economy. Conclusion: Both external and internal factors had impact on the participants adherence to PAP. The reasons explained by the participants were multifactorial and complex. Health care professionals who prescribe physical activity need to be responsive to the patients` needs and prerequisites. It is also important to offer support and follow-ups.

Title: Physical education of individuals with type 2 diabetes mellitus Objectives: The aim of this thesis is to evaluate the effect of physical education of individuals with type 2 diabetes mellitus cured in diabetologic outpatient clinic of Genereal University Hospital in Prague. The physical education was focused on nordic walking. Methods: Eight patients of diabetological outpatient clinic were chosen by the doctor for this survey. The physical examination was carried out with seven patients. It involved anthropometrical measurements (weight, waist circumference) and blood collection for biochemical parameters assessment (glycemia, glycated hemoglobin). Two-minute step test was chosen for assessment of subject's physical fitness. Results: The physical activity education of individuals with type 2 diabetes mellitus doesn't increase the amount of their physical activity. The physical activity of type 2 diabetes mellitus individuals is rather low as well as their exercise adherence. Nordic walking exercise program can improve anthropometrical parametres (weight, waist circumference) and can reduce HbA1c levels. Lower health-related quality of life in physical and physological aspects wasn't proved in type 2 diabetes patients. Key words: nordic walking, physical activity, type 2 diabetes management,...

Bakgrund Demenssjukdom utgör ett stort hälsoproblem med både emotionella och fysiska konsekvenser. Många av de personer som lever med demenssjukdom flyttar till särskilda boenden när de inte längre klarar sig på egen hand. Beteendemässiga och psykiska symtom vid demens (BPSD) innefattar olika vanligt förekommande symtom vid demenssjukdom. Symtombehandling med läkemedel medför risker i form av förvirring, olyckor och fall. Syfte Syftet med denna litteraturöversikt är att beskriva effekter och användande av icke-farmakologiska metoder för att lindra symtom vid demens. Metod Litteraturöversikten baserades på 13 vetenskapliga artiklar, varav 11 kvantitativa och 2 kvalitativa, publicerade mellan 2012 och 2021. Artiklarna inhämtades från databaserna CINAHL, PubMed och PsycInfo. Studierna granskades enligt Örebros universitets mallar och därefter analyserades innehållet. Resultat Resultatet utgjordes av två huvudkategorier; Interventioners effekter med underkategorierna BPSD, Kognition, ADL, Livskvalitet och Vårdgivarbörda samt Användande av icke-farmakologiska metoder, med underkategorierna Tillfällen för icke-farmakologiska metoder, Kunskap och Hindrande faktorer. Resultatet visade att icke-farmakologiska metoder hade god effekt vid lindring av symtom vid demens. Effekten på olika symtom och grad av demens varierade beroende på metod. Slutsats Eftersom effekterna av de icke-farmakologiska metoderna varierade, krävdes en personcentrerad inställning där interventionerna individanpassades. Vid sidan av symtomlindring sågs effekter i form av ökad ADL-förmåga, ökad livskvalitet och minskad vårdgivarbörda. / Background Dementia constitutes a large threat on health and has both emotional and physical consequences. Many people that live with dementia move into care facilities when they can no longer cope on their own. Behavioural and psychological symptoms of dementia(BPSD) include different symptoms that are common in dementia. To treat these symptoms with drugs entails risks, such as confusion, accidents and falls. Aim The aim of this study is to describe effects, and use of, non-pharmacological methods to alleviate symptoms of dementia. Method This literature rewiev is based on 13 scientific articles; 11 quantitative and 2 qualitative, published between 2012 and 2021. The articles were obtained from the databases CINAHL, PubMed and PsycInfo. The studies were reviewed according to templates by Örebro University and thereafter the content was analysed. Results The result was divided into two main categories; The effects of interventions, with the subcategories BPSD, Cognition, ADL, Quality of life and Caregiver burden and The use of non-pharmacological methods, with the subcategories Opportunities for non-pharmacological methods, Knowledge and Hindering factors. The result indicated that non-pharmacological methods were effective for alleviation of symptoms of dementia.The effect on different symptoms and degree of dementia varied depending on method. Conclusions Since the effects of the non-pharmacological methods varied, a person-centred approach with individualized interventions was necessary. In addition, there were positive effects in form om increased capability to perform ADL, increased quality of life and reduced caregiver burden.

This doctoral thesis aims to demonstrate the relevance of resting-state functional connectivity (RSFC) for the study of brain function. RSFC refers to the spontaneous brain activity structured in intrinsic connectivity networks. These networks mirror task-based activations and show significant variations across several behavioral domains and phenotypical traits. Furthermore, changes in these networks after, for instance, pharmacological manipulations, may disentangle the specific role of several neurotransmitters systems in normal and pathological functional connectivity. While various neuroimaging techniques enable the detection of intrinsic connectivity networks, data-driven methods, such as independent component analysis, provide a robust spatial representation of brain networks that are distinguishable from physiological signals and scanner noise. Within the above-mentioned framework, this thesis presents data from two studies designed to better understand 1) individual differences in decision making reflected in intrinsic network connectivity and 2) variations in intrinsic network connectivity following serotonergic manipulations. The first part is the general introduction where I present the theoretical background, the methodology used in both experiments and an overview of the current research related to the studies of this thesis. The second chapter presents the first study, which examined the relationship between a set of value-based decision-making parameters with large-scale intrinsic connectivity networks. Findings of this study revealed that individuals who prefer to gamble in order to avoid a sure loss, exhibit stronger connectivity between the default mode and left frontoparietal systems to their adjacent brain regions, especially to those involved in prospective thinking, affective decision making and visual processing. The third chapter presents the second experimental study, which examined changes in default mode network connectivity after two tryptophan interventions to increase and decrease brain serotonin synthesis, and a control condition. Results of this study showed decreased functional connectivity between the default mode network and emotion-related regions associated with higher serotonin brain levels. Finally, the fourth chapter includes a general discussion that integrates the significance of the findings from both studies. In this section, limitations and recommendations for future research are also considered before presenting the conclusion that highlights the contribution of this work for unraveling the continuous activity of the resting brain.:1.CONTENTS 1 LIST OF FIGURES 3 LIST OF TABLES 4 ABBREVIATIONS 5 ABSTRACT 7 GENERAL INTRODUCTION 9 1.1. Resting-state functional connectivity: the silent work of the resting brain 9 1.2. Intrinsic connectivity networks 12 1.3. Independent Component Analysis 17 1.4. Summary: research objectives and study hypotheses 20 STUDY I: Risk seeking for losses modulates the functional connectivity of the default 2.mode and left frontoparietal networks in young males 22 2.1. Abstract 23 2.2. Introduction 24 2.3. Materials and Methods 26 2.4. Results 33 2.5. Discussion 41 2.6. Notes 44 2.7. Supplemental Material Study I 45 3. STUDY II: Acute Tryptophan Loading Decreases Functional Connectivity between the Default Mode Network and Emotion-Related Brain Regions 49 3.1. Abstract 50 3.2. Introduction 51 3.3. Materials and Methods 53 3.4. Results 61 3.5. Discussion 67 3.6. Acknowledgments 71 3.7. Supplemental Material Study II 72 4. GENERAL DISCUSSION 78 4.1. Research objectives and summary of results 78 4.2. Risk seeking for losses is associated with changes in default mode and frontoparietal systems 79 4.3. Higher serotonin brain synthesis decreases DMN connectivity 80 4.4. Integration of findings 81 4.5. Limitations and future directions 83 4.6. General conclusion 85 5. ZUSAMMENFASSUNG 86 Hintergrund 86 Fragestellung 86 Material und Methoden 87 Ergebnisse 88 Schlussfolgerungen 89 6. SUMMARY 90 Background 90 Research question 90 Material and Methods 91 Results 92 Conclusion 92 7.REFERENCES 93 8.ANNEX 113 8.1. Publikationsverzeichnis 113 8.3.Danksagung 115 8.4. Erklärungen zur Eröffnung des Promotionsverfahrens 116 8.5. Erklärung zur Einhaltung gesetzlicher Vorgaben118 8.6. Erklärungen zur Publikation 119

Indiana University-Purdue University Indianapolis (IUPUI) / The present study sought to identify the effects of chronic lithium administration on ethanol intakes in high alcohol-preferring (HAP) mice. Lithium is a well-established treatment for bipolar disorder and has demonstrated efficacy in reducing impulsivity, an endophenotype of the disease. Impulsivity is also a prominent trait of alcoholism. HAP mice display a preference for consuming substantial amounts of ethanol and exhibit abnormally high levels of impulsivity. Previous work has determined that chronic lithium exposure in HAP mice reduces their levels of impulsivity. The present study analyzed fluctuations in established intake patterns after lithium exposure and how pre-exposure to lithium would affect ethanol intake acquisition. The results showed an increase in ethanol intake and no change in preference for ethanol over water in lithium treated mice. There was an increase in overall total fluid consumption in these mice, likely resulting from polydipsic effects. There also appeared to be a potentiated lithium toxicity effect found in those mice pre-exposed to lithium. The conclusion was that lithium therapy does not decrease ethanol consumption in HAP mice.

L’insuffisance cardiaque (IC) est associée à une mortalité élevée et de récurrentes hospitalisations. Sa détection précoce et sa prise en charge sont alors considérées fondamentales à une amélioration de la survie et de la qualité de vie des patients qui en souffrent. Pourtant, bien que des lignes directrices synthétisant les évidences des essais cliniques phares soient périodiquement publiées pour guider les cliniciens dans la prise en charge de l’IC, l’adhésion des professionnels de la santé à celles-ci semble être insatisfaisante. En effet, alors que les taux de prescription de certaines thérapies soient élevés, les doses prescrites n’atteignent pas toujours les cibles recommandées et d’autres thérapies sont moins utilisées. Ainsi, bien que l’inertie clinique puisse justifier une partie de ces lacunes, une caractérisation plus élaborée de cette adhésion aux lignes directrices en milieu clinique est nécessaire à une meilleure compréhension de ces écarts et par le fait même, à une meilleure prise en charge de l’IC. L’objectif de ce projet est alors de dresser, dans un premier temps, un portrait détaillé de la prise en charge des patients atteints d’IC avec une fraction d’éjection réduite suivis par une équipe interdisciplinaire dans une clinique ambulatoire spécialisée au Québec puis, dans un second temps, d’évaluer l’impact de cette adhésion sur le pronostic de ces patients. Le premier papier présenté dans ce travail démontre non seulement des taux de prescriptions élevés, mais également des taux d’optimisation des thérapies recommandées supérieurs à ce qui est rapporté dans la littérature, lorsque les paramètres physiologiques et biologiques propres à chaque patient sont considérés. Il reste néanmoins une proportion considérable de patients qui nécessitent une titration plus lente au-delà des 6 mois recommandés tandis que d’autres demeurent indéfiniment à des doses inappropriées. Le second papier présenté approfondit cette analyse et démontre que les patients recevant un traitement pharmacologique aux doses optimales sont ceux qui présentent le meilleur pronostic dans l’année suivant la période d’optimisation allouée, suivis de ceux nécessitant une titration prolongée puis, ceux demeurant à des doses sous-optimales. Or, les patients à plus haut risque de morbidité ou de mortalité sont ceux présentant une intolérance ou une contre-indication aux thérapies recommandées, une population de patients fragiles nécessitant une attention particulière lors de la prise en charge de leur IC. / Heart failure (HF) is associated with high mortality rates and recurrent hospitalizations. Hence, its early detection and optimal management are essential to improve the survival and quality of life of patients who suffer from it. Yet, although guidelines synthesizing evidence from landmark clinical trials are periodically published to guide clinicians regarding the management of HF, healthcare providers’ adherence to these recommendations appears to be unsatisfactory. Indeed, while the prescription rates for some therapies are high, doses prescribed do not always reach recommended targets, let alone other therapies that are less often used. Although clinical inertia has been suggested to potentially justify some of these care gaps, a more elaborate characterization of this adherence to guidelines in the real-world clinical setting is necessary for a better understanding of these deviations and ultimately, for a better management of HF. The objective of this project is therefore to, firstly, draw-up a detailed portrait of the management of patients with HF and reduced ejection fraction (HFrEF) followed by a multidisciplinary team in a specialized outpatient clinic in Quebec and then, to assess the impact of the different level of adherence to guidelines on the prognosis of these patients. The first paper presented in this work demonstrates not only high prescription rates, but also rates of optimization of recommended therapies higher than what was previously reported in the literature, when physiological and biological parameters specific to each patient are considered. However, there remains a considerable proportion of patients who require slower titration beyond the recommended 6 months while others remain indefinitely on inappropriately low doses. The second paper presented deepens this analysis and demonstrates that patients receiving pharmacological treatment at optimal doses are those with the best prognosis in the year following the allocated optimization period, followed by those requiring prolonged titration and then those remaining at suboptimal doses. However, the patients at the highest risk of morbidity or mortality are those presenting an intolerance or a contraindication to the recommended therapies, a population of fragile patients requiring special attention during the management of their HF.

Cystic fibrosis (CF) is a rare genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial anion channel expressed in several vital organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent mucus build up in the lungs-which increases the risk of infection and eventually causes death. CFTR is an ATP-binding cassette (ABC) transporter family protein composed of two transmembrane domains (TMDs), two nucleotide binding domains (NBDs), and an unstructured regulatory domain. The most prevalent patient mutation is the deletion of F508 (F508del), making F508del CFTR the primary target for current FDA approved CF therapies. However, no experimental multi-domain F508del CFTR structure has been determined and few studies have modeled F508del using multi-domain WT CFTR structures. Here, we used cryo-EM density data and Rosetta comparative modeling (RosettaCM) to compare a F508del model with published experimental data on CFTR NBD1 thermodynamics. We then apply this modeling method to generate multi-domain WT and F508del CFTR structural models. These models demonstrate the destabilizing effects of F508del on NBD1 and the NBD1/TMD interface in both the inactive and active conformation of CFTR. Furthermore, we modeled F508del/R1070W and F508del bound to the CFTR corrector VX-809. Our models reveal the stabilizing effects of VX-809 on multi-domain models of F508del CFTR and pave the way for rational design of additional drugs that target F508del CFTR for treatment of CF.

Nästan alla som har en kognitiv sjukdom utvecklar någon typ av beteendemässiga och psykiska symptom vid demens (BPSD). De olika symptomen vid BPSD kan ha många olika orsaker, däribland olika kroppsliga besvär eller otillfredsställda behov. Även biverkningar av läkemedel kan vara en orsak till att BPSD uppstår. Riktlinjerna säger att BPSD i första hand ska behandlas med icke-farmakologiska åtgärder. Trots detta behandlas BPSD ofta med läkemedel. Många av de läkemedel som används är olämpliga för personer med kognitiv sjukdom. Icke-farmakologiska åtgärder kan riktas till att tillfredsställa personens behov medan läkemedelsbehandling syftar till att minska ett symptom. Studiens syfte var att undersöka effekten av icke-farmakologiska åtgärder vid BPSD hos personer med kognitiv sjukdom som bor på vård- och omsorgsboende. Den metod som användes för att besvara studiens syfte var en integrerad analys för allmän litteraturöversikt. Data har sökts fram via CINAHL, PubMed och manuella sökningar. Femton artiklar inkluderades till resultatet i denna studie.  Resultatet är presenterat i kategorierna: Enkla interventioner och Komplexa interventioner med underkategorierna: Hundterapi, Ljusterapi och Pedagogiska föremål. Resultatet visar att ett flertal icke-farmakologiska åtgärder hade signifikant minskande effekt på BPSD men även att implementeringen av icke-farmakologiska åtgärder i vissa fall kunde leda till en ökning av somliga BPSD-symptom. Det fanns fall där olika studier kommit fram till olika effekt av liknande interventioner. Slutsatsen är att det finns underlag som motiverar prioriteringen av icke-farmakologiska åtgärder vid BPSD samt att dessa åtgärder ska utformas personcentrerat. / Almost everyone who has a cognitive disease will develop some type of behavioral and psychological symptoms of dementia (BPSD). The different symptoms of BPSD can have many different causes, including physical ailments or needs that have not been satisfied. Side effects from drugs can be another cause for BPSD. The guidelines recommend that BPSD should primarily be treated with non-pharmacological interventions. Despite this, BPSD is often treated with drugs. Many of the drugs used are inappropriate for people with cognitive disease. Non-pharmacological interventions focus on the person's needs while drug treatment is primarily focused on a symptom. The aim of the study was to investigate the effect of non-pharmacological interventions on BPSD in people with cognitive disease living in nursing homes. The method used to answer the aim of this study was an integrated analysis for a review of literature. Data was sought through CINAHL, PubMed and manual searches. Fifteen articles were included in the result of this study. The result is presented in the categories: Simple interventions and Complex interventions with the subcategories: Dog therapy, Light therapy and Pedagogic objects. The result shows that several non-pharmacological interventions had significantly decreasing effect on BPSD but also that the implementation of non-pharmacological interventions in some cases could lead to an increase of some BPSD-symptoms. There were cases where different studies showed different effects from similar interventions. In conclusion it is supported to prioritate non-pharmacological interventions in BPSD and that these interventions should be designed in a person centred way.