La maladie de Huntington est neurodégénérative, génétique, rare, multifacette et de durée d'évolution longue, induisant une grande. Les biothérapies en cours d'essai sont réalisées sur des petits effectifs, avec un effet mesurable à long terme et hétérogène. Identifier des marqueurs d'évolution de la maladie et de réponse au traitement permettrait de mieux comprendre et d'améliorer les résultats des futurs essais cliniques. Nous avons développé une méthode de clustering pour l'efficacité d'un traitement dans le cadre de données longitudinales afin de définir des répondeurs et non répondeurs au traitement. Notre méthode, robuste pour les petits effectifs, combine un modèle linéaire mixte à deux pentes et un algorithme de clustering. Le modèle mixte génère des effets aléatoires, associés à la réponse au traitement, propres à chaque patient. L'algorithme de clustering permet de définir des sous-groupes selon la valeur des effets aléatoires. Trouver des sous-groupes de patients répondeurs permet de définir des marqueurs prédictifs de la réponse au traitement qui seront utilisés pour donner le traitement le mieux adapté à chaque patient. Nous avons discuté de l'intégration (i) des marqueurs prédictifs dans les plans expérimentaux des essais cliniques, en évaluant leur impact sur la puissance de l'étude; et (ii) des marqueurs pronostiques, en étudiant l¿impact du polymorphisme COMT sur le déclin cognitif des patients. Enfin, nous avons évalué l'effet d'apprentissage des tests neuropsychologiques, et montré comment une double évaluation à l'inclusion dans un essai clinique permettait de s'en affranchir quand le critère de jugement principal est le déclin cognitif. / Huntington's disease is neurodegenerative, genetic, rare, multifaceted and has a long evolution, inducing heterogeneity of conditions and progression of the disease. Current biotherapy trials are performed on small samples of patients, with a treatment effect measurable in the long-term that is heterogeneous. Identifying markers of the disease progression and of the treatment response may help to better understand and improve results of biotherapy studies in Huntington's disease. We have developed a clustering method for the treatment efficacy in the case of longitudinal data in order to identify treatment responders and nonresponders. Our method combines a linear mixed model with two slopes and a classical clustering algorithm. The mixed model generates random effects associated with treatment response, specific to each patient. The clustering algorithm is used to define subgroups according to the value of the random effects. Our method is robust in case of small samples. Finding subgroups of responders may help to define predictive markers of treatment response which will be used to give the most appropriate treatment for each patient. We discussed integration of (i) the predictive markers in study design of future clinical trials, assessing their impact on the power of the study; and (ii) the prognostic markers of disease progression by studying the COMT polymorphism as a prognostic marker of cognitive decline in Huntington's disease. Finally, we evaluated the learning effect of neuropsychological tasks measuring cognitive abilities, and showed how a double baseline in a clinical trial could take it into account when the primary outcome is the cognitive decline.

Huntington disease (HD) is a genetically transmitted fatal neurodegenerative condition that currently has no cure. The symptoms of HD are manifested as cognitive declines, neuropsychiatric disturbances, and motor dysfunction. An autosomal dominant genetic defect is responsible for the onset of HD, which means that the children of an affected parent have a 50% chance of inheriting the disease. Predictive genetic testing for HD has been available since 1993, and a positive test result means that a person will develop HD with 100% certainty. People who have the HD-gene expansion, but have not yet manifested unequivocal motor signs, are said to be in the prodromal phase of HD. A number of studies have examined concerns about the utility of genetic testing and its negative psychological consequences for gene-expanded and non-expanded individuals (e.g., traumatization, suicidal ideation). Although research has understandably focused on the potential for distress, there has been some evidence suggesting that individuals may actually experience psychological growth related to a receiving a genetic test result (e.g., improved relationships, pursuing new opportunities). The aim of the present study was to understand the relationship between genetic testing, prodromal HD symptoms, and posttraumatic growth (PTG). Participants were recruited through the multinational PREDICT-HD study (Jane Paulsen, PI) and they completed the Posttraumatic Growth Inventory (PTGI; Tedeschi & Calhoun, 1996) to assess permanent positive psychological change as a result of learning about their HD-gene status. The Symbol Digit Modalities Test (Smith, 1991), Unified Huntington's Disease Rating Scale Motor Exam (Huntington's Study Group, 1996), and the SCl-90-R Depression subscale (Derogatis, 1994) were also completed. A total of 82 gene-expanded patients and 37 non-expanded patients took part in this study. Results revealed that gene-expanded and non-expanded individuals reported experiencing PTG, particularly in their appreciation for life and ability to relate to others. Gene-expanded and non-expanded participants did not differ in the amount of growth they reported, which indicated that the outcome of genetic testing was not related to how much growth people experienced. Age and gender were associated with PTG, with younger participants and women reporting the most growth. The amount of time elapsed since genetic testing, estimated proximity to a diagnosis of HD, and the clinical characteristics of prodromal HD were not related to PTG. In conclusion, people experience positive psychological change as result of genetic testing for HD. The findings of this study have important implications for future research and for mental health professionals assisting people through the genetic counseling process.

La maladie de Huntington (MH) est causée par une expansion de répétitions CAG sur l’exon 1 du gène huntingtine (htt), codant pour une protéine mutée. Il a été montré que la diminution d’expression de cette protéine est une piste thérapeutique très prometteuse. Dans ce projet, nous avons étudié et comparé trois approches dites «antisens» : une stratégie allèle non-spécifique, visant à diminuer de manière générale l’expression de htt ; une stratégie allèle spécifique ciblant les répétitions CAG afin d’impacter préférentiellement l’allèle muté ; et enfin une stratégie de saut d’exon permettant d’enlever des sites de clivage à l’origine d’une forme raccourcie et toxique de la protéine htt. Nous avons évalué ces approches grâce à deux outils différents : les tricyclo-DNA (TcDNA), qui sont une nouvelle classe d’oligonucléotides antisens (AON) plus performante que les chimies précédentes, et le système U7snRNA vectorisé, permettant d’induire une expression stable des séquences antisens. Dans un premier temps, ces différentes molécules ont été évaluées in vitro dans des lignées de fibroblastes de patients en quantifiant le niveau d’ARNm et de protéines htt par RTqPCR et Western blot respectivement. Par la suite, les séquences les plus efficaces in vitro ont été sélectionnées et les AON et AAV-U7snRNA correspondants ont été injectés en intracérébroventriculaire (ICV) dans un modèle murin de la MH (souris YAC128). Les résultats les plus encourageants ont été obtenus avec le TcDNA-NS (pour allèle Non Spécifique), permettant une diminution significative de l’expression de htt dans le cortex, l’hippocampe et le striatum 2 et 6 semaines après une injection ICV. Ces résultats prometteurs suggèrent le potentiel des TcDNA comme nouvel outil thérapeutique pour la MH. / Huntington’s disease (HD) is caused by a CAG repeat expansion in the exon 1 of huntingtin gene (htt), encoding for a mutant protein. It has been shown that the silencing/down regulation of huntingtin protein is a promising therapeutic lead. In this project, I have explored and compared three strategies using the antisense approach: a non-allele specific strategy, aiming to silence the global expression of htt; an allele specific strategy targeting CAG repeats to silence preferentially the mutant allele; and an exon-skipping strategy in order to remove cleavage sites which originally cause a shorter and toxic form of the htt protein. These strategies have been evaluated using two different tools: tricyclo-DNA (TcDNA), a new class of antisense oligonucleotides (AON) more efficient than the previous chemistries, and a vectorized approach using U7snRNA system allowing a stable expression of antisense sequences. Firstly, these different molecules have been assessed in vitro in HD fibroblasts quantifying mRNA and htt protein levels with RTqPCR and Western blot respectively. Subsequently, the most efficient sequences have been selected and intracerebroventricular (ICV) injections have been performed with corresponding AON and AAV-U7snRNA in a HD mouse model (YAC128). The most encouraging results have been obtained with the TcDNA-NS (for Non Specific allele), allowing a significant decrease of htt expression in cortex, hippocampus and striatum 2 and 6 weeks after ICV injection. These promising results suggest the potential of TcDNA as a new therapeutic tool for HD.

The image of Islam A historiographical study of Islam in Swedish research. A society`s image of a foreign people, culture and religion changes constantly depending on social, political and other important events. Today Islam is the second largest religion in Sweden after Christianity and that is why it has become important to study the Swedish image of Islam, Muhammed and the Islamic world during the last century. This study is a historiographical and examines the work of six different Swedish authors between the year 1918 to 1930 and 1979 to 2011. The aim of studying these works is to examine whether there has been changes in the Swedish view of Islam, Muhammed and Muslim societies. The theoretical starting point of this study is based on the economist Amartya Sen`s view on identity as multidimensional. According to Sen, a too strong emphasis on ethnic, cultural and religious identities tends to create antagonism and conflicts between different group of peoples. That is why, according to Sen, it is important to emphasize the similarities between different cultures instead of only focus on their differences. Also, Samual P. Huntington`s thesis that emphasizes the differences between religious civilizations in the world who struggle for power and influence is used in this study. The investigation shows that there are differences between the authors from 1918 to 1930 and 1979 to 2011 in their description of Islam, Muhammed and Muslim societies. While the older authors focus mostly on Islam`s past, the contemporary authors deal mostly with Islam in present times. The investigation also demonstrates that the older authors in general give a positive description of Islam`s earlier history, while they depict Islam and Muslim societies as stagnant and reactionary in modern times. The result confirms earlier studies who show similar tendencies on description of Islamic and other Non-Western societies.

The outbreak of the Arab Spring took place more than ten years ago and is currently of great interest to researchers. The suicide of the street vendor Bouazizi is considered the start of the revolution. As a result of the uprisings, both Tunisia and Egypt succeeded in overthrowing their authoritarian leaders and regimes. However, Tunisia managed to maintain and develop a democratic political system, unlike Egypt, which is still classified as an authoritarian dictatorship. The main purpose of this study has been to find explanations for why a regime change took place in both countries during the Arab Spring and why Tunisia’s democratization process remained successful compared to Egypt’s. Huntington’s transition processes and consolidation theory have been helpful in finding answers to these questions. The study is of a comparative nature where the most similar system design has been applied. A key conclusion concerns the fact that Egypt’s non-neutral and powerful military has undermined the country’s democratization process. In contrast, Tunisia’s democratization process has been characterized by a peaceful period with a neutral military and political actors willing to negotiate with each other despite divided political views.

This work examines relevancy of theoretical aproaches on the subject of democratization processes presented by Francis Fukuyama, Samuel Huntington and Fareed Zakaria, and it discusses a level of relevancy of their theoretical concepts and theses in comparison to the democratization process in Libya, which started in spring 2011. First, the theoretical part of this work presents specific historical, sociocultural, political, religious and economic contexts of Libya from a historical-sociology perspective with a focus on the democratization and liberalization processes in Libya. It discusses democratization factors and reasons, which are applied on the situation in Libya. The empirical part of this work presents reflections and perspectives of the democratization process in Libya from an emical perspective of a Libyan citizen. These reflections are confronted with the theoretical approaches presented in the first part, especially with Huntington's Third Wave. The empirical part reflects the processes of the previous non- democratic regime of Muammar Kaddafi, then the fall of the regime and the revolution situation in Libya, a new democratic regime and finally, the perspectives of consolidation of democracy in Libya.

The diploma thesis describes theory of Samuel Huntington about the clash of civilizations. Its focus is on the clash between Islam and the West. The thesis describes also history of Afghanistan until 2001 and the fall of the Taliban movement. In accordance with Huntington's thesis, and taking into account his critics, it aims to answer the question, whether there is a clash of civilization in Afghanistan. Powered by TCPDF (www.tcpdf.org)

This thesis aims to examine Ghana's and Zimbabwe's democratization process and why the outcome is so different in each country, what are the central factors that have played a role in the country's success or defeat? The theoretical framework is based on Juan j. Linz and Alfred Stepan’s work on how a state becomes democratically consolidated and what constitutes as a consolidated democracy. The essay is a theory-consuming comparative case study focusing on Ghana’s and Zimbabwe’s democratization and why one of them succeeded and the other didn’t.  The results shows that Ghana have come a long way towards consolidating their democracy based on the demands of the theories and that because of their peaceful transition their democracy had a bigger chance of succeeding. Zimbabwe lacks a lot of the democratic procedures and have had a hard time transitioning to a democratic system.

Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for so-called genetic disorders, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in either knock-in or knock-out mice. However, there are similarly, many identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. Constituent cellular defense mechanisms responsive to the challenge of increased reactive oxygen species represent only one crossroad whereby environment can influence genetic predisposition. In this paper we highlight some of the major neurodegenerative disorders and discuss possible links of gene-environment interplay. The process of adult neurogenesis in brain is also presented as an additional element that influences gene-environment interplay. And the so-called priming processes (i.e., production of receptor supersensitization by repeated drug dosing), is introduced as yet another process that influences how genes and environment ultimately and co-dependently govern behavioral ontogeny and outcome. In studies attributing the influence of genetic alteration on behavioral phenotypy, it is essential to carefully control environmental influences.

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