Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (Ph.D.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on May 1, 2009) Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2002. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Le Syndrome de Down ou trisomie 21 est une maladie congénitale complexe qui affecte le développement du système nerveux ainsi que de nombreuses autres fonctions. Ce syndrome résulte de la présence en trois copies de tout ou partie du chromosome 21. Plusieurs modèles murins existent et ont été largement étudiés, mais tous ne reproduisent pas la totalité du phénotype observé chez l’homme. Au sein de notre laboratoire, nous avons créé un modèle qui porte la délétion et la duplication de la région télomérique du HS2A21, localisée sur le MMU10. Avec le modèle comprenant la délétion nous avons réalisé une expérience de sauvetage de phénotype visant à réduire le nombre de copie fonctionnelle des gènes de cette région (Prmt2-Cstb) dans le modèle trans-chromosomique Tc1 (O’Doherty et al. 2005). La lignée Tc1 est un modèle de souris trisomiques pour l’ensemble des gènes homologues du chromosome 21. Elle présente un ensemble d’altérations morphologiques, comportementales et physiologiques similaires aux défauts observés chez les patients. Les résultats que nous avons obtenus montrent la robustesse du modèle TC1, puisque les phénotypes caractérisés ont été retrouvés dans nos expériences, malgré l’utilisation d’un fond génétique différent de celui d’origine. Cependant, nous n’avons pas obtenus de sauvetage de phénotypes dans les tests que nous avons réalisés en réduisant le nombre de copie de la région Cstb-Prmt2 dans ce modèle trisomique. Ces résultats tendent à montrer que cette région ne jouerait pas de rôle majeur dans les phénotypes du Syndrome de Down et permet de réduire les régions et gènes incriminés dans cette pathologie. / The Down syndrome or trisomy 21 is a complexe congenital disease, neuro-degenerative, which affects the embryonic development. It’s the most frequent human aneuploïdy and the leading cause of backwardness. This syndrome results from the presence in three copies of whole or part of chromosome 21. Within our laboratory, we created a model which carries the deletion and duplication of the telomeric part of the HS2A21, located on the MMU10. With this model, we carried out an experiment of phenotype rescue, by reducing the number of functional copy of genes in this region (Prmt2-Cstb) in the trans-chromosomal model Tc1 (O' Doherty et al. 2005). The Tc1 line is a model of trisomic mice for the whole of chromosome 21 genes. It presents a set of morphological, behavioral and physiological alterations similar to the defects observed among patients. To isolate the possible specific gene-phenotypes relations, the Tc1 line was examined in the Tc1- Ms4Yah context, in a phenotypical screening composed of learning, cognitive and motor tests. The results obtained do not show phenotypes rescue in the tests which we carried out by reducing the number of copy of the Cstb-Prmt2 region in this trisomic model. These results tend to show that this region would not play of important role in the Down syndrome phenotypes and makes it possible to reduce the genes implicated in this pathology.

Introduction: This study investigates cognitive theory of autistic spectrum disorder. Based on the argument that the disorder may have a genetic component to its aetiology, cognitive characteristics similar to those associated with the condition are hypothesised to be evident in the parents. Theory of mind, central coherence and executive function are therefore investigated. Relationships between these three areas of cognitive function are also explored. Methodology: Nineteen parents of children with high functioning autism or Asperger syndrome were compared with 18 gender-matched parents of normally developing children, on measures of theory of mind, central coherence, and executive function. Results: Executive function was significantly poorer in the parents of children with autistic spectrum disorder, than in the control group; but theory of mind and central coherence were similar across the two groups. Overall, 52.6 % of the autism group and only 5.6 % of the control group fell below age and IQ weighted cut-off scores on the Hayling and Brixton tests of executive dysfunction, A number of significant correlations between test measures were found. Discussion : These findings provide further support for the genetic argument and the executive function theory of autism, but fail to support the theory of mind or central coherence models. Possible interpretations of the significant associations between test scores were considered in the light of previous findings. Methodological issues were considered important. Limits of the executive dysfunction model as a stand-alone theory of autistic spectrum disorder were also highlighted. Ideas regarding clinical relevance and future research were discussed.

No description available.

A growing body of evidence generated from observational data has demonstrated the potential to influence decision-making and improve patient outcomes. For observational evidence to be actionable, however, it must be generated reliably and in a timely manner. Large distributed observational data networks enable research on diverse patient populations at scale and develop new sound methods to improve reproducibility and robustness of real-world evidence. Nevertheless, the problems of generalizability, portability and scalability persist and compound. As analytical methods only partially address bias, reliable observational research (especially in networks) must address the bias at the design stage (i.e., pre-analysis bias) including the strategies for identifying patients of interest and defining comparators. This thesis synthesizes and enumerates a set of challenges to addressing pre-analysis bias in observational studies and presents mixed-methods approaches and informatics solutions for overcoming a number of those obstacles. We develop frameworks, methods and tools for scalable and reliable phenotyping including data source granularity estimation, comprehensive concept set selection, index date specification, and structured data-based patient review for phenotype evaluation. We cover the research on potential bias in the unexposed comparator definition including systematic background rates estimation and interpretation, and definition and evaluation of the unexposed comparator. We propose that the use of standardized approaches and methods as described in this thesis not only improves reliability but also increases responsiveness of observational evidence. To test this hypothesis, we designed and piloted a Data Consult Service - a service that generates new on-demand evidence at the bedside. We demonstrate that it is feasible to generate reliable evidence to address clinicians’ information needs in a robust and timely fashion and provide our analysis of the current limitations and future steps needed to scale such a service.

Mitochondrial DNA (mtDNA) aberrations have been detected in a large proportion of tissue samples isolated from human tumours, although the functional significance of these mutations is yet to be determined. Proponents of the selective advantage mtDNA defect acquisition model believe these mutations arise spontaneously, but propagate because they afford some benefit to overall neoplastic cell proliferation. The most tantalizing of these growth advantage properties is an elevation of electron transport chain (ETC) generated reactive oxygen species (ROS), which are already associated with some pathogenic mtDNA defects. However, others theorize that these mutations may arise spontaneously and expand through the ambivalent process of genetic drift alone. The 2008 human ovarian cancer cell line and its cis-platinum(II)-diammine-dichloride (CDDP) resistant C13* cell variant have divergent phenotypes when mitochondrial morphology, membrane potential (ΔΨₘ), ROS production, and rate of oxygen consumption are considered. Furthermore, the increased ΔΨₘ observed in C13* cells has been implicated in its CDDP resistant characteristic. In order to determine if mtDNA mutations were responsible for these phenotypic variations, the complete mitochondrial genomes of both cell lines were directly sequenced. Two novel mtDNA mutations were identified within cytochrome c oxidase subunit II (COXII) and the d-loop of 2008 and C13* cells respectively, however the functional significance of these defects were not obvious. To expunge the effects of nuclear DNA (nDNA) cybrids were created by transferring the mtDNA of 2008 and C13* cells to a common 143B TK⁻ nDNA background, creating 2008cyb and C13cyb cells. C13*cyb cells did not demonstrate CDDP resistance, decrease in rate of oxygen consumption or increase in ΔΨₘ when compared to 2008cyb cells. However, C13*cyb cells did retain mitochondrial morphological properties as well as increased Rh123 sensitivity and ROS production. This data would imply that mtDNA mutations are responsible for a proportion of mitochondrial-associated changes in the context of carcinogenesis. / Thesis / Master of Science (MS)

No description available.