Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 6, 2008). Includes bibliographical references (p. 36-42).

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Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Congenital heart disease (CHD) is a risk factor for premature cardiovascular complications. Great advances have occurred in the past years leading to the identification of several genes essential for proper cardiac formation such as GATA4/5/6 mutated in some individuals with CHD. GATA6 is a zinc finger transcription factor whose presence is crucial for early embryonic development. GATA6 is expressed in many cell types of the heart including myocardial, endocardial, neural crest, and vascular smooth muscle. In human, mutations in GATA6 result in variable cardiac phenotypes. The objective of this thesis was to determine the roles that GATA6 play in the different cell types of the heart and to elucidate the molecular basis of the cardiac defects associated with Gata6 haploinsufficiency. For this, a combination of cell and molecular techniques were used in vitro and in vivo. First, we show that Gata6 heterozygozity leads to RL-type bicuspid aortic valve (BAV)- the most common CHD affecting 2% of the population. GATA6-dependent BAV is the result of disruption of valve remodeling and extracellular matrix composition in Gata6 haploinsufficient mice. Cell-specific inactivation of one Gata6 allele from Isl-1 positive cells, but not from endothelial or neural crest cells, recapitulates the phenotype of Gata6 heterozygous mice revealing an essential role for GATA6 in secondary heart field myocytes during valvulogenesis. We further uncovered a role for GATA6 as an important regulator of the cardiac conduction system and revealed that GATA6 expression regulates the activity of the cardiac pacemaker. GATA6 exerts its role via regulation of the cross-talk among the different cell types of the SAN. Lastly, some CHDs are characterized by abnormalities of both the limbs and the heart such as the Holt Oram syndrome (caused by mutation in TBX5 transcription factor). The molecular basis for limb-heart defects remain poorly understood. In the course of this work, we discovered that Gata6 haploinsufficiency resulted in a partially penetrant polysyndactyly (extra digits fused together) phenotype. Together, the data provide novel molecular and cellular insight into GATA6 role in normal and pathologic heat development. Our results also suggest that GATA6 should be added to the list of genes whose mutations are potentially associated with heart and limb abnormalities. Better knowledge of the molecular basis of CHD is a prerequisite for the development of diagnostic and therapeutic strategies to improve care of individuals with congenital heart disease.

Philosophiae Doctor - PhD / A technique was developed for the assessment of forensic identification using dental radiographs. The technique involved the digitisation of dental radiographs, cutting of a horizontal section from an antemortem radiograph and superimposing it over the same geographic location on the postmortem radiograph. The technique was useful in vitro and in an in vitro mock mass disaster. It was accurate within both the paediatric and permanent dentition and not useful in subjects with changing dentitions (mixed dentition). Image density (with and without optical enhancement) did not prove to be an impediment to the technique although extremes of image contrast did. Within the range of dental xray generators settings, contrast could be altered in a manner to allow matching. Differences in the vertical angulation of the x-ray beam did not influence the technique although horizontal angulation was a critical factor. Alterations in focal-film distance did not adversely affect the use of this technique. The three different scanning systems used were .all adequate for the purpose of the technique and the images could be compressed and transferred with little difficulty. Analysis of a group of actual Coroner's cases proved the technique to be useful in a timely fashion, for actual field identifications with minimal inter and intra operator error.

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Thesis--University of Oklahoma. / Bibliography: leaves 101-105.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The aim of this in vitro study was to evaluate the residual dentin thickness of palatal root of premolars after post space preparation with the new Brazilian drill Post Preparation and compare with the Gates-Glidden and Largo drills using cone-beam computed tomography (CBCT). A total of 21 premolars were selected and randomized into 3 groups: G1 - Post Preparation burs; G2 - Gates-Glidden burs #2 and #3; G3 - Largo burs #1 and #2. The residual dentin thickness in seven sections for the mesial, distal, buccal and palatal points was measured in three stages: initial (unprepared), after instrumentation to #35 apical file and after post preparation using the equipment Kodak CS 9000C 3D Extraoral Imaging System and CS 3D Imaging v. 3.4.3. software. The area of the root canal was analyzed in three stages through VRMesh Reverse v. 7.6.1. software. Statistical significance was set at 5%. Data from linear measurements and the area were analyzed using the Kruskal-Wallis test. The Post Preparation burs demonstrated similar performance to the Gates-Glidden and Largo drills in the analysis of residual dentin thickness for post space preparation. / O objetivo do presente estudo in vitro foi avaliar a espessura de dentina residual da raiz palatina de pré-molares superiores após o preparo para pino com a nova broca brasileira Post Preparation e comparar com as brocas Gates-Glidden e Largo por meio da tomografia computadorizada cone beam (TCCB). Um total de 21 pré-molares superiores foram selecionados e randomizados em 3 grupos: G1 broca Post Preparation; G2 brocas Gates-Glidden nº 2 e 3; G3 brocas Largo nº 1 e 2. A espessura dentinária remanescente em sete cortes das paredes mesial, distal, vestibular e palatina foi medida em três momentos: inicial (sem preparo), após a instrumentação até a lima #35 e após o preparo para retentor intrarradicular por meio do equipamento Kodak CS 9000C 3D Extraoral Imaging System com auxílio do software CS 3D Imaging v. 3.4.3. A área dos condutos radiculares nos três momentos foi analisada por meio do software VRMesh Reverse v. 7.6.1. O nível de significância estatística foi estabelecido em 5%. Os dados das medidas lineares e da área da dentina remanescente foram analisados por meio do teste de Kruskal-Wallis. A broca Post Preparation demonstrou comportamento similar às brocas Gates-Glidden e Largo quanto ao desgaste dentinário durante o preparo para retentor intrarradicular.

Le syndrome de Marfan (MFS) est une maladie génétique rare. Les signes cliniques sont principalement squelettiques, oculaires et cardiovasculaires. Le premier gène identifié est FBN1. Une LSDB UMD créée en 1995 a permis de colliger les mutations identifiées chez les patients. D’autres gènes ont été identifiés comme causant des syndromes apparentés : FBN2, TGFBR1, TGFBR2, ACTA2, SMAD3, MYH11 et MYLK. Ma thèse avait pour but de mettre à jour ces différentes bases et de créer celles des nouveaux gènes. Les techniques de séquençage nouvelle génération dans la pratique clinique amènent des médecins non spécialistes à rapporter des variations secondaires dans ces gènes « actionable ». Il s’agit de la ressource la plus complète pour les cliniciens et les généticiens pour interpréter les variants associés au MFS et ses pathologies associées pour les variants primaires et secondaires.La bicuspidie de la valve aortique (2 feuillets au lieu de 3) est la malformation cardiovasculaire la plus fréquente touchant 0,6 à 2 % de la population. Ma thèse avait pour but d’identifier de nouveaux gènes impliqués dans la BAV. Grâce à une cohorte de 200 patients, le gène HOXA1, un facteur de transcription, a pu être examiné de manière plus approfondie. Alors qu’il contient une répétition de 10 histidines, les individus hétérozygotes mutés en présentent 11. Mes études ont permis de démontrer l’imputabilité de cette mutation. Dans un second temps, un séquençage d’exomes entiers a permis de mettre en évidence de nouveaux variants prédits pathogènes. Ces données permettront de mieux comprendre le rôle physiologique d’HOXA1 et des nouveaux gènes candidats dans la pathogénèse de la BAV chez l’humain. / Marfan Syndrome is a rare genetic disorder. Clinical signs are mainly skeletal, ocular and cardiovascular. The first gene identified is FBN1. A LSDB UMD was created in 1995 to colligate all the mutations identified in. Thereafter, several others genes were identified involved in related disorders : FBN2, TGFBR1 and TGFBR2, ACTA2, SMAD3, MYH11 and MYLK. The objectives of my PhD were to update these databases and to create new ones for genes. Next generation sequencing in clinical practice leads non-specialized doctors to report pathogenic secondary variants in “actionable” genes. Our databases are the only resources providing access to the full spectrum of known pathogenic mutations with checked and interpreted data from many reference diagnostic laboratories and research centers worldwide, and the most comprehensive resources for clinicians and geneticists to interpret variations linked to Marfan syndrome and related disorders not only primary but also secondary variants.Bicuspid Aortic Valve is the most common cardiovascular malformation affecting 0.6-2% of the population (2 leaflets instead of 3). Thanks to a cohort of 200 BAV patients, HOXA1 gene, a transcription factor, has been screened. While HOXA1 contains a string of 10 histidine repeats, these individuals are heterozygous for an 11 histidine repeat variant. My studies showed the imputability of this mutation. In a second phase, whole exome sequencing allow us to highlight new variants predicted pathogenic. Studies are still ongoing to confirm their imputability. These data contribute to our better understanding of the physiological of HOXA1 and new candidate genes in the pathogenesis of BAV disease in humans.

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