Title page, table of contents and introduction only. The complete thesis in print form is available from the University of Adelaide Library. / Human congenital disorders impose a large impact not only on the affected individuals and their immediate families but also on communities, often inflicting great healthcare burdens. This thesis concentrates on one congenital disorder, Opitz Syndrome, which is a genetic disorder caused by mutations in MIDI. Opitz Syndrome (OS) patients present an array of clinical features including some of the more commonly found congenital structural anomalies, such as cleft lip and palate and hypospadias. The information gained from an enhanced understanding of the important cellular and molecular processes and pathways involved in Opitz Syndrome will subsequently aid in the elucidation of the basis of the individual clinical features. Only through an increased understanding of the underlying mechanisms of these congenital malformations can advances be made in prevention, diagnosis and ultimately treatment of them. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1141961 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2004

Title page, table of contents and introduction only. The complete thesis in print form is available from the University of Adelaide Library. / Human congenital disorders impose a large impact not only on the affected individuals and their immediate families but also on communities, often inflicting great healthcare burdens. This thesis concentrates on one congenital disorder, Opitz Syndrome, which is a genetic disorder caused by mutations in MIDI. Opitz Syndrome (OS) patients present an array of clinical features including some of the more commonly found congenital structural anomalies, such as cleft lip and palate and hypospadias. The information gained from an enhanced understanding of the important cellular and molecular processes and pathways involved in Opitz Syndrome will subsequently aid in the elucidation of the basis of the individual clinical features. Only through an increased understanding of the underlying mechanisms of these congenital malformations can advances be made in prevention, diagnosis and ultimately treatment of them. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1141961 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2004

Este estudo investigou a prevalência de disgenesias dentárias, alterações de tecido mole e características cefalométricas em pacientes com síndrome velocardiofacial e síndrome G/BBB. A presença de disgenesias dentárias foi avaliada em pacientes acima de seis anos de idade; para a análise cefalométrica, foram avaliadas telerradiografias laterais obtidas antes de qualquer intervenção ortodôntica. A amostra de estudo para a síndrome velocardiofacial incluiu 26 pacientes para análise de disgenesias dentárias e alterações de tecido mole e 18 pacientes para análise cefalométrica. Para a síndrome G/BBB, foram analisados 21 pacientes quanto à presença de disgenesias dentárias e alterações de tecido mole, e 23 pacientes para a análise cefalométrica. Foram incluídos apenas pacientes de etnia branca. A ocorrência de agenesias dentárias e dentes supranumerários foi comparada a pacientes sem nenhuma alteração morfofuncional, pareados para gênero e idade. Para a análise cefalométrica, as telerradiografias foram traçadas manualmente; os traçados foram digitalizados e as variáveis foram medidas com auxílio do software Dentofacial Planner 7.0. Nesta análise, os pacientes também foram comparados a pacientes sem nenhuma alteração morfofuncional, pareados para gênero e idade. Para a síndrome velocardiofacial, 76,92% dos pacientes apresentaram pelo menos uma disgenesia dentária, com predominância de alterações hipoplasiantes, principalmente representadas por hipodesenvolvimento da cúspide lingual do primeiro pré-molar inferior e opacidades de esmalte; a ocorrência de agenesias dentárias e dentes supranumerários foi semelhante à observada no grupo controle. Na análise cefalométrica, observou-se menor comprimento da base do crânio (total e da parte posterior); retrusão e redução da altura posterior da maxila; aumento do ângulo goníaco; aumento do ângulo interincisal; maior inclinação lingual dos incisivos inferiores; redução do ângulo nasolabial; e redução da profundidade nasal, comparado ao grupo controle. Com relação à síndrome G/BBB, 95,23% dos pacientes apresentaram pelo menos uma disgenesia dentária, com predominância de alterações hipoplasiantes; a freqüência de agenesias dentárias e dentes supranumerários foi significativamente maior comparada ao grupo controle. Foi observada anquiloglossia em 11 de 21 pacientes. A análise cefalométrica revelou aumento do ângulo da base do crânio; maior retrusão dos ossos nasais; encurtamento do ramo, redução do comprimento, e retrusão da mandíbula; maior discrepância maxilomandibular, com maior convexidade facial; maior inclinação lingual dos incisivos inferiores e superiores; padrão de crescimento mais vertical; nariz mais achatado, ponte nasal mais curta, maior retrusão nasal e redução da profundidade nasal, comparado ao grupo controle. Em conclusão, na avaliação de pacientes com hipótese diagnóstica das referidas síndromes, sugere-se investigar a anatomia oclusal de pré-molares inferiores no caso da síndrome velocardiofacial, e a presença de dentes supranumerários anteriores inferiores e anquiloglossia para a síndrome G/BBB. A análise cefalométrica também indicou diferenças significativas em diversas variáveis, simultaneamente servindo como parâmetro na descrição das síndromes e exigindo protocolo de tratamento diferenciado para estes pacientes. / This study investigated the prevalence of tooth abnormalities, soft tissue changes and cephalometric analysis in patients with velocardiofacial syndrome and G/BBB syndrome. The presence of tooth abnormalities was evaluated in patients older than six years; cephalometric analysis was conducted on lateral cephalograms obtained before any orthodontic intervention. The study sample for the velocardiofacial syndrome included 26 patients for analysis of tooth abnormalities and soft tissue changes, and 18 patients for cephalometric analysis. For the G/BBB syndrome, 21 patients were analyzed as to the presence of tooth abnormalities and soft tissue changes, and 23 patients for cephalometric analysis. Only white patients were included. The occurrence of tooth abnormalities and supernumerary teeth was compared to patients without any morphofunctional alterations, matched for gender and age. For cephalometric analysis, the lateral cephalograms were manually traced; tracings were digitized and the variables were measured on the software Dentofacial Planner 7.0. For this analysis, patients were also compared to individuals without malformations, matched for gender and age. For the velocardiofacial syndrome, 76.92% of patients presented at least one tooth abnormality, with predominance of hypoplastic alterations, especially represented by hypodevelopment of the lingual cusp of mandibular first premolars and enamel opacities; the occurrence of tooth agenesis and supernumerary teeth was similar to that observed in the control group. Cephalometric analysis revealed reduced length of the skull base (total and of the posterior portion); retrusion and reduction of posterior height of the maxilla; increased gonial angle; increased interincisal angle; greater lingual inclination of mandibular incisors; reduced nasolabial angle; and reduced nasal depth, compared to the control group. Concerning the G/BBB syndrome, 95.23% of patients presented at least one tooth abnormality, with predominance of hypoplastic alterations; the frequency of tooth agenesis and supernumerary teeth was significantly higher compared to the control group. Ankyloglossia was observed in 11 of 21 patients. Cephalometric analysis revealed increased cranial base angle; greater retrusion of nasal bones; shortening of mandibular ramus, reduced mandibular length, and mandibular retrusion; greater maxillomandibular discrepancy, with greater facial convexity; greater lingual inclination of maxillary and mandibular incisors; more vertical growth pattern; more flattened nose, shorter nasal bridge, greater nasal retrusion and reduced nasal depth, compared to the control group. In conclusion, during evaluation of patients with suspected diagnosis of the syndromes, investigation of the occlusal anatomy of mandibular premolars in case of velocardiofacial syndrome, and of the presence of mandibular anterior supernumerary teeth and ankyloglossia for the G/BBB syndrome are suggested. Cephalometric analysis also indicated significant differences in several variables, simultaneously serving as parameter for description of syndromes and requiring a customized treatment protocol for these patients.

Este estudo investigou a prevalência de disgenesias dentárias, alterações de tecido mole e características cefalométricas em pacientes com síndrome velocardiofacial e síndrome G/BBB. A presença de disgenesias dentárias foi avaliada em pacientes acima de seis anos de idade; para a análise cefalométrica, foram avaliadas telerradiografias laterais obtidas antes de qualquer intervenção ortodôntica. A amostra de estudo para a síndrome velocardiofacial incluiu 26 pacientes para análise de disgenesias dentárias e alterações de tecido mole e 18 pacientes para análise cefalométrica. Para a síndrome G/BBB, foram analisados 21 pacientes quanto à presença de disgenesias dentárias e alterações de tecido mole, e 23 pacientes para a análise cefalométrica. Foram incluídos apenas pacientes de etnia branca. A ocorrência de agenesias dentárias e dentes supranumerários foi comparada a pacientes sem nenhuma alteração morfofuncional, pareados para gênero e idade. Para a análise cefalométrica, as telerradiografias foram traçadas manualmente; os traçados foram digitalizados e as variáveis foram medidas com auxílio do software Dentofacial Planner 7.0. Nesta análise, os pacientes também foram comparados a pacientes sem nenhuma alteração morfofuncional, pareados para gênero e idade. Para a síndrome velocardiofacial, 76,92% dos pacientes apresentaram pelo menos uma disgenesia dentária, com predominância de alterações hipoplasiantes, principalmente representadas por hipodesenvolvimento da cúspide lingual do primeiro pré-molar inferior e opacidades de esmalte; a ocorrência de agenesias dentárias e dentes supranumerários foi semelhante à observada no grupo controle. Na análise cefalométrica, observou-se menor comprimento da base do crânio (total e da parte posterior); retrusão e redução da altura posterior da maxila; aumento do ângulo goníaco; aumento do ângulo interincisal; maior inclinação lingual dos incisivos inferiores; redução do ângulo nasolabial; e redução da profundidade nasal, comparado ao grupo controle. Com relação à síndrome G/BBB, 95,23% dos pacientes apresentaram pelo menos uma disgenesia dentária, com predominância de alterações hipoplasiantes; a freqüência de agenesias dentárias e dentes supranumerários foi significativamente maior comparada ao grupo controle. Foi observada anquiloglossia em 11 de 21 pacientes. A análise cefalométrica revelou aumento do ângulo da base do crânio; maior retrusão dos ossos nasais; encurtamento do ramo, redução do comprimento, e retrusão da mandíbula; maior discrepância maxilomandibular, com maior convexidade facial; maior inclinação lingual dos incisivos inferiores e superiores; padrão de crescimento mais vertical; nariz mais achatado, ponte nasal mais curta, maior retrusão nasal e redução da profundidade nasal, comparado ao grupo controle. Em conclusão, na avaliação de pacientes com hipótese diagnóstica das referidas síndromes, sugere-se investigar a anatomia oclusal de pré-molares inferiores no caso da síndrome velocardiofacial, e a presença de dentes supranumerários anteriores inferiores e anquiloglossia para a síndrome G/BBB. A análise cefalométrica também indicou diferenças significativas em diversas variáveis, simultaneamente servindo como parâmetro na descrição das síndromes e exigindo protocolo de tratamento diferenciado para estes pacientes. / This study investigated the prevalence of tooth abnormalities, soft tissue changes and cephalometric analysis in patients with velocardiofacial syndrome and G/BBB syndrome. The presence of tooth abnormalities was evaluated in patients older than six years; cephalometric analysis was conducted on lateral cephalograms obtained before any orthodontic intervention. The study sample for the velocardiofacial syndrome included 26 patients for analysis of tooth abnormalities and soft tissue changes, and 18 patients for cephalometric analysis. For the G/BBB syndrome, 21 patients were analyzed as to the presence of tooth abnormalities and soft tissue changes, and 23 patients for cephalometric analysis. Only white patients were included. The occurrence of tooth abnormalities and supernumerary teeth was compared to patients without any morphofunctional alterations, matched for gender and age. For cephalometric analysis, the lateral cephalograms were manually traced; tracings were digitized and the variables were measured on the software Dentofacial Planner 7.0. For this analysis, patients were also compared to individuals without malformations, matched for gender and age. For the velocardiofacial syndrome, 76.92% of patients presented at least one tooth abnormality, with predominance of hypoplastic alterations, especially represented by hypodevelopment of the lingual cusp of mandibular first premolars and enamel opacities; the occurrence of tooth agenesis and supernumerary teeth was similar to that observed in the control group. Cephalometric analysis revealed reduced length of the skull base (total and of the posterior portion); retrusion and reduction of posterior height of the maxilla; increased gonial angle; increased interincisal angle; greater lingual inclination of mandibular incisors; reduced nasolabial angle; and reduced nasal depth, compared to the control group. Concerning the G/BBB syndrome, 95.23% of patients presented at least one tooth abnormality, with predominance of hypoplastic alterations; the frequency of tooth agenesis and supernumerary teeth was significantly higher compared to the control group. Ankyloglossia was observed in 11 of 21 patients. Cephalometric analysis revealed increased cranial base angle; greater retrusion of nasal bones; shortening of mandibular ramus, reduced mandibular length, and mandibular retrusion; greater maxillomandibular discrepancy, with greater facial convexity; greater lingual inclination of maxillary and mandibular incisors; more vertical growth pattern; more flattened nose, shorter nasal bridge, greater nasal retrusion and reduced nasal depth, compared to the control group. In conclusion, during evaluation of patients with suspected diagnosis of the syndromes, investigation of the occlusal anatomy of mandibular premolars in case of velocardiofacial syndrome, and of the presence of mandibular anterior supernumerary teeth and ankyloglossia for the G/BBB syndrome are suggested. Cephalometric analysis also indicated significant differences in several variables, simultaneously serving as parameter for description of syndromes and requiring a customized treatment protocol for these patients.

Cholesterol plays a critical role in the health and normal function of every mammalian cell. Cholesterol has multiple cellular functions including maintenance of cell membrane stability and fluidity, steroid hormone and bile acid synthesis, and membrane receptor signaling. As with any critical metabolite, cholesterol is highly regulated. I will detail my research focusing on the two prevalent disorders of cholesterol homeostasis. The first is a disorder of cholesterol biosynthesis, Smith-Lemli-Opitz syndrome (SLOS), and the second a disorder of cholesterol trafficking, Niemann-Pick disease, type C1 (NPC). I have identified a unique cellular phenotypic overlap between these two previously unrelated disorders. Specifically, increasing concentrations of the precursor sterol present in SLOS, 7-dehydrocholesterol, leads to the induction of an NPC-like cellular phenotype. Aspects of the NPC cellular phenotype that can be induced in SLOS fibroblasts include lysosomal storage of unesterified cholesterol, sphingosine, and glycosphingolipids. Also, similar to what is observed in NPC, dysregulation of acidic calcium stores is present in SLOS. Further research indicates that this cellular phenotype extends into both the mouse models of SLOS and the patients. The dysregulation of cholesterol trafficking in SLOS cells likely decreases cellular cholesterol bioavailabilty and thus potentially limits the therapeutic efficacy of dietary cholesterol supplementation in SLOS patients. I also show that treatment of SLOS cells with miglustat, an established therapy for NPC, ameliorates the NPC-like cellular phenotype and thus may have therapeutic benefit in SLOS. The incidence of both SLOS and NPC has been the subject of debate. Thus, using data generated from massively parallel sequencing of the human exome, I demonstrate that the previously predicted incidence of SLOS of 1:40,000 births is likely correct, but call into question the predicted NPC rate of 1:120,000 . In fact, NPC maybe closer to a rate of 1:40,000. The role of oxysterols in the teratogenicity of SLOS and the underlying secondary storage of lipids in the phenotypic presentation of SLOS has been investigated.

Thesis (Ph. D.)--Westfälische Wilhelms-Universität Münster, 1933. / Vita. Includes bibliographical references (p. 81).

Thesis (Ph. D.)--Westfälische Wilhelms-Universität Münster, 1933. / Vita. Includes bibliographical references (p. 81).

Zugl.: Kairo, Univ., Diss., 2004

Tandis que la « civilisation de l’anatomie » qui définit la Première Modernité fait émerger un nouveau régime d’images artistiques et poétiques du corps en Europe, la bouche s’impose comme l’une des parties du corps les plus fréquemment représentées dans la littérature allemande du XVIIe siècle. Organe de la parole mais aussi de la sensualité par excellence, elle est considérée par certains comme ce qu’il y a de plus prodigieux chez l’homme après son entendement, au point de s’illustrer dans les textes poétiques comme un topos dense et prolifique. Erigée en organe noble dès qu’elle obéit à une rectitude morale, la bouche peut tout aussi bien s’avérer « ig-noble » dès qu’elle pervertit le langage et le corps en commettant des actes impies. La présente étude analyse ce qui prend la forme, à l’intérieur de cette topique, d’une dialectique entre logos et eros, qui s’ancre dans des présupposés théologiques et anthropologiques – conséquence de la confessionnalisation des cultures et des crispations religieuses qui en découlent. Or par la lorgnette de cette dialectique, l’étude donne à voir les rouages de la constitution tardive, poétique et esthétique, d’une littérature artistique de langue allemande. En proposant un parcours représentatif à travers des auteurs qui en sont des jalons majeurs et des types divers d’œuvres littéraires, dramatiques et poétiques – d’Opitz à Hoffmannswaldau –, la thèse montre in fine comment, sur fond de changements progressifs de repères et de paradigmes littéraires, s’instaure un nouveau système de représentation poétique qui va de pair avec une revalorisation ambiguë du logos. / While in Europe the culture of anatomy that characterizes the Early Modern Age has brought about a new kind of artistic and poetical images of the body, the mouth imposes itself as one of the most frequently represented parts of the body in the German literature in the 17th century. As the medium of speech but also of sensuality par excellence, it is considered by some as what is most prodigious in man beside his understanding, so much so that it has emerged in poetical works as a bounteous and fruitful topos. Presented as a noble instrument as soon as it respects moral rectitude, the mouth may also be featured as “ig-noble” as soon as it corrupts the language and the body through ungodly acts. The present study focuses on what comes to be – within this topos – the logos-eros dialectics, rooted in former theological and anthropological assumptions, ensuing the denominalization of cultures that triggered religious tensions. And through the close analysis of this dialectics, the research work unveils the workings of the build up of a German artistic literature. By relying on the exemplary career of its major writers – from Opitz to Hoffmannswaldau – and different kinds of literary works (drama and poetry), the thesis finally enhances how a new system of poetical representations going along with an ambivalent primacy of the logos is set up, with as a backcloth some gradual changes in literary landmarks and paradigms.

In der vorliegenden Arbeit sollten Ziel-Proteine der Mikrotubulus-assoziierten PP2A gefunden werden. Anhand phänotypischer Ähnlichkeiten zwischen OS- und Greig-, Acrocallosal- bzw. Pallister-Hall-Syndrom-Patienten wurde eine mögliche Interaktion zwischen dem MID1-alpha4-PP2A-Komplex und GLI3, einem zentralen Transkriptionsfaktor der SHH-Signaltransduktionskaskade, postuliert. In einer Reihe von zellbiologischen und proteinbiochemischen Experimenten konnte gezeigt werden, dass sowohl die intrazelluläre Lokalisation des GLI3 als auch der Phosphorylierungsstatus von Fu, einem Interaktionspartner von GLI3, über den MID1-alpha4-PP2A-Komplex und Mikrotubulus-assoziierter PP2A-Aktivität reguliert werden. Erhöhte Aktivität der Mikrotubulus-assoziierten PP2A führt hierbei zur Dephosphorylierung von Fu und zu einer Akkumulation des GLI3 im Cytosol, während verringerte PP2A-Aktivität zu einer Anreicherung der hyperphosphorylierten Form des Fu und zur Akkumulation des GLI3 im Nukleus führt. Darüber hinaus konnte GSK3beta als die der Mikrotubulus-assoziierten PP2A entgegenwirkende Kinase identifiziert werden. Eine verringerte Aktivität der GSK3beta führt zur Dephosphorylierung von Fu und zu einer Akkumulation des GLI3 im Cytosol. Außerdem wurde in der vorliegenden Arbeit eine Interaktion zwischen GLI3 und der hyperphosphorylierten Form des Fu beschrieben. Die Hyperphosphorylierung von Fu wird über die gegenläufigen Aktivitäten der Mikrotubulus-assoziierten PP2A und GSK3beta reguliert. Durch die Interaktion des hyperphosphorylierten Fu mit cytosolischem, nicht phosphorylierten GLI3 wird dessen Phosphorylierung gesteuert. Phosphoryliertes GLI3 reichert sich im Zellkern an und die Transkription von SHH-Zielgenen wird induziert. Die in dieser Arbeit identifizierten Mechanismen sind ein möglicher zellbiologischer Hintergrund der Übereinstimmung in den klinischen Erscheinungsbildern von OS und Syndromen, die mit Genen der SHH-Signaltransduktionskaskade assoziiert sind. / Misregulation of microtubule-associated phosphatase 2A (PP2A) activity as a result of mutations in the ubiquitin ligase MID1 plays a central role in the pathogenesis of Opitz BBB/G syndrome (OS). Features typical for OS are shared by patients with mutations in GLI3 and PATCHED1 (PTC1), two members of the Sonic Hedgehog (SHH) pathway. These observations suggest that MID1 / PP2A may also be involved in the transduction of the SHH signal. Here we demonstrate that nuclear translocation of the transcription factor GLI3, a major effector of the SHH pathway, is regulated by the activity of the microtubule-associated pool of PP2A. This effect is reproduced pharmacologically by lithium chloride (LiCl), a potent inhibitor of glycogen synthase kinase 3beta (GSK3beta), and correlates with the phosphorylation status of human Fused (hFu), a GLI3 interaction partner. Our data suggest an antagonistic relationship between PP2A and GSK3beta as regulators of SHH signaling and provide a molecular basis for the phenotypic overlap between patients with OS and SHH pathway mutations.