Thesis (M.S.)--University of Wisconsin--Madison. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 84-87).

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 4 uppsatser.

No description available.

Magister Scientiae Dentium - MSc(Dent) / Aim To analyze the demographic profile, clinical data and radiographs of patients who had third molar surgery under general anaesthesia at the Faculty of Dentistry at the University of the Western Cape over a 10 year period. Introduction Minor oral surgical procedures are carried out by Maxillofacial and Oral Surgeons daily. The surgical removal of third molars is a large part of Minor Oral Surgery which is common throughout the world. The general impression of third molar surgery performed by experienced professionals is the ease of the operation, however no-matter how experienced one may be, a simple procedure should never be underestimated (Carvalho and Do Egito Vasconselos, 2011). New surgical techniques, as well as extensive training, skill and experience have led to the evolution of oral surgery and allowed this procedure to be carried out in a less traumatic manner. Certain factors precipitate third molar surgery to be performed in theatre as opposed to the dental clinic setting. These factors will be discussed in this research report.

L'achondroplasie est une maladie génétique rare représentant la forme la plus courante de nanisme à membres courts. Elle se caractérise par des anomalies de croissance dont les mécanismes sont très étudiés et par une forte prédisposition à l'obésité pour laquelle les causes sont inconnues. Il s'agit d'une maladie autosomique dominante causée par une mutation dans le gène du "Fibroblast growth factor receptor 3" (FGFR3). A ce jour, aucun traitement n’est disponible et, notre équipe a mis au point une thérapie par protéine recombinante montrant que l’injection d'une forme soluble du récepteur FGFR3 (sFGFR3) permet de rétablir une croissance osseuse normale chez des souris transgéniques Fgfr3ach/+. Dans une étude rétrospective, nous avons rapporté des troubles métaboliques chez des patients achondroplases avec une prise de poids de ces patients excessive entraînant une obésité essentiellement viscérale. De façon inattendue, la glycémie à jeun, l'insulinémie, le cholestérol et les triglycérides restent dans les valeurs basses de la norme. Nous avons observé les mêmes résultats dans notre modèle murin. Nous avons alors montré qu’une modification des cellules souches mésenchymateuses pourrait modifier leur potentiel de différenciation. Il est intéressant de noter que, chez les souris traitées avec sFGFR3 pendant la période de croissance, ces dérégulations métaboliques sont corrigées et le potentiel de différenciation des cellules souches est rétabli. Le sFGFR3 s'avère être un traitement prometteur pour l'achondroplasie, non seulement pour rétablir la croissance osseuse mais aussi pour prévenir les dérégulations métaboliques et le développement de l'obésité viscérale. / Achondroplasia is a rare genetic disease representing the most common form of short-limb dwarfism. It is characterized by bone growth abnormalities whose the mechanisms are well-known and a strong predisposition to obesity whose cause are unknown. It is an autosomal dominant disease caused by a mutation in the Fibroblast growth factor receptor 3 (FGFR3) gene. To date, there is no therapeutic approach, and recently, our team developed a recombinant protein therapy showing that the injection of a soluble form of FGFR3 (sFGFR3) can restore normal bone growth in transgenic Fgfr3ach/+ mice. In a retrospective medical study, we have reported metabolic disturbances in achondroplasia patients that are not associated with classical obesity complications. Indeed, during childhood, achondroplasia patients have a tendency to gain excessive weight leading to android obesity. Unexpectedly, at any age, fasting glycemia, insulinemia, cholesterol and triglycerides remains in the low values of the range. We have reported the same results in a murine model of achondroplasia expressing the G380R mutation. We have demonstrated that modifications on stem cells biology could explain in part these metabolic alterations in mice. Interestingly, in mice treated with sFGFR3 during the growth period, for which bone growth is restored, these metabolic deregulations are corrected and the stem cell differentiation potential are fully restored. sFGFR3 proves to be a promising treatment for achondroplasia not only restoring bone growth but also preventing the metabolic deregulations and the development of visceral obesity.

Thesis (Ph. D.)--University of Texas Health Science Center at Houston, School of Public Health, 2006. / Includes bibliographical references (leaves 100-107).

Hypochondroplasia (MIM 146000) is a skeletal dysplasia characterized by disproportional dwarfism with rhizomelic or mesomelic shortening of the upper and lower extremities, with variable severity. Patients often have macrocephaly with normal facial features. Hypochondroplasia is a disease with autosomal dominant inheritance. In some patients it is caused by germline mutations in the FGFR3 gene, in others the cause of the disease remains unknown . The FGFR3 gene encodes a tyrosine kinase receptor. This receptor negatively regulates the conversion of cartilage to bone. FGFR3 gene mutations that cause hypochondroplasia lead to constitutive activation of the receptor and inhibit the growth of long bones. In this study, we analysed selected regions (exons) of the FGFR3 gene in 98 patients with disproportional dwarfism and clinical diagnosis of hypochondroplasia. Eighteen patients from 12 families had familial and 80 patients had sporadic form of the disease. All patients were previously tested negative for frequent germline mutations in exon 13 (codon 540) and exon 15 (codon 650). Genomic DNA was isolated from patient's peripheral blood leukocytes. The examination was conducted with the informed consent of the patient or his legal representative. We performed mutational analysis by direct sequencing of...

Des mutations faux-sens au niveau du récepteur à activité tyrosine kinase FGFR3 (Fibroblast Growth Factor Receptor 3) entrainent sa suractivation qui apporte des dysfonctions biologiques dans plusieurs maladies. L’achondroplasie, la forme la plus commune de chondrodysplasie liée à Fgfr3, est une maladie génétique rare, touchant 1 nouveau-né sur 20 000, caractérisée par des signes cliniques spécifiques : nanisme rhizomélique, membres courts, macrocéphalie, hypoplasie de l’étage moyen de la face, compression cervico-médullaire. L’activité anormale du récepteur induit des défauts de l’ossification endochondrale responsables du phénotype pathologique. Pendant longtemps le seul traitement pour cette maladie a été l’allongement chirurgical des membres, cependant au cours des dernières années de nombreux chercheurs ont développé des potentielles stratégies thérapeutiques basées sur des études moléculaires. L’objectif de ma thèse était d’évaluer une nouvelle approche thérapeutique pour l’achondroplasie. Une stratégie thérapeutique prometteuse prévoit l’utilisation de petits inhibiteurs chimiques, connus sous le nom d’inhibiteurs de tyrosine kinases, qui sont capables d’arrêter l’activité de FGFR3. J’ai estimé les effets d’un de ces composés, NVP-BGJ398, dans un modèle murin mimant le nanisme achondroplase (Fgfr3Y367C/+). Des expérimentations effectuées ont montré une amélioration des caractéristiques pathologiques dans les souris traitées avec NVP-BGJ398. Nous avons également examiné l’impact de la mutation activatrice de FGFR3 sur le développement mandibulaire. L’étude a reconnu un défaut dans la croissance mandibulaire chez l’homme et la souris atteints. En outre nous avons pu investiguer la croissance osseuse de la mandibule et corriger le défaut pathologique avec NVP-BGJ398. Enfin j’ai participé à des analyses moléculaires pour décrire comment trois mutations de FGFR3 localisées à la même position (Lys650) peuvent induire trois différents nanismes avec sévérité croissante. Les résultats ont fourni une meilleure compréhension des mécanismes moléculaires pathologiques et pourront mener à des nouvelles cibles pour des approches thérapeutiques. / Missense mutations in the tyrosine kinase receptor FGFR3 (Fibroblast Growth Factor Receptor 3) lead to its overactivation causing biological dysfunctions in several diseases. Achondroplasia, the most common Fgfr3-related chondrodysplasia, is a rare genetic disorder, affecting 1 in 20000 live births, characterized by particular clinical features: rhizomelic dwarfism, short limbs, macrocephaly, midface hypoplasia, cervicomedullary compression. The abnormal activity of the receptor induces endochondral ossification defects that are responsible for the pathological phenotype. For a long time the only treatment for this disease was the limb lengthening surgery, however in recent years several researchers have developed potential therapeutic strategies based on molecular studies. The objective of my thesis was to evaluate a novel therapeutic approach for achondroplasia. A promising therapeutic strategy involved the use of small chemical inhibitors, known as tyrosine kinase inhibitors, that are able to arrest the FGFR3 activity. I have assessed the effects of one of these compounds, NVP-BGJ398, in a mouse model mimicking the acondroplastic dwarfism (Fgfr3Y367C/+). The experiments performed showed an improvement of all pathological hallmarks in NVP-BGJ398 treated mice. We have also inspected the impact of the activating FGFR3 mutation on the mandibular development. The study established a defect in mandibular growth in both affected patients and mice. Furthermore we could investigate the mandibular bone growth and correct the pathological defect with NVP-BGJ398. Finally I have participated in molecular analyses to describe how three FGFR3 mutations at the same position could lead to three different dwarfisms with increasing severity. The results provided a better understanding of FGFR3 pathological molecular mechanisms and could lead to new targets for therapeutic approaches.

Estrogen-receptor-related receptor gamma, ERRγ, is highly expressed in cartilage and upregulates the chondrogenic transcription factor, Sox9, in a chondrocytic cell line. To assess the effect of increasing ERRγ activity on cartilage in vivo, we generated transgenic animals driving ERRγ expression with a chondrocyte-specific promoter. I verified that one transgenic line exhibited 26% increased ERRγ protein at E14.5. No major morphological defects were seen at this stage, but I observed significant reduction in the size of the appendicular skeleton in P7 mice, such that all elements of the appendicular skeleton were significantly reduced by 4 – 10%. I continued the phenotype analysis at the histological level and found that the P7 animals displayed significantly reduced growth plate height, caused by deficiencies in the size of the proliferative and hypertrophic zones of the growth plate. This suggests a previously unknown role for ERRγ in regulating endochondral ossification in growth plate chondrocytes.

Estrogen-receptor-related receptor gamma, ERRγ, is highly expressed in cartilage and upregulates the chondrogenic transcription factor, Sox9, in a chondrocytic cell line. To assess the effect of increasing ERRγ activity on cartilage in vivo, we generated transgenic animals driving ERRγ expression with a chondrocyte-specific promoter. I verified that one transgenic line exhibited 26% increased ERRγ protein at E14.5. No major morphological defects were seen at this stage, but I observed significant reduction in the size of the appendicular skeleton in P7 mice, such that all elements of the appendicular skeleton were significantly reduced by 4 – 10%. I continued the phenotype analysis at the histological level and found that the P7 animals displayed significantly reduced growth plate height, caused by deficiencies in the size of the proliferative and hypertrophic zones of the growth plate. This suggests a previously unknown role for ERRγ in regulating endochondral ossification in growth plate chondrocytes.