L’acétyl-coA occupe une place centrale dans le métabolisme intermédiaire. Il constitue le point de jonction de plusieurs voies métaboliques telles que la .-oxydation, la glycolyse, le catabolisme de certains acides aminés, la cétolyse, la cétogenèse et la synthèse d’acides gras. Il est également impliqué dans d’autres processus tels que l’acétylation des protéines. Au cours de mon travail de thèse, je me suis attachée à étudier différents aspects du métabolisme de l’acétyl-coA. La première partie de mon travail a porté sur la modulation pharmacologique de la .- oxydation dans le but de corriger des déficits de cette voie métabolique. L’intérêt de traitements par 400µM de bézafibrate ou 75µM de resvératrol dans les formes modérées de déficit en VLCAD et en CPT2 avait été montré précédemment. Par des méthodes de référence et grâce à la mise au point de nouvelles techniques, j’ai pu montrer sur des fibroblastes de patients déficitaires en LCHAD que des traitements par une combinaison de 35µM de bézafibrate et 30µM de resvératrol permettent d’augmenter les capacités d’oxydation du palmitate en stimulant la synthèse protéique. L’effet de cette combinaison était comparable à celui d’un traitement par 400µM de bézafibrate. Dans un second temps, je me suis intéressée à deux cofacteurs impliqués dans le métabolisme de l’acétyl-coA : l’acide lipoïque, cofacteur de quatre .-cétoacides déshydrogénases (PDHc, BCKDHc, .- KGDHc et GCS) et la riboflavine, cofacteur d’acyl-coA déshydrogénases de la .-oxydation et de déshydrogénases impliquées dans le catabolisme des acides aminés ramifiés. Ainsi, j’ai participé à la description d’anomalies du métabolisme de l’acide lipoïque, un nouveau groupe de maladies héréditaires du métabolisme caractérisé par un déficit combiné en .-cétoacides déshydrogénases. Par ailleurs, j’ai pu montrer qu’une hyperprolinémie constitue un biomarqueur intéressant pour le diagnostic d’acidurie glutarique de type II primaire ou secondaire, ces dernières pouvant se rencontrer en cas d’anomalie du métabolisme de la riboflavine. J’ai également évalué l’utilisation d’un mélange racémique de L,D-3-hydroxybutyrate afin de corriger les déficits énergétiques induits par un déficit en PDHc ou GLUT1. Via la cétolyse, le L,D-3- hydroxybutyrate génère de l’acétyl-coA. De façon surprenante, l’administration de ce composé s’est traduite par une amélioration de l’état clinique des patients atteints de déficits en PDHc, alors qu’une dégradation a été observée chez les patients atteints de déficits en GLUT1. Cette évolution différente pourrait souligner l’importance de l’anaplérose chez les patients déficitaires en GLUT1. Enfin, la dernière partie de mon travail de thèse porte sur la description d’un patient atteint d’une forme modérée de déficit en pyruvate carboxylase, cette enzyme étant régulée par l’acétyl-coA. Les difficultés diagnostiques rencontrées devant ces formes modérées sont rapportées, ainsi que des essais de traitement par des composés anaplérotiques et par le bézafibrate, malheureusement sans bénéfice net que ce soit in vitro ou in vivo. En conclusion, le métabolisme de l’acétyl-coA est altéré dans de nombreuses maladies héréditaires du métabolisme, dont certaines sont de description récente. Il peut être modulé par différentes approches pharmacologiques. Le développement de nouvelles techniques et notamment les analyses de flux métaboliques fournissent des outils utiles à son exploration et à l’étude de nouveaux traitements. / Acetyl-CoA is crucial for intermediary metabolism. It is at the crossroad of several metabolic pathways such as beta-oxidation, glycolysis, aminoacid catabolism, ketolysis, and fatty acid synthesis. It is also involved in other processes such as protein acetylation. In this document I studied different aspects of acetyl-CoA metabolism. First, I tried to correct fatty acid oxidation defects through pharmacological approach. Thanks to well- known methods and new ones, I showed that a combination of 30µM resveratrol and 35µM bezafibrate increased fatty acid oxidation capacities by increasing protein synthesis, as well as 400µM bezafibrate. Acetyl-CoA metabolism is also altered due to cofactors defects such as lipoic acid or riboflavine deficiency. I was involved in new diseases description and research for new biomarkers in this context. PDHc and GLUT1 deficiency are two different diseases with the same consequence : a defect in acetyl- CoA production from glucose. In order to improve patients’ quality of life, I evaluated the substitution of ketogenic diet with a racemic mix of L,D-3-hydroxybutyrate in PDHc and GLUT1 deficiency. The clinical evolution of patients was strikingly different, with an improvement in PDHc patients, whereas a degradation was noticed in GLUT1 patients. This difference might underline the role of anaplerosis in GLUT1 deficiency. Finally, I evaluated anaplerotic treatment and bezafibrate treatment in pyruvate carboxylase deficiency, an enzyme allosterically regulated by acetyl-CoA. To conclude, acetyl-CoA metabolism is altered in numerous inherited errors of metabolism, some of them being recently described. It can be modulated by pharmacological approaches. The development of new techniques such as metabolic flux analysis are useful for its study and for new treatments evaluation.

Traditional technologies are revelations of knowledge, skill, and wisdom of ancestors that have been used to facilitate and enhance the performance of socio-economic activities, overcome environmental challenges, and magnify symbolic presentations of cultural and spiritual engagements. Traditional technologies are still practiced in many communities despite the strides made in the advancement of modern technologies. The socio-economic significance of traditional technologies in the context of Ethiopia is even more profound. There are hardly social, economic, and spiritual activities that are not, directly or indirectly, influenced by the application of traditional technologies. The irony is, however, they are not appreciated and conserved in spite that they have been proving a sustained significance across generations while, to the contrary, modern technologies are even staggering to outlive the stage of product introduction. Although still proving to be useful, traditional technologies have been marginalized as if they are symbols of backwardness belonging to the past as irrelevant to the modern day settings. It was, therefore, the urge to look into this dilemma that became the basis for the initiation to conduct a research on the captioned topic. The study has endeavored to address how traditional technologies, specifically that of Ethiopia, are able to sustain contrary to extant theoretical predictions of technologies, and investigate why they have been deterred from getting the conservation and transformation they deserve in spite of the socio-economic significant role they have continued to play as capitulated in the statement of the problem. In addressing the statement of the problem, the paradigm of the world outlook within which the research was situated is found to be related to the Critical Theory paradigm. As a result, a qualitative research methodology based on a case study design was framed and a longitudinal field study on the sampled cases was conducted. The data generated from the study were ix filtered, coded, organized, categorized, and ultimately analyzed and interpreted using apparent analytic models until saturated and triangulated findings were established. Accordingly, the core constructs that has been defining the fate of traditional technologies were induced and their impact in deterring or promoting the conservation and transformation of traditional technologies were synthesized. Based on the outcomes of data analysis and interpretation, appropriate methods of reshaping the societal attitude and orientation in terms of conserving and transforming traditional practices are proposed as induced recommendations ultimately requiring a timely intervention. / Business Management / D. Litt. et Phil. (Business Leadership)

Text in Afrikaans / Dr. J D Vorster het gedurende sy bedieningstyd in die N.G.Kerk [1935-1978] ontwikkel en gegroei tot 'n invloedryke kerkleier. Die faktore en omstanighede wat tot sy vorming bygedra het is die onderwerp van hierdie studie. Die f eit dat hy in die Stormberge gebore en getoe is asook .karaktereienskappe wat hy van sy voorsate geerf het, was belangrike komponente in sy vorming. Boustene soos godsdiens en volksliefde het in sy ouerhuis die grondslag gele vir sy teologiese beskouings wat op universiteit ontwikkel het. Sedert 1935 is hy in die bediening verder gevorm deur pastorale werk, kerklike vergaderings en briefwisselings. Kulturele en politieke betrokkenheid asook gevangenisstraf het horn bekend gemaak en gebrei. 'n Doktorsgraad in die Kerkreg was verder die regte skoling vir die amp va.n Aktuarius - 'n pos wat met soveel deeglikheid uitgevoer is dat hy later as kerkleier erken is met sy verkiesing as Moderator. / During his ministry in the D.R.Church, dr.J D Vorster developed and grew to become an influential church leader. The subject of this study is the factors and circumstances which contributed to his forming. The fact that he was born and bred in the Stormberge as well as the characteristics he inherited from his ancestors were important components in his forming. Building stones such as religion and nationalism in his parents home laid the .foundation of his theological views which developed at university. He was further formed in his ministry through pastoral work, church meetings and correspondence. Cultural and political participation as well as imprisonment made him well-known and tough. His doctorate in church law put him on the right track for the post of Actuary - an off ice which he filled with so much efficiency that his leadership in the church was recognised with his election as Moderator. / Christian Spirituality, Church History and Missiology / Th. M. (Church History)

Inherited metabolic disorders (IMD) form a diverse group of several hundred different diseases with a relatively high cumulative incidence (stated up to 1:600). They are associated with accumulation of the substrates and lack of the products in specific metabolic pathways, which is caused by deficiency of the enzyme or its activator, or dysfunction of the transport protein. However, the underlying cause is at the DNA level. The grounds for different phenotype manifestation in patients with the same genotype are often not known. During my work at the Institute of Inherited Metabolic Disorders, I designed several new methods for the research of IMD and applied them in the patients and their families. I created procedures for the isolation of lysosomal membranes that are used for the research of lysosomal storage disorders and general properties of lysosomes. Next, I introduced several novel assays for determination of the X-inactivation ratio, which led to a significant increase of informative women. Nowadays, we use these methods in heterozygous women with X-linked diseases in order to study the influence of X-inactivation on the manifestation of the diseases. The cases of a girl with mucopolysaccharidosis type II, a girl with OTC deficiency and a family with the mutation in HPRT1 gene are described...

Inherited metabolic disorders (IMD) form a diverse group of several hundred different diseases with a relatively high cumulative incidence (stated up to 1:600). They are associated with accumulation of the substrates and lack of the products in specific metabolic pathways, which is caused by deficiency of the enzyme or its activator, or dysfunction of the transport protein. However, the underlying cause is at the DNA level. The grounds for different phenotype manifestation in patients with the same genotype are often not known. During my work at the Institute of Inherited Metabolic Disorders, I designed several new methods for the research of IMD and applied them in the patients and their families. I created procedures for the isolation of lysosomal membranes that are used for the research of lysosomal storage disorders and general properties of lysosomes. Next, I introduced several novel assays for determination of the X-inactivation ratio, which led to a significant increase of informative women. Nowadays, we use these methods in heterozygous women with X-linked diseases in order to study the influence of X-inactivation on the manifestation of the diseases. The cases of a girl with mucopolysaccharidosis type II, a girl with OTC deficiency and a family with the mutation in HPRT1 gene are described...