Thesis (M.S.)--University of Michigan, 1986.

Recent epidemiological data have implicated prenatal events in the development of cardiovascular disorders. Thus low birth weight strongly predicts the later occurrence of hypertension, type II diabetes mellitus, syndrome X and deaths from ischaemic heart disease. The mechanism linking prenatal events and later disease is not clear, although maternal malnutrition has been advocated. We have advanced the hypothesis that glucocorticoids might be important as they retard foetal growth and programme offspring hypertension in rats. The foetus has been thought to be protected from the 2-10 times higher maternal glucocorticoid levels by the placental enzyme 11B-hydroxysteroid dehydrogenase (11B-HSD), which is present in many tissues and in humans catalyses the conversion of the active glucocorticoid cortisol to inert cortisone (corticosterone to 11-dehydrocorticosterone in rats). The precise role of 11B-HSD as a barrier to maternal glucocorticoids during prenatal life has not been fully characterised. The role of 11B-HSD in controlling prenatal glucocorticoid exposure in humans and animals has thus been examined. Two isoforms of 11B-HSD exist, type 1, a widespread NADP dependent reversible enzyme and type 2, a high affinity NAD dependent dehydrogenase found mainly in placenta and kidney. 11B-HSD was found in abundance in the ovary and placenta. The main site of immunohistochemical staining and expression of mRNA (11B-HSD-1) in the rat ovary was in the oocyte. 11B-HSD was oxidative, inactivating corticosterone. In both rat placenta in-vitro (11B-HSD-2), and human placenta in-vitro and ex-vivo (11B-HSD-2) the bioactivity was also predominantly oxidative. The lowest placental enzyme activity at term (and hence the greatest foetal glucocorticoid exposure) was found in the smallest rats with the largest placentas, i.e. those in human studies who would be predicted to develop the highest adult blood pressures (birth weight vs. placental 11B-HSD activity: n = 56; r = 0.46; p < 0.0005). A method to examine 11B-HSD function in fresh intact human placentas was developed (ex-vivo dual circuit cotyledon perfusion) which allows close approximation to the in-vivo situation. The majority of cortisol, from low to high nanomolar concentrations, infused through the maternal circulation was metabolised to inert cortisone by the time it reached the foetal circulation, although considerable individual variation was observed. 118-HSD was the only significant contributor to placental cortisol metabolism at physiological maternal concentrations and inhibition of 118-HSD with either the liquorice constituent glycyrrhetinic acid or its hemi-succinate, carbenoxolone, resulted in abolition of the glucocorticoid barrier, allowing maternally administered cortisol to pass unmetabolised through the placenta. In a prospective study, on 16 normal primiparous women whose placentas were studied with this technique, a positive and significant correlation was found between the effectiveness of 118-HSD and offspring birth weight (r = 0. 67; p < 0. 005). The relationship between placental 118-HSD effectiveness in-vivo and term cord blood osteocalcin (a sensitive marker of glucocorticoid exposure) was prospectively examined in 19 women. Cord blood levels of the bone specific protein osteocalcin were determined with radioimmunoassay. The lowest cord blood osteocalcin levels were found in the foetuses whose placental 118-HSD barrier function was poorest (r = 0.58; p < 0.02), (and had presumably had the greatest glucocorticoid exposure), suggesting that term cord blood osteocalcin levels might be a useful predictor of hypertension, ischaemic heart disease and possibly metabolic bone disease. The findings presented in this thesis represent direct evidence that 118-HSD is the barrier to maternal glucocorticoids, its effectiveness correlating with foetal growth in rats (in-vitro), in humans (ex-vivo), and in-vivo with human cord blood osteocalcin levels (osteocalcin may be a marker of glucocorticoid exposure). In the light of studies on pregnant rats in which administration of exogenous glucocorticoids or 118-HSD inhibitors reduces birth weight and programmes hypertension in the offspring, it is reasonable to propose that increased foetal glucocorticoid exposure consequent upon attenuated placental 118-HSD function may play a role in intrauterine programming of later hypertension.

PhD, Faculty of Health Sciences, University of the Witwatersrand, 2008 / Fetal alcohol spectrum disorders (FASD) describe the range of disorders that result from in utero alcohol exposure. FASD is a serious global health problem and is observed at exceedingly high frequencies in certain South African communities. Although in utero alcohol exposure is the primary trigger, there is evidence that genetic- and other susceptibility factors contribute towards FASD development. To date, no genome-wide association or linkage studies have been performed for any of the FASD syndromes. The main objectives of this study were to develop an innovative approach to computationally identify biologically plausible candidate genes for FASD, for a future association study, and to evaluate the appropriateness and validity of this approach. Further, an in silico analysis of known single nucleotide polymorphisms (SNPs) within the top-ranked candidate gene was performed in conjunction with de novo SNP detection, to select a subset of SNPs based on proposed functional impact on gene expression and protein function, for a prospective association study. A computational binary filtering technique was designed that can be employed to prioritize genes in a candidate list, or could be used to rank all genes in the genome in the absence of such a list. 10174 FASD candidate genes were initially selected from the whole genome using a previously described method. Hereafter the candidates were prioritized using a binary filtering technique. The biological enrichment of the ranked genes was assessed by investigating the protein-protein interactions, functional enrichment and common promoter element binding sites of the top-ranked genes. A group of 87 genes was prioritized as candidates highlighting many strong candidates from the TGF-/, MAPK and Hedgehog signalling pathways, which are all integral to fetal development and potential targets for alcohol's teratogenic effect. To assess the effectiveness and accuracy of this computational approach, X-linked mental retardation (XLMR) was used as a test disease, considering that XLMR is a set of heterogeneous disorders of which some of the underlying genetics is known. This implementation resulted in a prioritized gene list with a noted enrichment of known XLMR genes among the top-ranked genes. Furthermore, the top-ranked list contained genes that were biologically relevant to XLMR, and could potentially be as yet unknown candidate genes for XLMR. Indeed, many of the top-ranked genes mapped to XLMR candidate regions, confirming their status as good candidates. Finally, a subset of seven known and novel SNPs was selected within FGFR1 based on putative functional impact. Data from the HapMap project was used to identify tag SNPs for FGFR1 to complement the selection made based on function. The main limitation of the proposed computational approach to candidate gene prediction is that it is primarily based on gene annotation, and that it is therefore biased towards selecting better-annotated genes. However, the results obtained in this study suggest that the described computational method is an effective approach that can identify likely candidates that are biologically relevant to the disease of interest, and therefore appropriate for a candidate-gene association studies. In practice, this technique is an appropriate approach to select a workable set of candidate genes for a complex disease, in a setting where a whole-genome association study is not a viable option.

Includes bibliographical references (leaves 165-225) / xx, 298 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, School of Molecular and Biological Sciences, Discipline of Physiology, 2004

Thesis (M. Med. Sc.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 26-32).

published_or_final_version / Medicine / Master / Doctor of Medicine

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Thesis (Ph. D.)--University of Adelaide, 1994. / Includes examples of information booklets as appendices. Includes bibliographical references (p. 232-251).

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaf 57-70) Also available in print.