Includes bibliographical references (p. 169-206).

While antiretroviral therapy (ART) has extended the life expectancy of those infected with HIV, it is also associated with a number of metabolic complications, such as dysglycaemia, insulin resistance and lipodystrophy. Lipodystrophy is characterised by an increase in trunk fat (lipohypertrophy) and/or a decrease in limb fat (lipoatrophy). This thesis investigates the metabolic complications associated with ART, and develops simple anthropometric cut-points for identifying those with lipodystrophy. Data for this thesis comes from three datasets (a cross sectional study and two longitudinal studies), collected between 2007 and 2013. All datasets consisted of black HIV-infected men and women presenting to ART clinics in Cape Town. The same measurements were collected in all studies: anthropometry, self-reported lipodystrophy, dual-energy X-ray absorptiometry (DXA), blood pressure (BP), cholesterol and glucose. Longitudinal data were used to assess long-term ART exposure on BP, glycaemia, insulin secretion and anthropometric measures in women on ART. We found that weight, waist circumference, and waist-hip ratio increased, limb skinfold thickness decreased, and the proportion of participants with hypertension and diabetes increased. Longitudinal data was used to describe changes in body fat distribution over a 24 month period. We found that women gained more overall weight and more regional fat in all areas compared to men. The risk of lipoatrophy was two-fold greater in men than in women. Simple, objective measures to define lipoatrophy and lipohypertrophy by comparing patient report to anthropometric and DXA-derived variables, were developed using cross sectional data. In women, the best predictors of lipoatrophy were triceps and thigh skinfold thicknesses, and for lipohypertrophy it was waist/hip ratio. Longitudinal data was used to validate the objective measures that were developed by comparing change in limb fat and trunk fat as measured by DXA to anthropometric variables. We showed that the best predictors of lipoatrophy in women were hip and mid-thigh circumference, and mid-arm circumference in men. The thesis findings highlight the importance of early identification of these cardiometabolic risks in Africa. The development of anthropometric measures are of particular relevance in resource limited settings, where health professionals need simple and inexpensive methods for diagnosing patients with lipoatrophy and lipohypertrophy.

Includes bibliographical references. / Black South Africans are at high risk of hypertension, stroke and blood pressure-related target-organ damage. In South Africa, the limited resources at primary health care level allocated to the prevention, early diagnosis and management of hypertension necessitate a non-pharmacological population-based approach to curb the escalating burden of cardiovascular disease, for which raised blood pressure is an important major contributory risk factor. The series of five studies included in the thesis provide a systematic approach to developing an appropriate nutritional population-based approach to lowering blood pressure in a high risk population. Firstly, valid, reliable, and updated information was obtained to identify habitual intake of sodium, potassium, magnesium and calcium in the target population, using the gold standard method of assessing sodium intake, namely 24-hour urinary excretion collections (Chapter 3). This information was necessary to inform the levels of sodium and other cation modification required in order to obtain a physioligically relevant change in blood pressure. As well as quantitative data on levels of sodium intake, the food sources that are the most important contributors to overall non-discretionary salt intake, and the pattern of intake of these foods, is described (Chapter 4). This data allowed identification of commonly consumed foods that could be targeted for modification on their cation content.

Bibliography: 140-197 leaves .

Includes bibliographical references. / In my research and academic work over 35 years l have addressed a wide range of issues relevant to the health of individuals, the structure and nature of health care delivery systems, and the ethical, social and economic forces that influence the health of individuals and whole populations in South Africa and globally. The attached selected publications (92 of 231 peer review articles and book chapters) are representative of my research and serial academic involvement with health care considerations that cut across many disciplines (medicine, public health, applied ethics, political science, sociology and anthropology).

Includes abstract. / Includes bibliographical references (p. 201-229). / Hypertension is a major worldwide predictor of morbidity and mortality. The search for genes that contribute to blood pressure is ongoing. The epithelial sodium channel genes were implicated when the beta subunit (SCNN1B, gene ID 6338) was found to have a mutation that caused Liddle’s syndrome. The R563Q mutation in the beta subunit has been associated with hypertension and pre-eclampsia in the Xhosa and Coloured people in Cape Town. The thesis consists of a cross-sectional analysis of the prevalence of the R563Q mutation in multiple ethnic groups in South Africa and a longitudinal functional assessment in response to saline infusion. The objectives were to determine the prevalence of the R563Q mutation and association with hypertension, and if it persists within families; to speculate as to the origins of the mutation; to determine if there were any relevant clinical differences between comparable patients with essential hypertension; to determine if the mutation predicted a difference in response to acute sodium loading and if a physiological difference is observed in sodium channel activity when expressed in oocytes. A high frequency of hypertensives in Johannesburg and Cape Town were found to be heterozygous and the mutation associated with hypertension, including within families. In the Khoisan the R563Q mutation was found at a high frequency (19%) in a random sample, suggesting the mutation originated from this population. The saline challenge illustrated the in vivo effects of the mutation. The results suggest that the sodium channel is innately overactive in heterozygous subjects and that counter-regulatory mechanisms are in place to compensate for changes in renal sodium handling. However, preliminary in vitro testing in oocytes did not show a difference in sodium channel activity.

Includes abstract. Includes bibliographical references.

Includes abstract. / Includes bibliographical references. / This thesis aimed to address a number of unanswered research questions in Addison's Disease: investigate whether autoimmunity is the predominant cause of Addison's disease in South Africa and if a human leukocyte (HLA) DQ antigen association exists; the extent to which lipids, lipoproteins and biochemical markers of cardiovascular disease are abnormal; the degree to which replacement doses of hydrocortisone are supra-physiological; the impact of glucocorticoid receptor (GCR) polymorphisms on risk factors, markers of cardiovascular disease and replacement doses of hydrocortisone.

Bibliography: leaves 113-130. / Tuberculosis has been widespread from earliest history as demonstrated by skeletal deformities suggestive of spinal tuberculosis (Potts Disease) seen in Neolithic man (5000 BC) [Sager P, Schalimtzek M and Moller-Christensen V, 1972]. The earliest written reports similar of tuberculosis probably come from Chinese writings of about 2700 BC, which mention "lung fever" and "lung cough".

Bibliography: p. 215-241. / Variegate porphyria (VP) is the clinical disorder associated with a deficiency of the haemsynthesising enzyme protoporphyrinogen oxidase (PPO). VP is one of the commonest monogenic inherited disorders in South Africa. The clinical effects include photocutaneous sensitivity and the development of potentially life-threatening acute porphyric crises. Section 1 of this dissertation examines the molecular basis for VP in South Africa.