Introduction: The prevalence of overweight and obesity is increasing worldwide. It has been estimated that every kilogram of weight gain during adulthood represents a 3% to 6% risk increased of cardiovascular disease. There are some studies showing an inverse relationship between calcium intake and body weight. Overweight and obese women are advised to lose weight before conception, however the evidence on how to achieve this is scarce. No studies have investigated the effect of calcium supplementation on weight management before conception or during pregnancy. Aims and objectives: The overarching purpose of this project was to provide information and enrich the body of evidence of the effect of calcium intake on body weight. The first aim was to evaluate the effect of calcium intake on body weight of fertile or pregnant women; secondly to investigate the pre-pregnancy weight status, weight gain during pregnancy and adequacy of dietary intake of pregnant women participating in the Calcium and Pre-eclampsia (CAP) trial. The third aim was to perform a systematic review of studies evaluating the effect of calcium intake on body weight. I was part of the core research team throughout the CAP trial duration and also lead the nutritional component. The trial sample size included 540 pregnant women recruited between 2012 and 2017 in South Africa, Zimbabwe and Argentina. Women were randomized pre-pregnancy to receive 500 mg of elemental calcium or placebo until 20 weeks´ gestation, whereafter they received 1500 mg. Weight was measured pre-pregnancy and at 8, 20 and 32 weeks’ gestation. Diet was assessed at 20 weeks´ gestation. Ethical approval was obtained from appropriate national and institutional ethical review bodies as applicable for each study site. Results: There was a high proportion of women who started their pregnancy overweight or obese (73.7% in South Africa and 60.2% in Zimbabwe). Most women had an inadequate intake of micronutrients at 20 weeks pregnancy. For the most basic micronutrients like iron, calcium, folate and zinc, the percentage of women with intakes below requirements was above 90%. Although there was no effect of calcium supplementation on body weight in the sample of the CAP trial, the calcium group had a no statistically significant smaller increase in body weight during pregnancy especially in those who were obese at the start of the trial. The systematic review shows a small but statistical effect of calcium supplementation in body weight (Mean Difference (MD) -0.33 kg, 95% CI -0.57 to -0.09); (p=0.007); 819 participants; 15 studies) and in BMI (MD -0.17, 95% CI -0.21 to -0.13); p < 0.00001; 695 participants; 10 studies). Conclusion: We found a high prevalence of obesity found together with the micronutrient inadequacy which show a very poor nutritional status of women who have the possibility of getting pregnant again. This needs to be addressed so that maternal and perinatal outcomes are improved. There is a need to implement nutritional counselling preconceptionally to these women before they fall pregnant. The results of this thesis show a no statistically significant smaller increase in body weight in women supplemented with calcium, opening a promising area of research for weight management including the study of the mechanisms involved. Before making clinical recommendations further studies are needed with higher sample size to have the power to detect clinically significant effects.

Bibliography: leaves 175-194.

Includes abstract. / Includes bibliographical references. / Several methods have been used to quantify the internal training load of a bout of exercise. However, arecent novel approach to quantify the internal training load has been to investigate the dynamic returntowards resting homeostasis at the cessation of exercise. Objective and non-invasive methods ofmonitoring the return towards resting homeostasis include measures of heart rate recovery (HRR) andexcess post-exercise oxygen consumption (EPOC). However, the relative potential of autonomic- vs. metabolic-type recovery measurements to represent the internal training load or homeostatic stress of the preceding exercise bout has not been established. Therefore, the broad aim of this thesis was to investigate the magnitude of EPOC (EPOCMAG), the time constant of the EPOC recovery curve (EPOCτ),HRR within the first minute post-exercise (HRR60s) and the time constant of the HRR curve (HRRτ) as measures which might reflect the homeostatic stress of an exercise bout. It was hypothesized that a measure representing the homeostatic stress of an exercise bout could have the following possible applications; - to identify inter-individual variation in the homeostatic stress of a standardized exercise bout - to detect intra-individual variation in the homeostatic stress of different exercise bouts- to detect intra-individual variation in “readiness to train”, based on the response to a standardized exercise bout. Therefore, the investigations of this thesis aimed to assess the relative potential of EPOCMAG, EPOCτ,HRR60s and HRRτ in these different roles. The experimental work was divided into 4 studies.

Includes abstract. / Includes bibliographical references) / The primary aim of this thesis was to identify additional genetic elements predisposing individuals to risk of AT using a candidate gene, case-control genetic association approach, and to propose the biological mechanisms underlying this genetic risk. Candidate genes (COMP, THBS2, COL27A1, TNC, COL3A1, COL5A2 and COL5A3) were selected based on their chromosomal location and/or the biological function of their encoded proteins within the extracellular matrix (ECM) of the tendon.

Includes bibliographical references (p. 244-259) / It is likely that masters runners may experience an intolerance to exercise primarily due to the age-related changes in their bodies, and specifically of those systems and organs most utilised during running. A more disturbing phenomenon, however, is that of younger runners becoming exercise intolerant. One study described exercise intolerance in athletes who were only 40 +/- 10 years old. The muscle of these athletes had greater levels of markers of structural pathology and showed evidence of having undergone more regeneration compared to age- and mileage-matched apparently healthy athletes. The authors attributed their intolerance to exercise to their large volumes of endurance training and racing which compromised their skeletal muscle. Therefore, the objective of this thesis was to examine the effects of chronic exposure to endurance running on the athlete, with particular emphasis on skeletal muscle.

Includes bibliographical references. / Clinical evaluation of the injured runner requires identification and correction of the multiple factors commonly implicated in running injury. Effective management of running injuries requires that the concerned health professional identify all implicated factors. In this regard it is essential that the relationship between running style and injury he determined, because if there is an association between the gait analysis variables descriptive of running style and injury, these would be important in the management of the injured runner. The Gait Analysis Laboratory at the Sports Science institute of South Africa and the University of Cape Town with its three-dimensional Vicon 370 motion analysis system and Advanced Medical Technology industry® strain gauge force platform is appropriate for collecting data to study running style. These data include the movement patterns and estimated mechanical power and work required to effect the observed movement of the ankle and knee. The forces applied by the supporting surfaces on the runners were collected. The data captured with the Workstation® programme (Oxford Metric, Oxford, England), was processed with GaitLab® (Kiboho Publishers, Cape Town, South Africa), collated in Excel ® (Microsoft Corporation, Redmond, USA) and statistically analysed (StatSoft, Inc. (2000). STATISTICA for Windows [Computer program manual]. Tulsa, OK, USA). In this thesis a series of studies are presented with the aim of determining the relevance of running style to the assessment of the injured runner and the conventional treatment methods used to treat common running injuries.

Includes bibliographical references (leaves 167-200)

Includes abstract. / Includes bibliographical references. / Spinocerebellar ataxia type 7 (SCA7) is a dominantly-inherited neurodegenerative disease, resulting from a CAG trinucleotide repeat expansion in the ataxin-7 gene. The Ataxin-7 protein is known to play a role in transcriptional regulation through association with cellular histone acetylation complexes, and several studies have highlighted the role of transcriptional dysregulation, caused by the presence of mutant Ataxin-7, in the neuronal dysfunction that precedes the onset of disease symptoms.This study aimed to establish patient-derived cell models of SCA7, for use in the investigation of pathogenesis (with particular reference to transcriptional alterations), and in the evaluation of previously-developed therapies for the disease.The high prevalence of SCA7 in the South African population, as a result of a founder effect, makes this disease particularly amenable to allele-specific RNA interference (RNAi)-based therapy. Thus, this study also evaluated the feasibility of these cell models as a vehicle to test previously-developed RNAi therapeutics, using the alteration of expression of key transcripts as a phenotypic marker. SCA7 patient and control dermal fibroblasts were reprogrammed to pluripotency by retroviral transduction. The resultant induced pluripotent stem cell (iPSC) lines were characterised with respect to endogenous markers of pluripotency, differentiation capacity and transgene silencing. These cells were then subjected to neuronal differentiation, the success of which was confirmed by the expression of early neuronal markers.

Bibliography: leaves 139-178. / Induction of tumor differentiation through manipulation of regulatory genes is a relatively unexplored area of cancer therapy, however, it might suggest and additional approach for tumour-specific treatment. Therefore, in view of this idea, the present study hypothesized that neuroblastomas (NBs) and pulmonary neuroendocrine tumors (NETs), which are neoplasms of neural origin, are molecularly different based on their expression of regulatory genes and that exposure to extrinsic factors will alter their growth potential. Using reverse-transcription polymerase chain reaction (RT-PCR) analysis, the present study compared the expression of about 50 regulatory genes that are expressed at early stages of neurogenesis in five human NBs and NETs, also upon GDNF/TGF-β1 and retinoic acid (RA) treatment. According to our results, individual NBs and NETs reflected a certain stage of neural development characterized by their expression of discrete sets of regulatory genes.

Includes abstract. / Includes bibliographical references (p. 173-214). / Overweight, obesity and declining levels of physical fitness have been identified as a problem in many developed countries (1). More recently concern has been raised as a result of the rapid increase in the prevalence rates of overweight and obesity in developing nations ((2); (3); (4); (5)). However, little information is available at a national level for South African primary school children. In this thesis, the current nutritional status and baseline measures of physical fitness are established for a large and representative sample of South African primary school children from a range of ethnic and socioeconomic groups. Interactions between nutritional factors and physical fitness are also considered.