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Call number: LD2668 .T4 1950 S676 / Master of Science

M.Tech.

M.Tech.

M.Tech.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science (Medicine) in Human Genetics / Maintaining suitable bone health is emerging as a serious point of concern worldwide, as the prevalence of skeletal disorders threatens to reach unmanageable proportions. Despite unfavourable environmental factors, black South Africans demonstrate elevated bone mass, especially at the femoral neck, when compared to whites. Genetic factors are thought to mediate this effect, which may have clinical or therapeutic value. Using a candidate gene approach, this study investigated associations of six candidate genes (ESR1, TNFRSF11A, TNFRSF11B, TNFSF11, SOST and SPP1) with bone mineral content amongst pre-pubertal black South African children that formed part of the longitudinal Birth to Twenty cohort. The GoldenGate genotyping assay with VeraCode microbeads was used to genotype 151 black children at 366 polymorphic loci, including 112 previously associated and 254 tagging SNPs. A linear regression approach was implemented to highlight significant associations whilst adjusting for height, weight, sex and bone area. Twenty seven markers (8 previously associated and 19 tag SNPs; P <0.05) were found to link to either femoral neck (18) or lumbar spine (9) BMC. These signals derived from three genes, namely ESR1 (17), TNFRSF11B (9) and SPP1 (1). One marker (rs2485209) maintained its association with the femoral neck after correction for multiple testing (P = 0.038). These results fully support the existence of a strong genetic effect acting at the femoral neck in African ancestry individuals. Tagging SNP signals suggest the presence of a number of population specific variants that require further investigation. Combined, these markers may help to account for increased bone mass amongst black South Africans, when adjusted for covariates.

The association between diabetes and coronary artery disease (CAD) has been recognized as a major public health problem in the developed world. While there is an increased prevalence of silent myocardial ischaemia among asymptomatic individuals with diabetes, diabetic individuals with CAD in their larger number are usually asymptomatic, and when they present with signs of disease, there is extensive and severe CAD. It should be noted that amongst black South African, ischemic heart disease (IHD) remains rare, and there is little data linking diabetes mellitus with IHD. However, contrary to early reports that have suggested a low prevalence of CAD in black population in Africa, many studies have indicated a rapid change on the spectrum of CAD in numerous parts of the African continent. Despite the emerging report of high prevalence of risk factors there are only limited data investigating prevalence of CAD in black African with diabetes. The purpose of this thesis was to use myocardial perfusion imaging (MPI) at rest and after stress testing to detect CAD in a group of asymptomatic black patients suffering from diabetes and therefore assess the prevalence of CAD; to assess the changes in myocardial perfusion in asymptomatic diabetic black individuals and compare the differences seen in myocardial perfusion changes between the asymptomatic diabetic black and, the asymptomatic diabetic white and Indian individuals; to include data from symptomatic diabetic patients who were referred for MPI as part of their routine clinical management for possible comparison Consecutive 94 asymptomatic diabetic black patients and 50 asymptomatic diabetic white and Indian patients were recruited from the outpatient diabetic clinic of the Johannesburg hospital. Data from 90 subjects forming a group of symptomatic diabetic patients, 45 blacks and 45 whites and Indians referred for MPI as part of their clinical management were also analyzed. A two-day protocol for SPECT MPI was used in all participants: on the first day the stress testing MPI while the rest MPI was consistently done on the second day. Both exercise and pharmacologic stress testing were used. Technetium-99m methoxy-isobutylisonitrile (MIBI) was used as the myocardial perfusion radiopharmaceutical. Myocardial perfusion was assessed by means of semi-quantitative scoring system to measure the extent and severity of perfusion abnormality. Visual inspection of the reconstructed SPECT MPI images was carried out to assess perfusion deficit where there was a doubt on the extent and severity of perfusion abnormality. The QPS/QGS software allows obtaining resting and post stress left ventricular ejection fraction (LVEF). The means and percentages on study variables were obtained. The Spearmen correlation coefficient was used to calculate correlations between variables. The Kruskal-Wallis test was used to assess differences between black diabetic and white or Indian diabetic patients and Wilcoxon scores (rank sum) two-sided were used to measure differences within these racial groups. There were 123 females (52.6%) and 111 males (47.4%) in total. From the recruited participants, 53 (56.4%) asymptomatic females and 41 (43.6%) asymptomatic males were blacks whereas 24 (48%) asymptomatic females and 26 (52%) asymptomatic males were whites or Indians. The symptomatic group was comprised of 26 (57.8%) female and 19 (42.2%) male black patients and 20 (44.5%) female and 25 (55.5%) male white or Indian patients. Asymptomatic diabetic black participants were younger than the participants from the asymptomatic diabetic white and Indian group with a mean age of 60 (SD±7.2) years Vs 64 (SD±7.7) [p=0.003]. Fourteen percent of asymptomatic black participants had evidence of ischaemia by showing improvement of perfusion on stress testing versus twenty eight percent of white and Indian asymptomatic participants (p=0.62). Perfusion defects that did not change from rest to post stress testing MPI (fixed defects) were also noted in 20% of asymptomatic black and 26% of asymptomatic white and Indian diabetic participants. These fixed perfusion defects are indicative of previous myocardial infarctions and therefore suggestive of CAD. No significant difference was noted on the changes of perfusion that could account either for ischaemia or infract between asymptomatic diabetic black participants and their white and Indian counterparts (p=0.47). The difference on the improvement of perfusion from rest to post-stress MPIs or reversibility of perfusion to suggest only the presence of ischaemia did not also show a significant difference between these two racial groups (p=0.62). Our data demonstrated a high prevalence of CAD in asymptomatic diabetic black participants similar to other racial groups. Our study has demonstrated evidence to recommend screening of asymptomatic diabetic black individuals in equal manner than other races for the detection of CAD. More importantly, stress MPI should be routinely used as a noninvasive investigation in our environment and be utilized more actively in the management of all asymptomatic diabetic patients.

Thesis (Ph.D.(Public Health))--University of the Witwatersrand, Faculty of Health Sciences, 2012 / Introduction Personal exposure to respirable crystalline silica (commonly in the form of quartz) causes serious adverse health effects and has been well documented in industries formally known as the ‘dusty trades’. Very little information exists on personal quartz exposure in agricultural settings. Silica exposure is an important public health issue particularly in settings of high tuberculosis (TB) and Human Immunodeficiency Virus (HIV) rates. The mineral has contributed to serious epidemics of TB in southern Africa and other low and middle - income regions of the world because of the increased risk of pulmonary tuberculosis in silica exposed workers. It is well known that HIV infection increases the incidence of TB and the risk of tuberculosis in individuals with both HIV and silicosis is larger than the sum of each factor. Globally (especially in resource poor countries), agriculture employs a very large population that may be affected. Objectives The objectives of the PhD were to review the published literature on respirable quartz exposure and associated disease in agricultural related settings systematically; to measure personal time weighted average respirable dust and quartz on sandy, sandy loam and clay soil farms in the Free State and North - West provinces of South Africa; to ascertain whether soil type is a determinant of exposure to respirable quartz; to identify additional determinants of quartz exposure in farming; to estimate annual cumulative respirable quartz exposure; and to discuss some occupational health implications and research needs. Methodology Published studies on exposure to silica and quartz in agriculture and related settings as well as silica - associated disease in farming were searched systematically through “PubMed”; and, critiqued. Three farms, located in the Free State and North West provinces of South Africa, had their soil type confirmed as sandy, sandy loam and clay; and, from these, a total of 298 respirable dust and respirable quartz measurements were collected between July 2006 - November 2009 during periods of major farming operations. These measurements were collected using standard international measurement and analytical methods. Quartz determinations were done using X - ray diffraction by a quality - assured, accredited laboratory, and were verified by a leading external agency. Respirable quartz values below the limit of detection (22 μg.m-3) were estimated using multiple imputation. Non - parametric tests were used to compare quartz exposure from the three different soil types. Variables such as soil type, commodity farmed, activity (nature of work done), process (manual vs mechanical), quartz % and weather variables (e.g. wind and humidity during the week prior of and during sampling) were used in bivariate and multiple regression modeling to identify determinants of respirable quartz exposure. Logistic regression was done aiming to identify determinants of respirable quartz greater than 50 μg.m-3 and to deal with data points below the detection limit without including multiple imputation methods. The annual cumulative exposure was estimated for a typical farm worker on the sandy soil farm using activity - specific measurements and duration of each activity in a year. Particle sizes of respirable dust fraction were determined using laser light scattering. Results Literature review In total, 17 studies were identified: 11 investigated respirable dust and quartz exposure on farms and six quartz related disease in agricultural settings. They provided convincing evidence of a respirable quartz risk on sandy soil farms but scant evidence of associated disease. Exposure to respirable dust and quartz Respirable quartz measurements from the three South African farms ranged from not detectable to 626 μg.m-3 and confirmed the quartz hazard: some concentrations exceeded generally accepted occupational exposure limits in all activities evaluated, even though 278 (93.3 %) of the respirable dust concentrations were well below a commonly used occupational exposure limit of 2 mg.m-3. Fifty seven percent, 59% and 81% of the respirable quartz measurements on the sandy soil, sandy loam soil and clay soil farm respectively exceeded the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) of 25 μg.m-3. Twelve percent and 13% of respirable quartz concentrations exceeded 100 μg.m-3 on the sandy soil and sandy loam soil farms respectively, but none exceeded this level on the clay soil farm. Determinants of exposure The proportions of measurements greater than 100 μg.m-3 were not significantly different between the sandy and sandy loam soil farms (prop.test; p = 0.65), but both were significantly larger than for the clay soil farm (prop.test; p= 0.001). The percentage of quartz in respirable dust was determined for all three farms using samples of a size such that all measurements were well above the analytical detection limit. Percentages ranged from 0.5 - 94.4% with no significant difference in the median quartz percentages across the three farms (Kruskal - Wallis test; p = 0.91). Bivariate analyses showed that commodity (Kruskal - Wallis test; p = 0.001), activity (Kruskal-Wallis test; p = 0.001) and process (Wilcoxon test; p = 0.003) were associated with respirable quartz concentrations. Multiple linear regression showed that soil type, season, commodity, activity, process, quartz percentage, humidity on the morning of measurement and interactions between activity, respirable dust exposure and quartz percentage were significantly related to respitable quartz exposure. Logistic regression showed that, during univariate analyses, cereal planter operator, increased quartz % in respirable dust, decreased humidity on the day of measurement and increased respirable dust concentration were all significantly associated with quartz levels above 50 μg.m-3. Multivariate analyses showed that cereal planter operator remained a strong determinant of higher level of exposure relative to other activity (OR 3.76 95% CI 1.64 - 8.63). Increased levels of quartz % in respirable dust increased the ORs for exposure above 50 μg.m-3. Annual cumulative exposure The estimated annual cumulative exposure of a farm worker exposed at the highest concentration measured for each task exceeded the cumulative exposure had the worker been exposed at 100 μg.m-3 by 1.46 times. At median quartz exposures measured for each of the activities done during the year, the chances of exceeding the cumulative exposure if exposed at the South African OEL are small: the ratio of the estimated cumulative exposure indices to occupational exposure limit cumulative exposure = 0.29. Particle size The median D50 particle size of the 30 respirable dust samples measured in this study was 5.53 μm with the smallest D50 value reported by the laboratory being 3.39 μm. Conclusion Despite its ubiquity, little is known about quartz exposure in the agricultural industry. This thesis not only demonstrates significant potential for overexposure in some settings, it also may be the biggest study of its kind: it is the first study to have measured a large number (298) of personal respirable quartz concentrations across various activities on three farms known to have different soil types. It is also the first study in farming that attempted to relate personal respirable quartz exposures to possible determinants, to consider potential modifiers of quartz exposure and to estimate annual cumulative quartz exposure. The study adds considerably to the evidence that over - exposure to quartz may be a risk in farming and has identified the need for practical interventions and research gaps. In addition, this study makes it possible to use the detailed analyses of silica exposure determinants in farming in other settings with similar conditions. Soil type may determine whether exposure is greater than 100 μg.m-3, but the job type and the manner in which the task is performed (e.g. mechanical or manual) may be important determinants of exposure. Identifying quartz exposure determinants (e.g. type of job) and modifiers will be of value to focus implementation of controls, which is of particular importance in developing countries. The nature of farming and weather variables may add information about exposure risk and should be included with soil type in future farming exposure assessment studies. Given the large numbers of farm workers possibly exposed to silica and the seriousness of silica - associated diseases, some dust - related occupational health interventions should be considered in South African farming, particularly because during the course of the studies none of the South African farms had medical surveillance programmes in place and few, if any, dust control measures were observed. Practitioners working in farming areas should be aware that silica - associated diseases may occur in farm workers; therefore despite limited evidence for silica associated disease, occupational health interventions appear justified. No study previously has defined the burden of silica – associated diseases in farming. A starting point may be to perform radiological surveys on long service farm workers (possibly more than 20 years service and performing dusty activities) on a sandy soil farm, as sandy soils are likely to produce the highest silica levels. An effort should also be made to define the duration and intensity of silica exposure in farming over the annual cycle. Lastly, cost - effective methods to reduce respirable dust and silica exposure in farming should be identified.

A Dissertation Submitted to the Faculty of Health Sciences, University of the Witwatersrand, in the Fulfilment of the Requirements for the Degree for Master of Science in Medicine (Pharmaceutics) Department of Pharmacy and Pharmacology, University of the Witwatersrand, Johannesburg, 2016 / MT2016

Thesis (M.Sc. (Med.) (Pharmaceutical Affairs))--University of the Witwatersrand, Faculty of Health Sciences, 2012