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Mseleni Joint Disease is a disabling polyarticular disorder occurring with a high prevalence in the Mseleni area of Northern Zululand. During the past three years the series of epidemiological, genealogical and clinico-radiological studies carried out in the Mseleni Joint Disease Project have resulted in: 1. the localisation of a high prevalence area and a neighbouring control or low prevalence area; 2. the identification of individuals affected by the disease and of families consisting of many such individuals; 3. the definition of the clinical and radiological aspects of the disease. The description of these studies forms the subject of this thesis.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Public Health in the field of Hospital Management October, 2014 / Background: The World Health Organization predicts that the deaths related to Non- Communicable Diseases in Africa will rise by 27% over the next decade. As a response to the problem, the National Department of Health in South Africa introduced interventions that focussed on implementing health facility based Non- Communicable Diseases register and a monitoring tool. The Gauteng Department of Health in South Africa started introducing the monitoring tool in public health facilities since April 2011 in a phased manner. This study used a one week data collected in the month of April 2011 in selected health facilities within the Johannesburg Health District. Aim: To describe the socio-demographic and clinical profiles of the study population attending the health facilities in Johannesburg Health District. Methodology: A cross-sectional study design was used for the study. The data was collected from the selected Community Health Centres using the monitoring tool developed by the National Department of Health. The data were collected for a week from randomly selected health facilities in 2011. Results: Nine-hundred and sixty eight study participants were recruited from the five community health centres for the assessment of non-communicable diseases. Among the study participants, the prevalence of hypertension (94.6%) was highest followed by diabetes (39.4%) and hyper-cholesterolaemia (4.6%). A number of study participants had comorbidity associated with all three conditions. The majority of them were 45 years and above (88%), female (53%), and black (98%); There were no significant association between these three conditions and risk factors such as smoking and alcohol drinking. The complications among the study participants include nephropathy, cardiac diseases and retinopathy. Annual screening was done for a number of study participants but it was erratically done so that all study participants were not screened. Twenty-two percent of 968 study participants have blood pressure of more than 140/90mmHg. Twenty percent of study participants have a weight more than 90kg. The sugar level of 22% study participants was more than 7mmol/l. Conclusion: The NCD monitoring tool could be used as an effective tool for management of NCD in PHC setting like Johannesburg Health District.

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Globally, infectious diseases are responsible for major conservation and economic losses in wild and farmed fish populations. Prevention tools, including vaccination and breeding for genetic disease resistance, are used in many systems to prevent mortality by such diseases. Studies are often done to evaluate the efficacy of a preventative method at reducing disease, but the impact on transmission is rarely studied. Protection under diverse field conditions, such as variable pathogen exposure dosages, is also not fully understood. Furthermore, there is little information on how preventative methods alter host-pathogen relationships. For example, it is largely unknown how vaccination impacts non-target pathogens that co-infect the host. These knowledge gaps make it difficult to infer the epidemiological impacts of disease prevention tools. In an attempt to fill these gaps, we investigated two leading pathogens in rainbow trout (Oncorhynchus mykiss) aquaculture: infectious hematopoietic necrosis virus (IHNV) and Flavobacterium psychrophilum. We evaluated the impacts of vaccination and genetic disease resistance on mortality and transmission across a range of challenge dosages of IHNV and F. psychrophilum to accurately reflect field variability. There was evidence of a dosage effect; as dosage increased, shedding increased and vaccine efficacy decreased. We also evaluated how vaccination and genetic disease resistance impact transmission dynamics during simultaneous and sequential co-infection of IHNV and F. psychrophilum. Our results indicate co-infected fish shed more of both pathogens than they do in single infections, and the order that the pathogen infected the host may impact transmission in both pathogens. Furthermore, vaccine efficacy may be diminished by co-infection. These studies are aimed at developing a more robust framework for inferring the efficacy of disease prevention strategies. Our results will also help to inform and improve disease management in one of the top aquaculture species in the United States.

Given the importance of innate defense mechanisms in the skin, we have examined the interactions of the arbovirus La Crosse virus (LACV) with serum factors that serve as a first line of antiviral defense, and the outcome of LACV infection of human keratinocytes, one of the main cell types present at viral entry. Incubation of LACV derived from insect cells (I-LACV) with normal human serum in vitro did not result in neutralization, but instead stabilized LACV virions and enhanced infectivity. Enhanced infectivity was also seen with heat inactivated serum devoid of complement activity and with serum from a range of animals including mouse, ferret and non-human primates. Depletion of antibodies from serum removed enhancement of I-LACV infectivity and sucrose gradient sedimentation assays showed IgG co-sedimenting with I-LACV particles. Serum-enhancement of LACV infectivity was not seen with virus derived from human cells, suggesting that insect cell-derived LACV is unique in its ability to subvert factors in serum to facilitate the initial infection of animal cells. In modeling initial replication following delivery of insect-derived virus to the skin, we show that I-LACV replication in HaCaT cells was restricted in culture by an antiviral response elicited by both IFN-β and IFN-λ. Media from I-LACV-infected cells induced killing of bystander non-infected HaCaT cells, and this cell death was relieved by blocking IFN-β signaling. Bystander cell killing was not seen with I-LACV infection of a human fibroblast cell line. Our data suggest that keratinocytes produce IFNs which limit virus spread through both antiviral signaling and by induction of cell death of potential new target cells for infection. These results are further evidence that virus and host immune interactions are complex and raises the question on how the combined outcome of these interactions determines the success of a virus infection and dissemination.

Cardiovascular disease is currently the foremost cause of death within the United States. Heart failure (HF) is a syndrome defined by the inability of the heart to adequately execute requisite pump function in order to deliver nutrients and oxygen to peripheral tissues, irrespective of etiology. One of the most common causes of HF is chronic pressure overload due to hypertension. Ischemic heart disease is also a common driver of HF, often in conjunction with hypertension. Pressure overload initially causes compensatory metabolic changes. Structural changes follow shortly thereafter typically resulting in left ventricular hypertrophy. Eventually, the heart loses the ability to compensate for the aberrant hemodynamic load and begins failing. The failing heart is unable to supply adequate adenosine triphosphate (ATP) for contractile function as evidenced by falling phosphocreatine (PCr) levels. This energy deficit occurs concurrently with a metabolic re-programming that results in a fuel utilization pattern resembling the fetal heart. Notably, enzymes involved in catabolism of fatty acids, the chief fuel substrate for ATP generation in the normal adult heart, are downregulated in the failing heart. However, the extent to which alternative fuels compensate for decreased fatty acid oxidation (FAO) is not well-known. Furthermore, consequences of the fuel substrate switches that occur in heart failure are not well established. In this work, we discover a new paradigm for alternate fuel utilization in the failing heart and define consequences of altered fuel metabolism in HF. We discovered a post-translational modification resultant from an accumulation of acetyl groups (C2) present in a mouse model of early-stage HF and human HF. Mitochondrial proteins were found to be hyperacetylated in the failing heart, and at least some of these alterations result in diminished electron-transport chain (ETC) capacity as shown by mutagenesis studies on succinate dehydrogenase A (SDHA). We also found an accumulation of C4-OH carnitine, a by-product of ketone oxidation in HF. This metabolite aggregation occurred alongside an increase in b-hydroxybutyrate dehydrogenase 1 (BDH1) transcript and protein levels. This signature suggested that the failing heart shifted to ketone bodies as a fuel. Subsequent experiments confirmed increased capacity for myocardial ketone oxidation in compensated cardiac hypertrophy and in HF. The consequences of increased ketone oxidation were then assessed using a cardiac-specific BDH1 knockout (BDH1 KO) mouse. Despite not having any apparent defect at baseline, we found BDH1 KO mouse hearts are completely unable to oxidize 3-hydroxybutyrate. The deficit for ketone oxidation capacity became consequential upon subjugation to transverse aortic constriction with a small apical myocardial infarction (TAC/MI). The BDH1 KO mice exhibit altered pathological cardiac remodeling compared to wild-type controls. These latter data suggest the increased reliance on ketone oxidation in HF, mediated by BDH1, is an adaptive response. Together the results of these studies provide important information regarding the consequences of altered fuel metabolism in HF. Recent reports of reduced HF mortality and elevated circulating ketone levels in patients prescribed Empagliflozin make cardiac ketone metabolism research in this dissertation particularly apropos.