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A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg in partial fulfilment of the requirements for the degree of Master of Sciences in Medicine (Emergency Medicine) Johannesburg, 2014 / Background: Patients with acute coronary syndrome (ACS) may present with a wide range of symptoms that may easily be misdiagnosed. Methods: This cross-sectional, hospital-based, descriptive, retrospective audit of medical records was based at the Ladysmith Provincial Hospital ED and consisted of the last 160 consecutive patients (from the date of initiation of data collection) with accessible medical records and with a final hospital discharge diagnosis of ACS. Results: The frequency of patients presenting with ACS was approximately 53 patients per annum. There was a male to female ratio of 1.3: 1. The mean age was 55.8 years (SD 12.8 years). The study population consisted of Asian (103/160, 64.4%), black (36/160, 22.5%) and white (21/160, 13.1%). The majority of the study patients were unemployed (98/160, 61.25%), urban resident (143/160, 89.4%), not alcohol users (137/160, 85.6%), and not smokers (88/160, 55.0%). Risk factors and comorbidity included previous acute coronary syndrome (44/160, 27.5%), family history (29/160, 18.1%), previous cardiovascular surgery (10/160, 6.25%), obesity (45/160, 28.1%), hypercholesterolemia (49/160, 30.6%), diabetes (42/160, 26.25%), hypertension (76/160, 47.5%), and renal failure (27/160, 16.9%). Approximately three quarters (119/160, 74.4%) of the study patients had typical chest pain, 16.3% (26/160) had atypical chest pain, and 9.4% (15/160) had no chest pain. The median length of hospital stay was 3 days and the in-hospital mortality was 8.1 % (13/160). Conclusion: The relatively high frequency of ACS reported in this study, when compared to other similar studies, is concerning. Also of concern in this study, is the alarming proportion of Asians that presented with ACS.

Understanding the nature and timing of leukaemogenic events during the development of childhood acute lymphoblastic leukaemia (ALL) will enable intervention that could prevent ALL in the future. We hypothesised that 9p21 deletion in childhood ALL may unmask predisposing genetic events that would allow us to determine the "nature" of initiating events in childhood ALL; whereas the inclusion, or exclusion, of random �N� nucleotides in normal immunoglobulin gene rearrangements from the developing fetus and the expression of terminal deoxynucleotidyl transferase (TdT) in fetal lymphocytes may allow us to unmask the developmental window during which the first transforming leukaemic event occurs in a pre-leukaemic B cell. The most frequent genetic abnormality in childhood ALL is deletion of chromosome 9p21, with the minimal region of deletion including the CDKN2-locus, making genes at this locus candidates for a predisposing genetic event in ALL. To determine whether genomic imprinting might be involved in ALL at the 9p21 locus we investigated the imprinting status of the candidate genes CDKN2A, CDKN2B and ARF. No evidence for genomic imprinting of ARF was found in this study. Because no expressed polymorphisms could be identified for CDKN2B, and CDKN2A expression was too low in normal tissues, the imprinting status of these genes could not be evaluated. Furthermore investigations in our laboratory have been unable to find genomic imprinting at any of these genes in mice. However, we have shown variation in allelic expression of ARF, which suggests a role for ARF haploinsufficiency in the onset of childhood ALL. A key feature of early human fetal lymphoid development is the absence of random �N� nucleotides between the rearranged V[H], D[H] and J[H] gene segments. The addition of �N� nucleotides at these junctions requires the enzyme terminal deoxynucleotidyl transferase (TdT). TdT is reported to not be expressed during early fetal lymphopoiesis but has been observed by the end of the first trimester, but data are sparse. The reported absence of N nucleotides in the majority of childhood ALLs suggests an early fetal origin. By defining the window-in-time during which TdT-negative B cell development occurs, we will be able to refine the timing of the origin of the B cells that give rise to ALL. Therefore we have sequenced and analysed the V[H]-DJ[H] and D[H]-J[H] junctions from immunoglobulin rearrangements in developing B cells in normal human fetuses aged from 5.1 to 11 weeks gestation. In this study 73 fetal IgH gene rearrangements were amplified from 21 different fetal liver samples. Only eight of the seventy-three rearrangements (11%) analysed in this study had no �N� nucleotides at the N1 (D[H]-J[H]) junction. This finding contrasts with the 24-28% of fetal rearrangements with no �N� nucleotides that have been reported in the literature. Furthermore, �N� nucleotides were shown to be present in the earliest sample, 5.1 weeks gestation. TdT expression was demonstrated by immunohistochemistry at 7.3 weeks and by RT-PCR at 8.3 weeks. B cell development in the fetal liver was detected as early as 6.5 weeks using flow cytometric analysis. Then, IgH gene rearrangements from 99 cases of childhood ALL were analysed. In total, 134 clone-specific IgH gene rearrangements were examined in this study. No association was found between the number of �N� nucleotides from complete and incomplete rearrangements at either the N1 (D[H]-J[H]) or N2 (V[H]-DJ[H]) junctions. Nor was any association observed between ALLs from children [less than or equal to] 3 years of age and those >3 years of age at diagnosis. These findings indicate that ALL IgH rearrangements do not have the paucity of �N� nucleotides that has been previously reported. The findings in this thesis suggest that there is no TdT-negative timepoint during B cell development and that there is no paucity of �N� nucleotides at the N1 junction in either fetal or childhood ALL IgH gene rearrangements.

The repetitive ballistic movements in highland dancing, which occur at more than 100 beats/min while the dancers try to reach a maximal vertical height with each jump, could possibly develop chronic injuries similar to ballet and aerobic dance. This study aimed to determine the following: number of injuries/dancer, number of injuries/100 hours of training, the number of chronic injuries compared to acute, anatomical location of the injuries and possible predictors for sustaining an injury in highland dancers. The 76 participants, aged 7 through 22, were from two Saskatoon Dance Schools. The information was collected by retrospective and prospective questionnaires and data analyzed using a Chi-square, analysis of variance and a binary logistic regression. The six-month retrospective survey found a total of 6 dance-related injuries compared to the 42 dance-related injuries in the four-month prospective questionnaire. When analyzing only the injured dancers the CHD (competitive) had 1.62 injuries/dancer, RHD (recreational) had 1.86 injuries/dancer and the Control group (non-highland dancers) had 2.0 injuries/dancer. Significant differences were not found for the number of injuries sustained in these three dance groups (X2 = 0.72, p<0.70). The injury rate per 100 hours of training for only the injured dancers in each group was as follows; CHD 2.59 injuries/100 hours, RHD 4.51 injuries/100 hours and the Control group 4.97 injuries/100 hours. The majority of the chronic versus acute injuries were sustained by the CHD (9 chronic, 8 acute), however they were not statistically different from the RHD (4 chronic, 7 acute) (X2 = 0.738, p<0.05). Most of the injuries occurred to the lower leg, with the knee, shins/calf, ankles and the feet as the major sites. Significant differences were found for these four lower leg sites versus the rest of the body (X2 = 11.20, p<0.05). There were also no differences for the number of lower leg injuries between the CHD and RHD (X2 = 4.605, p<0.05). The three variables associated with an increased risk for sustaining an injury were age, having a previous injury and the onset of menarche.

The repetitive ballistic movements in highland dancing, which occur at more than 100 beats/min while the dancers try to reach a maximal vertical height with each jump, could possibly develop chronic injuries similar to ballet and aerobic dance. This study aimed to determine the following: number of injuries/dancer, number of injuries/100 hours of training, the number of chronic injuries compared to acute, anatomical location of the injuries and possible predictors for sustaining an injury in highland dancers. The 76 participants, aged 7 through 22, were from two Saskatoon Dance Schools. The information was collected by retrospective and prospective questionnaires and data analyzed using a Chi-square, analysis of variance and a binary logistic regression. The six-month retrospective survey found a total of 6 dance-related injuries compared to the 42 dance-related injuries in the four-month prospective questionnaire. When analyzing only the injured dancers the CHD (competitive) had 1.62 injuries/dancer, RHD (recreational) had 1.86 injuries/dancer and the Control group (non-highland dancers) had 2.0 injuries/dancer. Significant differences were not found for the number of injuries sustained in these three dance groups (X2 = 0.72, p<0.70). The injury rate per 100 hours of training for only the injured dancers in each group was as follows; CHD 2.59 injuries/100 hours, RHD 4.51 injuries/100 hours and the Control group 4.97 injuries/100 hours. The majority of the chronic versus acute injuries were sustained by the CHD (9 chronic, 8 acute), however they were not statistically different from the RHD (4 chronic, 7 acute) (X2 = 0.738, p<0.05). Most of the injuries occurred to the lower leg, with the knee, shins/calf, ankles and the feet as the major sites. Significant differences were found for these four lower leg sites versus the rest of the body (X2 = 11.20, p<0.05). There were also no differences for the number of lower leg injuries between the CHD and RHD (X2 = 4.605, p<0.05). The three variables associated with an increased risk for sustaining an injury were age, having a previous injury and the onset of menarche.

Acute Myeloid Leukaemia (AML) is a disease normally found in elderly patients, with the median age of presentation at about 68 years. At this age, many of the patients are frail and unlikely to respond well to intensive chemotherapy treatments. Conventional chemotherapy eradicates the proliferating leukaemic progenitors while leaving the quiescent leukaemic stem cells undisturbed. These quiescent LSCs are able to then bring about leukaemic relapse. Fumagillin is a natural metabolite from Asperigillus fumigatus that is generally used as an anti-microbial agent but it is also known to bind to intracellular MetAP-II and inhibit endothelial cell growth. Many cancers are found to have an over expression of MetAP-II. In the past, MetAP-II inhibitors have been tested and shown success in angiogenesis inhibition and tumor reduction. The aim of this study is to observe whether methionine aminopeptidase-2 inhibitors can be used in the treatment of acute myeloid leukemia. The investigation included a dose response comparison of various AML cell lines to fumagillin treatment, cell proliferation assay, a colony forming unit assay, and cell cycle analysis of KG-1 cells following three days of fumagillin treatment. I have determined that fumagillin does indeed decrease the cellular proliferation of KG-1 in vivo and at 10μM, prevents colony formation in methylcellulose plating. There is an increase in cells found in the sub-G1 phase with fumagillin treatment, as analyzed by flow cytometry. It is interpolated that fumagillin treatment increases AML cell apoptosis, in addition to hindering its ability to grow in culture. / published_or_final_version / Medicine / Master / Master of Medical Sciences