Cisplatin, a potent chemotherapeutic agent, is widely used in the treatment of numerous soft-tissue cancers. Although high cure rates can be achieved when cisplatin is incorporated in chemotherapy regimens, the therapeutic utility of the drug may be limited by the development of dose-limiting adverse reactions in patients. A prevalent reaction to cisplatin is ototoxicity, or drug-induced hearing loss, which occurs when the drug accumulates in and damages cells of the inner ear, leading to permanent and progressive hearing impairment. In this investigation, two approaches were employed to explore the role of genetics in cisplatin response amongst South African cancer patients (n = 214). Using a candidate gene approach, which investigated variants in six genes which are involved in drug transport and processing, potential modifiers in the genes nuclear factor, erythroid 2-like 2 (NFE2L2) and solute carrier family 22, member 2 (SLC22A2) were identified. SLC22A2 encodes a known transporter of cisplatin, and the variant rs316019 conferred potentially protective effects against Chang- and TUNE-graded ototoxicity through a reduced transport of the drug (p = 0.039 and p = 0.031, respectively). Similarly, the variant NFE2L2 rs6721961 was possibly protective, as it occurred more frequently in patients who did not develop hearing impairment according to four different ototoxicity grading scales during high-dose (≥ 200 mg/m2) cisplatin treatment (ASHA, p = 0.001; Chang, p = 0.022; CTCAE, p = 0.001; TUNE, p = 0.028). When supplementing the prospective cohort with retrospective patient data, an increased susceptibility of indigenous African patients to Chang grade > 0 ototoxicity was observed (p = 0.001). For this reason, whole-exome sequencing was conducted on a subset of the patient cohort (n = 11), focussing on individuals of African origin who represented the phenotype extremes. Potential genetic modifiers were identified in genes involved in various biological processes, including transmembrane transport, development, hearing, the response to DNA damage, immune reactions and signalling pathways, implicating many previously unreported genes in the cellular response to cisplatin as well as its ototoxicity. The results reported in this study indicate that genetic information can improve predictive models of cisplatin response, although there are many novel genes which should be explored in the South African population. Identifying these genetic modifiers, such as those in SLC22A2 and NFE2L2, has the potential to further our understanding of this adverse drug reaction, and may assist in the future personalisation of treatment plans in the management of cancer.

Although there have always been sporadic reports of spontaneous cures in tuberculous meningitis, up to a few years ago this diagnosis almost invariably meant death within a few weeks or months. The therapeutic use of Streptomycin in this disease has created new hope for these patients and has stimulated tremendous interest in all aspects of the disease.

Includes bibliographical references. / Henssge observed that even a slight but permanent air movement accelerates cooling of a naked body significantly. However in those experimental studies the rate of air movement was not quantified. Today Henssge’s Nomogram method of thermometric thanatochronometry (mathematic estimation of the post-mortem interval using body temperature measurements) is used the world over and utilises various corrective factors for naked and clothed bodies in still/moving air. The purpose of this research was to correlate measured air flow rates (wind speed) and measured relative air humidity levels (RH) with post-mortem cooling rate in order to formulate appropriate corrective factors to be used with Henssge’s Nomogram. The effect of air flow rates and air humidity on the post-mortem cooling curve was studied within a range of air temperatures using gel-based models (Cooling Dummies) as substitutes for human bodies.

Includes bibliographical references (leaves 117-138). / This study of pregnant women in Zimbabwe therefore set itself the following aims: To describe lipid and lipoproteins during and after pregnancy, To examine the prevalence of apoE variants, To evaluate dysβlipoproteinaemia in pregnancy, The correlation between dysβplipoproteinaemia and the apoE genotypes. This is the first study to systematically examine lipids and lipoproteins during pregnancy in black Africans.

Sepsis is among the leading causes of death in health facilities worldwide. Even with adequate treatment, severe sepsis results in approximately 50% mortality, which indicates that the individual response to the infection is variable. (Moitra, Beal, Belikoff, & Remick, 2012) In a previous paper published by the Remick laboratory it was determined that the presence of pre-existing, plasma IgG antibodies in mice prior to the onset of sepsis could be responsible for differences in their survival. A Plasma Enhanced Killing (PEK) assay was used to calculate the PEK capacity of plasma i.e. the ability of plasma to augment phagocytic killing of bacteria. PEK was calculated as PEK= (1/log (N)) X 100; where N= number of surviving bacteria; a higher PEK indicated better bacterial killing(Moitra et al., 2012). The prior study also determined that inhibitory IgG probably binds inhibitory Fc receptors on phagocytic cells to result in reduced killing of bacteria. This published work used the value of the PEK to predict which mice would live and which mice would die when subjected to sepsis from cecal bacteria through the method of cecal ligation and puncture (CLP) to induce sepsis. The goal of this study was to build on what was already found and go further to demonstrate the pathway of how the blocking of IgG occurs via the Fc𝛄R in bacteria. In prior experiments by the Remick lab it was determined that the plasma from the in vitro plasma enhanced killing assay was related to the survival status of septic mice subjected to cecal ligation and puncture (CLP) model of bacterial peritonitis. The PEK assay relies on the presence of pre-existing antibodies in the plasma augmenting the killing of bacterial cells by polymorphonuclear cells. A high PEK value mean the plasma had the capability to kill bacteria and the mice were more likely to survive compared to those with a lower PEK value who were more likely to die from sepsis. Two sets of plasma were used, plasma collected with Ethylenediaminetetraacetic acid (EDTA) and plasma collected with heparin as anticoagulants. The data showed the likely presence of inhibitory IgG to be present more in the plasma sample collected with heparin than in those collected with EDTA.

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