Includes abstract. / Includes bibliographical references. / This study investigates imprinting of the murine fetal immune system by maternal infection with the helminth Nippostrongylus brasiliensis (Nb) prior to pregnancy and its effect on control of the Salmonella enterica serovar typhimurium (STm) in offspring. We show that maternal Nb infection in BALB/c mice results in the transfer of Nb antigen (NES)-specific IgG1 in utero and through breastmilk, changes in lymphocyte populations and early germinal center formation in naive offspring. Maternal Nb infection does not interfere with control of STm in offspring in BALB/c mice, but may interfere with control of STm in C57BL/6 mice.

An earlier observation by E.H. Harley (supervisor of this thesis) of curious metabolic anomalies in the red cells of black rhinoceros, and in particular a high free tyrosine level, suggested that a range of unusual, but presumeably physiological, processes might be found in mammalian red blood cells. As a follow-up to this, low molecular weight metabolites were examined in a range of mammalian species, using HPLC-based methods to compare levels in red cells with plasma levels. A remarkable interspecies diversity in red cell HPLC profiles was observed, with the unprecedented accumulation of substances including tyrosine, tryptophan, urate, and urate riboside occuring within the red cells of some species. Whereas novel evolutionary adaptations may characterise most of these species-specific variations, the ability of red cells to produce urate is proposed to be an inducible feature common to the red cells of many, or possibly even all, mammalian species. A surprisingly high degree of intraspecies genetic heterogeneity was evident in tyrosine and urate levels within horse, and urate riboside levels within cow red cells. This was in contrast with the greater homogeneity seen in levels of these and other low molecular weight substances in red cells from the other species evaluated. The next phase of investigation addressed the potential function(s) of these soluble substances accumulating within the red cell, particularly relating to a role in antioxidant defense. Using in vitro antioxidant assays such as the 'oxygen radical absorbance' (ORAC) and 'ferrous ion oxidation-xylenol orange' (FOX) assays, results were obtained consistent with a role for these substances as endogenous red cell antioxidants against a variety of reactive species produced by pathophysiological processes in the body. The demonstration that haemoglobin is involved in facilitating some of this activity further substantiates the idea that the red cell may be playing a crucial role in maintaining circulatory redox balance, and hence protecting other tissues from oxidative damage. If indeed such low molecular weight substances contribute to systemic antioxidant activity in some mammalian species, then apart from the intrinsic interest of such unexpected biological phenomena, these findings could pave the way for a plethora of further investigations, geared towards potential clinical applications (eg. as biomarkers or therapeutic approaches) in human and/or veterinary conditions associated with oxidative stress.

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Includes abstract. Includes bibliographical references.

Includes abstract. / Includes bibliographical references. / The Expanded Programme on Immunisation has the potential to substantially reduce child mortality and contribute to achieving the Millennium Development Goals. We assessed the programme’s performance in Africa, the reasons for poor performance, and effective interventions for improving its performance on the continent. We used a combination of methods including systematic reviews, bibliometric analyses, generalised linear models, and grading of the quality of evidence. We found that African countries have made extraordinary advances since childhood immunisation programmes began in 1974. However, there exist wide inter-country and intra-country differences, and the quality of immunisation data is poor. Besides, vaccines are administered well after the recommended ages in many countries; leaving children exposed to deadly vaccine-preventable diseases for long periods. In addition, Africa’s contribution to the global immunisation research output is minimal. There is no association between research productivity and immunisation coverage in Africa, which may signal lack of interactive communication between policymakers and researchers. Furthermore, individual and contextual factors (defined at community and country levels) are independently associated with low immunisation coverage; suggesting that immunisation system strengthening should address people and the communities and societies in which they live. Lastly, we found moderate-to-high quality evidence that interactive educational meetings, audit and feedback, supportive supervision; and use of community health workers, parent reminders, home visits, interactive communication, mass media, and material incentives have the potential to improve childhood immunisation coverage in Africa.

Includes abstract. Includes bibliographical references (leaves 200-218).

Includes abstract. Includes bibliographical references (leaves 154-171).

Includes bibliographical references. / The clinical success of cisplatin and its derivatives for the treatment of different cancers has had a profound effect on the use of metal-containing agents in medicine. Despite the successes, the drawbacks of platinum-based therapy, such as drug resistance, toxicity and the emergence of unwanted side effects, have bred a need for effective and novel anticancer agents. Hence, the design and study of bioorganometallic complexes as potential therapeutic agents may eventually lead to the identification of new drug candidates. The purpose of this study was to synthesize and characterize a series of polynuclear transition-metal-containing complexes based on a (poly)propyleneimine dendritic scaffold, and investigate the in vitro antiproliferative activity of these complexes.

Includes abstract. / Includes bibliographical references. / The aim of this study was to evaluate the importance of CD28 in initiating protective Th2 immunity against both primary and secondary infections with N. brasiliensis. Our findings demonstrate that CD28 is required for initiation of protective Th2 immunity against primary infection with N. brasiliensis. Furthermore, the absence of CD28 impairs development of memory CD4⁺ T cell responses resulting in failure to clear adult N. brasiliensis worms during secondary infection. Failure to resolve infection was associated with reduced production of Th2 cytokines particularly IL-13 and IL-4, abrogated humoral immunity and failure to expand CXCR5⁺ TFH cells.

A body's axial temperature distribution at death was experimentally demonstrated by the author to predict the postmortem temperature plateau (PMTP), which is known to affect the measured core temperature value and hence death-time estimation. Yet today's methods of death-time estimation apply only a single-point approximation of a body's core temperature in life as well as a single-point measurement of a body's core temperature after death. Four studies were carried out to understand the relationship between a body's axial temperature distribution and the PMTP. The first study numerically approximated antemortem temperature distribution in an MRI-built, high-definition, anatomicallys egmented 3D computational human phantom consisting of several hundred tissues. Metabolic heat generation (QQmm) and blood perfusion (wwbb) parameters were applied to all thermogenic tissue using the Pennes BioHeat Model. The study demonstrated that the antemortem axial temperature distribution was nonlinear, that tissue temperature distribution was inhomogeneous, and that the position and size of the antemortem central isotherm was predicted by the size, shape and location of the most thermogenic internal organ in a given axial plane. Numerical approximation of a body’s antemortem axial temperature distribution using this study’s materials and methods was proposed for death-time estimation. The second study examined postmortem axial heat transfer. The approximated antemortem axial temperature distribution constituted the initial condition. QQmm and wwbb were set to zero to simulate death. Postmortem cooling was simulated in still air, on a cold concrete floor and on a heated floor. The antemortem central isotherm that single-point core thermometry detects was the PMTP. Its size at death, body radius, axial thermometry-depth and length of the postmortem interval (PMI) all predicted PMTP length. The cold concrete floor shifted the central isotherm away from the floor, while the heated floor shifted it towards the floor. Ground temperature and material properties, along with the aforementioned PMTP predictors, result in variation in measured single-point core thermometry values, yet today’s death-time estimation methods do not measure, approximate or standardise them. This is a source of uncertainty. This study demonstrated that a body’s postmortem axial thermal profile was very specific to the PMI at which it exists, including during the PMTP that single-point core thermometry detects. This study proposed a body’s measured postmortem axial thermal profile for death-time estimation to reduce PMTP uncertainties. The study also proposed numerical modelling of the ground, its temperature and material properties. The third study proposed a multipoint axial thermometry (MAT) device to measure a body’s postmortem axial thermal profile. The author designed the device prototype. Its fabrication was outsourced. Empiric and numerical MAT studies were conducted on a cooling dummy and 3D human phantom, respectively. MAT curves indicated a parabolic shape. The fourth study proposed a numerical protocol for death-time estimation that iteratively tested a MAT profile measured at an unknown PMI from a decedent using the proposed MAT device against MAT profiles predicted by numerical simulations of sequentially longer candidate PMIs. A candidate PMI whose MAT profile matched was considered the PMI estimated by the protocol. The proposed protocol applied the exact historical meteorological temperatures that existed during the final estimated PMI. Application of the protocol was demonstrated using a fictitious scenario in which a candidate PMI within 120s of the final estimated PMI was excluded. Potential sources of uncertainty of the proposed protocol were discussed and concluding remarks on future research were made.