Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 66-76). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 66-76). Also available on the Internet.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1994. / Vita. Abstract. Includes bibliographical references (leaves 58-64). Also available via the Internet.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1984. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 189-202).

In this thesis we will consider two mathematical models on malaria transmission and patho- genesis. The transmission model is a human-mosquito interaction model that describes the development of malaria in a human population. It accounts for the various phases of the disease in humans and mosquitoes, together with treatment of both sick and partially im- mune humans. The partially immune humans (termed asymptomatic) have recovered from the worst of the symptoms, but can still transmit the disease. We will present a mathematical model consisting of a system of ordinary differential equations that describes the evolution of humans and mosquitoes in a range of malarial states. A new feature, in what turns out to be a key class, is the consideration of reinfected asymptomatic humans. The analysis will include establishment of the basic reproduction number, R0, and asymptotic analysis to draw out the major timescale of events in the process of malaria becoming non-endemic to endemic in a region following introduction of a few infected mosquitoes. We will study the model to ascertain possible time scale in which intervention programmes may yield better results. We will also show through our analysis of the model some evidence of disease control and possible eradication. The model on malaria pathogenesis describes the evolution of the disease in the human host. We model the effect of immune response on the interaction between malaria parasites and erythrocytes with a system of delay differential equations in which there is time lag between the advent of malaria merozoites in the blood and the training of adaptive immune cells. We will study the model to ascertain whether or not a single successful bite of an infected mosquito would result in death in the absence of innate and adaptive immune response. Stability analysis will be carried out on the parasite free state in both the immune and non immune cases. We will also do numerical simulations on the model to track the development of adaptive immunity and use asymptotic methods, assuming a small delay to study the evolution of the disease in a naive individual following the injection of small amount of merozoites into the blood stream. The effect of different levels of innate immune response to the pathogenesis of the disease will be considered in the simulations to elicit a possible immune level that can serve as a guide to producing a vaccine with high efficacy level.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with an unknown aetiology characterized by joint destruction. Both genetic and environmental factors contribute to the disease development with HLA-DRB1* alleles and smoking identified as most important. The disease is characterized by the presence of autoantibodies, originally by rheumatoid factor (RF) and more recently by anti citrullinated protein/peptide antibodies (ACPA) and antibodies against carbamylated peptides (CarP). These autoantibodies are present, not only after the onset of disease, but also prior to the onset of symptoms. The development of RA is a gradual process lasting several years before the onset of any joint symptom, but when and if there is a temporal difference in the development both between and within the different antibody systems is currently unknown. B-cells produce the antibodies, and a subset of B-cells, i.e., B-regulatory (Breg) cells, produces interleukin-10, and thus have the ability to down-regulate pro-inflammatory cytokines. Whether the Breg cells are involved in the pathogenesis of RA is, as yet, unknown. The aim of this thesis was to increase knowledge of the pathophysiological processes in the development of RA through identification of factors involved. The analyses involved detection of autoantibodies to post-translationally modified peptides/proteins in addition to RF isotypes, cell surface markers on immune cells in asymptomatic individuals, who have an increased risk of developing RA. In a co-analysis of the registers of patients with RA attending the Department of Rheumatology, with the registers from population based screening programmes within the Biobank of Northern Sweden, blood samples collected from individuals prior to the onset of symptoms were identified, as were those from population control subjects. A cohort of pre-symptomatic individuals also donated samples at the time of receiving a diagnosis of RA. First-degree relatives (FDR) of patients with RA were also identified and included for analyses. The levels of ten different ACPAs, i.e., (fibrinogen (Fib) α563-583(573), Fibα580-600(591), Fibβ62-81a(72), Fibβ62-81b(74), Fibβ36-52, a-enolase (CEP-1), triple helical collagen type II (citC1III), filaggrin (Fil307-324), vimentin (Vim) 2-17, and Vim60-75) were measured using the ImmunoCAP ISAC system (Phadia/ThermoFischer, Uppsala, Sweden) in blood samples from individuals before the onset of symptoms and when diagnosed with RA in comparison with those in population based controls. In a subset of samples, the levels of anti-CarP antibodies were measured using ELISA coated with anti-CarP-FCS, as well as analysis of RF of IgM, IgG and IgA isotype using the EliA assay (Phadia, Uppsala, Sweden). Breg cells were analysed both with and without stimulation ex vivo along with other cell types using flow cytometry in samples from patients with RA, their first degree relatives (FDR) and healthy controls. In paper I it was shown that levels of ACPA were initially restricted to a few antibodies but disseminated over time to involve additional different antibodies. The levels of antibodies to CEP-1, Fibß36-52, and filaggrin were significantly increased. In paper II, anti-CarP antibodies were positive in 5-13% of the individuals negative for the various ACPA studied. The presence of anti-CarP antibodies was significantly related to radiological destruction of joints at baseline, at follow-up after 24 months and to the radiological progress between baseline and 24months. In paper III, the relationships between the frequencies of RF isotypes, the ten different ACPA, anti-CCP2 and anti-CarP antibodies before the onset of any symptoms and the presence of certain combinations of antibodies were associated with a very high risk of developing RA. In paper IV Breg cells from patients with RA are functionally impaired and FDR showed a similar pattern by responding less to stimulation ex vivo than cells from healthy controls. In conclusion, individuals who subsequently develop RA have an increased number and amount of ACPAs, anti-CarP antibodies and RF of IgM, IgG and IgA isotype, several years before symptom onset. Most of the different antibodies analysed remain associated with disease development after adjustments for each separate antibody. In FDRs, Breg cells were functionally altered in that they produce less IL-10 and consequently contribute to a more inflammation-prone status, as in their relatives with RA. These findings contribute to information about the development of RA as well as a given individual’s risk(s) of developing RA and its progression.

A major contributing factor to the onset of early hip osteoarthritis is attributed to an enlarged, aspherical femoral head deformity, characterized as cam-type femoroacetabular impingement (FAI). The presence of the cam deformity alone does not explain differences in pathomechanisms and it has been theorized that adverse loading to the subchondral bone may play a predominant mechanical role in early joint degeneration. This doctoral thesis examined the adverse hip joint loading due to cam FAI and characterize mechanical stimuli associated with symptoms. Specifically, this research: 1) examined anatomical and functional characteristics associated with the cam morphology; 2) developed subject-specific finite element hip joint models to examine hip joint stresses, incorporating subject-specific geometries, materials properties, and joint loading; and 3) implemented loading parameters during level walking and squatting to examine hip joint stresses. First, a classification study was conducted to recruit three participant groups: 1) symptomatic (where participants had the cam deformity and pain); 2) asymptomatic (where participants had the cam deformity, but no pain); and 3) control (where participants did not have the cam deformity or clinical signs). Each participant's CT data were evaluated for multiple anatomical hip joint parameters and then re-classified into their respective subgroups, using a discriminant function analysis, based on the most significant parameters. In addition to the cam deformity, symptomatic individuals had a lower femoral neck-shaft angle and reduced pelvic range of motion. Second, using the classified participants, hip joint loading was determined for the various severities of cam FAI, with respect to alterations in hip contact forces and anatomical considerations. Hip joint assemblies were segmented and reconstructed from subject-specific CT and MRI data, where bone densities were quantified from CT data. A parametric study was conducted to understand how varying material properties and loading conditions affected the sensitivity of the predictive models, examining the most appropriate modelling parameters to capture relative measurements. Third, in conjunction with the first two studies, hip contact forces for level walking and squatting tasks were applied to corresponding subject-specific models and simulated. As a cross-sectional analysis, the stress magnitudes and regions described the joint loading in vivo for each subject group and ascertained the risk of remodeling. For each subgroup (symptomatic, asymptomatic, control), the participants with the largest and smallest femoral neck-shaft angles were selected and compared. The symptomatic model with the lowest femoral neck-shaft angle demonstrated the highest stress on the cartilage, during walking and squatting, and on the subchondral bone, during squatting. The asymptomatic models showed cartilage stresses similar to the control group, but experienced high-risk subchondral bone stresses, similar to the symptomatic group. For both symptomatic and asymptomatic groups, the acetabular subchondral bone stresses coincided with known areas of bone adaptation and proteoglycan depletion. The outcome of this research program supported that cartilage degradation might not be due to direct contact shear stresses, but perhaps rather attributed to the indirect effects of a stiffer subchondral bone plate. Individuals with a large cam deformity and decreased femoral neck-shaft angles are likely to experience severe subchondral bone stresses during higher amplitudes of hip motion. This provides clinicians with indications of how the pathology exacerbates and where initial cartilage delamination will likely occur, allowing them to perform the correct assessments and proceed with the correct form of care. From a patient's perspective, an early and accurate diagnosis could inhibit cartilage degradation and the progression of osteoarthritis.

Parkinson’s disease (PD) impairs the quality of life of patients and causes substantial social and economic burden. However the currently available symptomatic treatments, although initially effective, do not satisfactorily control the progressive disability experienced by patients with PD in the long run. In order to develop effective treatments for patients that aim to attain the desired effect with as few adverse events as possible, it is crucial to be able to follow and understand the biological mechanisms underlying the continued neural degeneration and treatment failure. The efforts to understand the precise pathway by which neurodegenerative processes proceed and the development of approaches to modulate them offers the promise to eventually enable the prevention of these neurodegenerative diseases. This dissertation focused on two potential synthetic methods to produce pharmaceutical grade Fluorodopa, ultimately to be able to produce positron emitting 18Fluorodopa in South Africa with its potential for studying neuronal mechanisms in the brain. 18Fluorodopa allows a unique almost non-invasive in vivo approach to the evaluation of neurochemical function in the human brain and its local introduction will be a valuable addition to medical research within South Africa’s borders. The successful implementation of safe and efficient non-radioactive models for Fluorodopa synthesis was achieved. The successful demonstration of locally synthesised Fluorodopa safety, as well as a low toxicity profile, both in vitro using cell cultures and in vivo in mouse models was achieved. These were both positive outcomes of objectives set out for this study. Copyright / Dissertation (MSc)--University of Pretoria, 2010. / Pharmacology / unrestricted

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