published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Dentistry / Master / Master of Dental Surgery

published_or_final_version / Medicine / Master / Doctor of Medicine

Ischemic stroke is a leading cause of death and long-term disability in the world. Although many pathological aspects of mechanisms are considered to be involved in the stroke, accumulating evidences implicated that inflammation accounts for its progression and complications. Tumor necrosis factor-alpha (TNF-α) and nitric oxide are considered as key mediators produced by cells like microglia in the pathogenesis of the disease. Therefore, the development of therapies targeting at the suppression of nitric oxide and TNF-α productions may ameliorate the severity of ischemic stroke. Gastrodia and Uncaria Decoction (GUD) is a traditional herbal decoction that is commonly used in the therapy of post-ischemic stroke in China. Although it shows great efficacy in clinical treatment, few studies have been conducted to investigate the mechanisms of action of GUD. Furthermore, GUD contains a complex mixture of constituents and the effects of these compounds are unknown. In this study, individual herbs from GUD were extracted and the bioactive fractions were further separated using liquid-liquid partition, silica gel chromatography and high performance liquid chromatography (HPLC). The inhibitory effect of the extracts on lipopolysaccharide (LPS)-stimulated nitric oxide production in BV-2 microglial cells was utilized as the biological marker for the screening. After several rounds of purification, a purified bioactive compound was isolated. After spectroscopic analysis by nuclear magnetic resonance and gas chromatography-mass spectrometry, the compound was identified as genipin (1R,4aS,5,7aS-tetrahydro-1-hydroxy-7-(hydroxymethyl)-cyclopenta[c]pyran-4-carboxylic acid, methyl ester). Mechanisms of the suppressive action on signaling pathways were investigated in the LPS-activated BV-2 cells. Our results demonstrated that genipin can dose-dependently inhibit LPS-stimulated nitric oxide overproduction. It can also suppress mRNA levels and protein expressions of inducible nitric oxide synthase (iNOS) and TNF-αupon LPS-induction. In addition, the phosphorylations of phosphoinositide-3 kinase (PI3K) and protein kinase B (Akt) were suppressed. In contrast, the phosphorylations of mitogen-activated protein kinases (MAPKs), nuclear translocation of nuclear factor-κB (NF-κB) p65 and degradation of inhibitory κB-α (IκB-α) were not affected by genipin. Finally, genipin protected murine Neuro-2a neuroblast against neurotoxicity stimulated by the conditioned media transferred from LPS-challenged BV-2 cells. In conclusion, the anti-inflammatory effects of genipin are via the modulation of PI3K/Akt signaling pathway. Genipin and its synthetic analogues may have great potential for developing into new drugs in treating ischemic stroke. In addition, genipin can be used as the chemical marker to standardize the extract of Eucommia ulmoides Oliver as anti-inflammatory agents for treating inflammatory conditions associated with ischemic stroke. / published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

The aim of this research was to implement and evaluate guidelines that will be used by treatment support counsellors in an attempt to increase client adherence to antiretroviral treatment.

Introduction There is a pressing clinical need to treat patients with acute coronary syndrome (ACS) timely and efficiently in order to improve their prognosis. Standard tools available in ED, while useful, do not comprehensively characterize ACS for either diagnosis or risk stratification. The role of CMR in ACS is emerging because it allows assessment of both myocardial composition and function. Newer CMR techniques such as: a) T2 W imaging for assessing myocardial oedema and area at risk B) pre contrast T1 mapping techniques for quantitative characterization of the tissue composition, are adding further utility for CMR in ACS. At present the clinical use of these techniques is still limited and further investigations are needed to assess their clinical applicability in ACS patients. Aims The aims of this thesis were several. Firstly we sought to establish a CMR protocol for imaging ACS patients on a 3T CMR scanner. In order to do so, we validated a novel T2 W technique for oedema imaging (T2 prep SSFP) at 3T. Second, we aimed to perform a detailed study of the time course of oedema in ACS patients in order to establish the appropriate imaging time for the assessment of area at risk. Third, by applying T2W acute oedema imaging, we sought to investigate the functional and pathological meaning of complicated remote plaques in patients with multivessel disease. Finally, we aimed to establish whether, in comparison to standard CMR techniques, novel precontrast Tl mapping allows better characterisation of the acutely injured myocardium and whether it can predict long-term functional recovery. Methods The research studies were all performed on a 3T Trio Siemens scanner. In the initial stage of the research, we validated the T2 W technique performing phantom work and scanning both volunteers and patients to assess the uniformity of signal intensity in the myocardium and to establish a threshold based method to post process the images. We then established a CMR protocol for ACS including oedema imaging, T1 mapping imaging, perfusion, functional and late gadolinium enhancement imaging. Patients with acute myocardial infarction (both ST elevation myocardial infarction (STEMI) and non STEMI) were scanned at 4 different time points after the acute event (3 scans within 2 weeks and one at 6 months). All STEMI patients underwent primary percutaneous coronary intervention (PCI) while the non-STEMI patients underwent coronary angiography and for PCI. Results We validated the T2prep SSFP technique at 3T, highlighting its limitations and establishing a threshold of mean ± 2SD to assess myocardial oedema. We found that the optimal imaging window to assess the maximal expression of myocardial oedema was within 1 week from the acute event in patients with ST elevation MI. Also, our results showed a reduction of LGE over time (from acute to chronic) in segments which also showed improvement in contractile function indicating that even segments with transmural LGE assessed in the early hours post event could be viable. By applying these techniques in acute patients with bystander disease undergoing percutaneous coronary intervention, we found that: l) T2W imaging can detect myocardial injury downstream from a vessel identified as "non culprit" 2) in 20% of NSTEMI patients, the angiographic assessment alone failed to identify the culprit vessel. Finally, we found that the diagnostic performance of acute pre-contrast Tl-mapping was at least as good as that ofT2W CMR for detecting myocardial injury. There was a significant relationship between the segmental damaged fraction assessed by either by LGE or T2W, and mean segmental Tl values and the likelihood of improvement of segmental function at 6 months decreased progressively as acute Tl values increased. Conclusions In summary, we defined a stable imaging window for the retrospective evaluation of area at risk and we also indicated that acutely detected LGE does not necessarily equate with irreversible injury and may severely underestimate salvaged myocardium. Furthermore, in NSTEMI patients with multivessel disease, by revealing acute myocardial damage in territories pertaining to vessels not treated acutely, we raised the issue of the need for better tools for the correct identification of the culprit vessel and to stratify patients rather than by angiographic assessment alone. Finally, we demonstrated how pre-contrast Tl mapping allows for assessment of the extent of myocardial damage and how Tl mapping might become an important complementary technique to LGE and T2W for the identification of reversible myocardial injury and the prediction of functional recovery in acute MI.

HIV-associated lipodystrophy (HIVLD) syndrome is a condition comprising abnormalities in distribution of body fat and metabolism of lipids and glucose that arises in HIV-infected patients on long-term antiretroviral therapy. This thesis describes clinical research into aspects of the natural history and treatment of HIVLD, as well as molecular research into its pathogenesis centred on subcutaneous adipose tissue. Results demonstrate HIVLD to be a treatment-induced syndrome characterised by initial gains in body fat followed by selective, progressive loss of limb fat. Exposure to thymidineanalogue nucleoside reverse transcriptase inhibitors (tNRTI) induces lipoatrophy through mitochondrial dysfunction of which inhibition of mitochondrial RNA expression, rather than mitochondrial DNA depletion, is an early feature. Mitochondrial dysfunction is associated with decreases in expression of peroxisome proliferatoractivated receptor gamma (PPAR??), an adipocyte transcription factor, which helps explain how tNRTI exposure leads to the loss of adipocyte function. Once established, lipoatrophy is characterised by mitochondrial DNA depletion, although this depletion occurs throughout the mitochondrial genome, suggesting an underlying cause other than inhibition of DNA polymerase gamma. HIVLD is a difficult syndrome to treat. Lipoatrophy is resistant to treatment with rosiglitazone, an agonist of PPAR??, which is ineffective in the setting of ongoing tNRTI therapy and mitochondrial dysfunction. Dyslipidaemia is also difficult to treat as use of pravastatin in the setting of ongoing exposure to protease inhibitors results in only modest declines in fasting cholesterol concentrations. Gains in central fat, such as that seen in patients with buffalo hump, are associated with insulin resistance and diabetes, but only occur in a relatively small percentage of treated patients, suggesting a role for genetic factors in its development. Use of strategies such as avoidance of tNRTI in firstline ART, genetic screening to identify those at risk of toxicities and targeted selection of interventions in subgroups of affected patients, may help prevent this syndrome occurring and better treat those patients in which it has already occurred.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

South Africa and the province of KwaZulu-Natal (KZN) has one of the greatest HIV burdens in the world with an estimated 5.7 mHIion people living with HIV/AIDS. One of the interventions that the government introduced to address this situation was the provision of antiretroviral treatment (ART) to those individuals that are eligible for HIV treatment in order to reduce the morbidity and mortality. Despite widespread availability of ART in KZN, children do not access ART to the extent that adults do, and therefore continue to die because of HIV and AIDS. This qualitative study explored the psychosocial and health system factors that influence paediatric access to ART in KZN from parents and caregivers perspectives. The ecological theory and the social cognitive theory was used to formulate an interview schedule used in conducting the in-depth interviews with adults (parents or guardians) who were bringing their children for ARTservices and those attending these services themselves and not their children at Edendale and King Edward Hospitals in KZN. Purposive sampling was used to select clients for interviews and thematic was done in accordance with the aims and objectives of the study. A total of 42 participants were interviewed in this study. The low uptake of child ART was found to be influenced by several psychosocial and economic factors such as the poor knowledge about ART, stigma and disclosure associated with HIV, extent of support provided by parents/caregivers, parent's own ART was a determinant for bringing children for ART, use of traditional / alternative medicines, disintegrated families, especially the issue of multiple caregivers, complexity of paediatric ART, poor referrals of children from community institutions, unsatisfactory service at clinics, and some health policy and legislation with respect to health care for HIV-infected children that had an unintended effect of restricting child access to ART as well as poverty related Issues. Improving knowledge and self-efficacy related to ART, prevention of mother to child transmission ofHIV, re-training of health workers on child issues and addressing stigma and discrimination and other psychosocial and institutional problems and logistics could help to improve the low paediatric uptake of ART. / Thesis (M.A.)-University of KwaZulu-Natal, Durban, 2009.

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