Dysfunction of the N-methyl-D-aspartate (NMDA) receptor is thought to contribute to the cognitive deficits of many neurodegenerative diseases and psychiatric disorders. Cognitive symptoms of Alzheimer's disease can be treated with NMDA receptor antagonists or drugs targeting the cholinergic system; however, there are no effective treatments for cognitive deficits of schizophrenia or Huntington's disease. With the discovery of a potent and selective allosteric modulator of the NMDA receptor, there is the possibility of new treatments based on NMDA receptor functional-enhancement through neuroactive steroids, closely related in structure to the endogenous neurosteroid, cerebrosterol. The aim of this thesis was to examine steroidal modulation of the NMDA receptor both in vitro and in vivo. In chapter 2, NMDA receptor enhancement of both the synthetic and endogenous neuroactive steroids was assessed in neurons maintained in cell culture using calcium imaging techniques. Sulphation of the steroids greatly increased the efficacy of NMDA receptor enhancement compared to the unsulphated steroids. Chapters 3 and 4 investigate the potential for neuroactive steroids to treat cognitive impairments of Huntington's disease. Using a mouse model, tests were selected that were analogous to those in which patients are impaired; however, no impairments were found in the mouse model. Chapter 5, therefore, used a different model of cognitive impairment – namely, rats with a set-shifting impairment, as is seen in many psychiatric and neurological disorders, including Huntington's disease – to assess the effect of the synthetic steroid administration. Unfortunately, the rats did not show the expected impairment. The lack of reliable animal models compromised testing the efficacy of these promising NMDA receptor positive allosteric modulators. Nevertheless, the promising in vitro results suggest that there could still be therapeutic potential. In addition, the compound is a useful research tool for exploring NMDA receptor function in health and disease.

African Potato (Hypoxis hemerocallidea), (AP) is an African traditional medicine (TM) that is commonly used for various nutritional/medicinal purposes and also by people infected with the human immuno deficiency virus HIV and AIDS patients as an immune booster. The use of AP has also been recommended by the former Minister of Health of South Africa for use by HIV positive people. The main phytochemical component of AP is a norlignan glucoside, hypoxoside, and other relatively minor components have also been reported. A recent in vitro study reported the effects of AP extracts, hypoxoside and rooperol (the metabolite of hypoxoside) on human metabolic enzymes such as the cytochrome P450 (CYP450) group of enzymes and also on the transporter protein, p-glycoprotein (P-gp). This research focussed on investigating the clinical significance of those in vitro effects on the pharmacokinetics of efavirenz (EFV) in humans. EFV was chosen as the substrate drug because it is in first-line regimen of treatment of HIV/AIDS in South Africa, and also has been reported to be a substrate for the specific CYP isozymes, 3A4 and 2B6, in common with APs metabolic involvement with 3A4. A high performance liquid chromatography method with ultra-violet detection (HPLC-UV) for the quantitative determination of EFV in plasma was developed and successfully validated according to international standards with good reproducibility, accuracy, recovery, linear response and requisite sensitivity. The preparation of the plasma samples for analysis was effected by using a simple and rapid precipitation method, and the mobile phase consisted of readily available solvents. EFV in plasma samples was found to be stable under the relevant storage conditions studied. The oral dose of AP, administered as a freshly prepared traditional decoction, was standardised based on the hypoxoside content, and the quality of all the AP decoctions was analysed immediately prior to administration, using a validated HPLC-UV method. A single dose, two-phase sequential study was conducted over a period of 31 days in 10 healthy volunteers. The clinical study was approved by the Rhodes University Ethical Standards Committee, and all the participants agreed to the conditions of the study by giving their informed consent. On day 1 of the study, human subjects were administered a 600 mg EFV tablet and blood samples were collected before dosing and at various intervals over a period of 48 hr post dosing. From day 16, a traditionally prepared AP decoction was administered daily at a standardized dose of 15 mg/kg/day per subject until day 30. On day 29, volunteers were administered a single 600 mg dose of EFV as was done on day 1. Plasma samples were harvested immediately after blood sample collection and frozen at -80 ºC until assayed. Geometric mean ratios of relevant pharmacokinetic parameters, Cmax (maximum plasma concentration achieved following dosing) and AUC0-48 (area under the curve of a plot of drug plasma concentrations versus time representing the extent of absorption) of EFV before and after co-administration of 14 successive daily doses of AP were compared and evaluated to determine whether an interaction had occurred. All subjects completed the study and the geometric mean ratios of Cmax and AUC0-48 were 97.30 and 102.82 with corresponding 90% confidence intervals (CIs) of 78.81-120.14% and 89.04-118.80%, respectively. Whereas the acceptance criteria for the ratios of the AUCs fell within the preset 90% CIs indicating no interaction, the Cmax ratios fell outside the limits. Although the protocol was developed in accordance with the United States of America Food & Drug Administration’s Guidance for Drug Interactions, a priori stating that both criteria need to fall within the acceptance limits to indicate no interaction, an argument is presented to waive the Cmax requirement for the declaration of an interaction. As a result, the pharmacokinetic data generated during this study indicated that the effect of AP on the pharmacokinetics of EFV is not clinically significant. Hence, co-administration of AP is unlikely to affect the clinical use of EFV. In summary the objectives of this project were: 1. To develop and validate a suitable HPLC-UV method for the quantitative determination of EFV in plasma. 2. To perform a mini-validation of the determination of hypoxoside for use as a marker in the quality control and standardisation of AP decoctions. 3. To conduct a clinical interaction study in order to determine whether AP affects the pharmacokinetics of EFV following concurrent administration. 4. To apply the validated HPLC-UV method to determine plasma concentrations of EFV in plasma of human subjects. 5. To use appropriate statistical methods and treatments such as a non-compartmental pharmacokinetic analysis to determine the occurrence of an interaction.

Submitted in fulfilment of the requirements for the Degree of Doctor in Public Management, Durban Universit of Technology, 2017. / HIV-AIDS has infected more than 37 million individuals globally and has resulted in approximately 35 million HIV-AIDS related deaths globally since its discovery 35 years ago. HIV-AIDS remains a global and local health crisis as, despite innovative and accessible HIV-AIDS prevention efforts, the disease continues to spread. UNAIDS estimated over 2 milliion new HIV-AIDS infections with 700 000 of these infections occurring in young African women in 2015, revealing that the burden of HIV-AIDS is far from over (UNAIDS, 2016). As more individuals become infected with HIV-AIDS, more infected individuals are living longer, productive lives due to the international rollout and scale-up of life-saving antiretroviral (ARV) therapy aimed at halting disease progression. In 16 years, the world has initiated over 16 million HIV-infected individuals onto ARV programmes across the world aimed at preserving first line drug effectiveness of treatment, less resistance and lower mortality and morbidity rates( UNAIDS, 2016). This number is set to double as countries across the globe take bold steps to provide ARV treatment for all, based on latest WHO guideline changes. The initiative of ARV roll out for all HIV-positive individuals globally, brings with it the challenges and complexities of infrastructure support, resource allocation, uninterrupted drug supply, global access and clinical training requirements for HIV-AIDS programmes across the globe. Quality management systems with monitoring and evaluation frameworks in particular play a pivotal role in planning, allocating and utilising resources for optimal health benefits.This research study reviews available data on the prevalence of quality management systems in HIV-AIDS healthcare and identifies gaps and smart practises towards recommendations for comprehensive global HIV-AIDS standards development. This research study aims to propose a conceptual monitoring and evaluation framework derived from quality management systems for management of HIV-AIDS private sector programmes that can be used in both public and private healthcare sectors through analysis of current conceptual frameworks in the HIV-AIDS healthcare and the HIV-AIDS programmes within the South African context of HIV-AIDS healthcare provision. / D

M.Cur. / During the time as an infection control professional, there was close contact with patients with Acquired Immunodeficiency Syndrome (AIDS). During this contact period many needs regarding health support were identified. Discrimination and the testing of patients for Human Immunodificiency virus anti·bodies (HIV) without their permission, were the main problem areas. The purpose of the study was to determine the nature and extent of comprehensive health care services for patients with AIDS. The research design is a contextual, exploring and descriptive study. This study was done in the Northern half of economic development area H where 16 health care services were identified. These include clinics, community hospitals, regional- and academic hospitals and the local authority clinic. Private hospitals were not included in the study. Criteria for the nature and extent of comprehensive health care services were based on literature studies. Data was collected by means of structured interviews with nursing professionals in the employ of identified services and patients making use of those services. The results of the research showed various needs in the nature and extent of the comprehensive health care services of the patients with AIDS In order to improve the health care services, recommendations were made and guidelines given to nursing professionals. Recommendations were also made regarding other aspects of the multi·disciplinary team approach. Based upon this study other topics were identified to enable the health care services to provide health care to the patient with AIDS.

South Africa, with an estimated 5.7 million people living with HIV, continues to have one of the largest epidemics in the world. The introduction of HAART resulted in prolonged and improved quality of life of many infected patients. However, adverse effects caused by these drugs have become a major concern as they affect the adherence of patients and in some cases even result in the death of patients. Although much research has been and is still being conducted in the area of understanding, preventing and management of ARV adverse effects, there is still a need for patients to be actively involved in self-monitoring for adverse effects. This will assist health care professionals in early identification of serious or potentially serious ARV effects. This study aimed at evaluating the usefulness of strategies developed and employed in the identification, recording and monitoring of adverse effects. The study was conducted with patients receiving HAART from a private HIV and AIDS clinic in Uitenhage, Eastern Cape, South Africa. The research project was approved by the Nelson Mandela Metropolitan University Research and Ethics Committee and the research site. This was an experimental, randomized controlled study carried out over a period of three months (August to October 2009), with a sample size of 160 patients divided into four study groups of 40 patients each. Two monitoring strategies, namely an ARV adverse effect monitoring tool and a patient self-monitoring diary were developed and used for the identification and recording of adverse effects. The four study groups included a Control group, a Tool group, a Diary group and a Tool-Diary group. Willing patients, after signing an informed consent form, were randomly assigned to one of the four groups by participating health care workers at the study site. Data was retrieved from the patient files by the researcher. Descriptive statistical analysis of the findings of the study was conducted using SPSS®. One hundred and forty nine patients were included in the final data analysis. Of the 80 diaries handed out to patients, only 33 were returned and due to errors only 31 were suitable for analysis. Monitoring tools were completed and analysed for 36 patients. The tool was found to be more effective in identifying adverse effects of a physical nature (such as peripheral neuropathy and lipodystrophy) than the usual methods of monitoring employed by the clinic, whilst the diary, used alone, was found to be less effective. Use of the tool and diary combined resulted in the most significant identification and recording of central nervous system related adverse effects and physical adverse effects. However due to the low return rate of the diaries and the majority of the monitoring tool not being completed in many instances the results of this study may not be generalisable. The study results did however suggest that combining the tool and the diary methods of adverse effect identification, yielded the most favourable results when compared to each method alone. This may be attributed to the fact that the tool is useful in identifying objective symptoms and the diaries subjective symptoms, particularly in instances where the patients forget to report their symptoms to healthcare professional whilst at the clinic. The diaries were also reported to improve adherence for more than 90 percentage (n=31) of the patients. More research would be needed in order to verify the exact significance of the tool and the diary in identifying and recording adverse effects and symptoms of adverse effects.

Currently South Africa has the highest number of persons living with HIV-AIDS (PLWAs) in the world. Focus-group discussions conducted by Moon (2005:3) in the Eastern Cape indicated that people may not want to get tested for HIV or to access antiretroviral therapy (ART) for fear of disclosure of their HIV-positive status and of stigmatization. These findings prompted the researcher to conduct a study in this field. The objectives of this study are to explore and describe the experiences of PLWAs with regard to the comprehensive ART management received from registered nurses at selected public primary healthcare clinics in Nelson Mandela Bay; and to develop guidelines for registered nurses that could facilitate them in rendering appropriate comprehensive ART management. The research study is based on a qualitative, explorative, descriptive, phenomenological and contextual research design. The research population comprised of HIV-positive patients who received treatment at the selected public primary healthcare clinics. Criterion-based, purposive sampling was used to select participants for the interviews. Ten in-depth unstructured interviews were conducted. Data was then transcribed and coded. One central theme identified the fact that PLWAs experienced both positive and negative experiences at the clinics. The main findings of this research included evidence of various forms of stigma experienced by the PLWAs; distrust of the lay health counselors; but also that PLWAs were generally well-treated and satisfied with the service they had received. Broad guidelines for registered nurses was formulated that could facilitate them in rendering appropriate comprehensive ART management. The study concludes with recommendations made with regards to the areas of nursing practice, education and research. Throughout the study the researcher abided by the ethical considerations. The aspects of trustworthiness implemented in this study, included dependability, credibility, transferability and confirmability (Holloway & Wheeler, 2002:354).

The aim of the study was to examine the procedures followed by traditional healers treating people living with HIV and AIDS in the Instika Municipality and the challenges faced by them in this endeavour. Using the qualitative research method, in-depth interviews and focus group discussions were conducted with twenty traditional healers. Among the significant findings of this study were the hardships encountered by traditional healers in terms of finance, the transport needed to collect medicinal plants, the shortage of medicinal plants, the lack of co-operation from the formal health care sector and the discrimination and abuse suffered at the hands of members of the community, with Christians and members of the SAPS being among the chief antagonists. It is also acknowledged in this study that traditional healers have been trained by the Department of Health concerning issues of hygiene and that traditional healers have knowledge of the symptoms of HIV and AIDS. It can therefore be concluded that traditional healers have a significant role to play in preventing the spread of HIV and AIDS if they employ preventative measures such as the use of protective gloves and limiting the use of a blade to one patient only. However, traditional healers are not supplied with safety kits or condoms to distribute to patients who consult them for treatment of STIs.

Indiana University-Purdue University Indianapolis (IUPUI) / Stroke is a sudden and devastating medical condition. People who experience a stroke tend to have long-term physical limitations including impaired walking as part of the ongoing consequences of stroke. While a variety of rehabilitation interventions have demonstrated efficacy for improving walking after stroke, none of the interventions have emerged as superior, and prior to this study, therapeutic-yoga had not been tested as an intervention to improve walking recovery after stroke. METHODS: This study was a secondary data analysis of group therapeutic-yoga on walking recovery measures including walking speed, walking distance, and spatiotemporal step parameter symmetry. The walking recovery measures were collected as secondary outcomes in a sub-sample (n=12) in a pilot randomized controlled study (n=47) designed to test the efficacy of 8-weeks of group therapeutic-yoga on balance and fear of falling. Participants in the current study completed 12-weeks of group therapeutic yoga with outcome assessments at baseline, 8-weeks, and 12-weeks. The main analysis was repeated measures ANOVA to assess the main effect of time with additional analyses including effect sizes, percent of participants achieving change greater than or equal to minimal detectable change (MDC), and mean change score comparisons between baseline and 8-weeks, 8-weeks and 12-weeks, and baseline and 12-weeks. RESULTS: Twelve people with chronic stroke enrolled in the study with 9 completing the intervention and all 3 assessments. No significant main effect of time was found on any of the variables of interest. Walking distance demonstrated a trend toward significant change (p=0.064) and step length symmetry demonstrated significant change (p=0.05) between baseline and 12-weeks. Several spatiotemporal step parameter symmetry ratios demonstrated small to medium effect sizes with the majority (91%) being a negative effect. CONCLUSION: Twelve weeks of group therapeutic-yoga appears to be feasible in a population of people with chronic stroke. Walking distance and step parameter symmetry should be tested in a larger sample. An improved understanding of the impact, progression, and remediation of walking asymmetry is needed.

Indiana University-Purdue University Indianapolis (IUPUI) / Huntington’s Disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder. There is no cure for HD and the existing therapies only alleviate HD symptoms without eliminating the cause of this neuropathology. HD is linked to a mutation in the huntingtin gene, which results in an elongation of the poly-glutamine stretch in the huntingtin protein (Htt). A major hypothesis is that mutant Htt (mHtt) leads to aberrant Ca2+ homeostasis in affected neurons. This may be caused by increased Ca2+ influx into the cell via the N-methyl-Daspartate (NMDA)-subtype of glutamate receptors. The contribution of two major Ca2+ removal mechanisms, mitochondria and plasmalemmal Na+/Ca2+ exchangers (NCX), in neuronal injury in HD remains unclear. We investigated Ca2+ uptake capacity in isolated synaptic (neuronal) and nonsynaptic mitochondria from the YAC128 mouse model of HD. We found that both Htt and mHtt bind to brain mitochondria and the amount of mitochondriabound mHtt correlates with increased mitochondrial Ca2+ uptake capacity. Mitochondrial Ca2+ accumulation was not impaired in striatal neurons from YAC128 mice. We also found that expression of the NCX1 isoform is increased with age in striatum from YAC128 mice compared to striatum from wild-type mice. Interestingly, mHtt and Htt bind to the NCX3 isoform but not to NCX1. NCX3 expression remains unchanged. To further investigate Ca2+ homeostasis modulation, we examined the role of collapsin response mediator protein 2 (CRMP2) in wild-type neurons. CRMP2 is viewed as an axon guidance protein, but has been found to be involved in Ca2+ signaling. We found that CRMP2 interacts with NMDA receptors (NMDAR) and disrupting this interaction decreases NMDAR activity. CRMP2 also interacts with and regulates NCX3, resulting in NCX3 internalization and decreased activity. Augmented mitochondrial Ca2+ uptake capacity and an increased expression of NCX1 in the presence of mHtt suggest a compensatory reaction in response to increased Ca2+ influx into the cell. The role of NCX warrants further investigation in HD. The novel interactions of CRMP2 with NMDAR and NCX3 provide additional insight into the complexity of Ca2+ homeostasis regulation in neurons and may also be important in HD neuropathology.

The field of cognitive neuroscience has benefited greatly from multimodal investigations of the human brain, which integrate various tools and neuroimaging data to understand brain functions and guide treatments for brain disorders. In this dissertation, we present a series of studies that illustrate the use of multimodal approaches to investigate brain structure and function, brain connectivity, and neuromodulation effects. Firstly, we propose a novel landmark-guided region-based spatial normalization technique to accurately quantify brain morphology, which can improve the sensitivity and specificity of functional imaging studies. Subsequently, we shift the investigation to the characteristics of functional brain activity due to visual stimulations. Our findings reveal that the task-evoked positive blood-oxygen-level dependent (BOLD) response is accompanied by sustained negative BOLD responses in the visual cortex. These negative BOLD responses are likely generated through subcortical neuromodulatory systems with distributed ascending projections to the cortex. To further explore the cortico-subcortical relationship, we conduct a multimodal investigation that involves simultaneous data acquisition of pupillometry, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). This investigation aims to examine the connectivity of brain circuits involved in the cognitive processes of salient stimuli. Using pupillary response as a surrogate measure of activity in the locus coeruleus-norepinephrine system, we find that the pupillary response is associated with the reorganization of functional brain networks during salience processing. In addition, we propose a cortico-subcortical integrated network reorganization model with potential implications for understanding attentional processing and network switching. Lastly, we employ a multimodal investigation that involves concurrent transcranial magnetic stimulation (TMS), EEG, and fMRI to explore network perturbations and measurements of the propagation effects. In a preliminary exploration on brain-state dependency of TMS-induced effects, we find that the propagation of left dorsolateral prefrontal cortex TMS to regions in the lateral frontoparietal network might depend on the brain-state, as indexed by the EEG prefrontal alpha phase. Overall, the studies in this dissertation contribute to the understanding of the structural and functional characteristics of brain network systems, and may inform future investigations that use multimodal methodological approaches, such as pupillometry, brain connectivity, and neuromodulation tools. The work presented in this dissertation has potential implications for the development of efficient and personalized treatments for major depressive disorder, attention deficit hyperactivity disorder, and Alzheimer's disease.