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Student Number : 0400188H - MSc(Eng) Dissertation - School of Mining - Faculty of Engineering and the Built Environment / The occurrence of fracturing due to high stress levels is a major factor with regard to hangingwall stability in deep level gold mine stopes. However, rock falls cannot be the result of these fractures alone. Blocks in the hangingwall strata must be defined by a combination of the stress induced fractures and naturally occurring geological planes of weakness. These planes include bedding planes and joint planes. The importance of the natural joints and bedding planes in defining the instability has not been given the attention that it deserves, to the extent that there are apparently no documented, published data available on joint set characteristics. This is perhaps an indication that such data do not exist on the mines. To remedy this situation, detailed scan-line joint mapping exercises have been carried out in several geological environments in two gold mines. The joint data collected on joint geometry included orientation, spacing and length. The results presented in this dissertation are believed to be the first such data available on jointing in gold mines. The main conclusions from the interpretation of these data are that there are two dominant joint sets in stope hangingwalls and at least one of these sets is shallow dipping. In development tunnels there is one predominant set of shallow dipping bedding planes. Both in stope hangingwalls and in development tunnels, steeply dipping random joints constitute half of the mapped joints. The statistical joint data obtained was used to investigate and analyse the potential for rock falls in stopes. This involved the prediction of characteristic block parameters such as expected block sizes and rock fall thicknesses. These predictions show good agreement with measurements made of actual rockfalls (generic results). Most unstable blocks in stope hangingwalls are less than a cubic meter in size. These blocks are more likely to fall between support elements than fail the supports, whilst failure of the fewer large blocks (20%) usually involves failure of support elements. It is concluded that failure probabilities are largely related to joint geometry. Common failure modes for small blocks are single plane sliding and ‘dropping out’ whilst larger blocks usually fail by rotation. The study increases understanding of rock fall mechanisms and the support-block interaction. The results of the analyses of block stability that have been reported in this dissertation show disturbingly high probabilities of failure in the stope face area (or working area), particularly for blocks that are smaller than about 1.5 cubic metres in size. The study has demonstrated the important influence that natural joints have on hangingwall block stability, and the importance of joint mapping to produce statistical joint data that can be used in the assessment of stability against rock falls. Although joint mapping may be a tedious exercise in mines, it has been shown to give similar results regarding heights of rock falls to that interpreted from collection of empirical incident and accident record data over a ten-year period. It is considered that this could provide good input data for the design of stope support.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand , in fulfillment of the requirements for the degree of Master of Science in Medicine, 2013 / Sequence analysis from HIV-1 (human immunodeficiency virus type 1) subtype B and more recently subtype C infected patients has revealed that mutations in the HIV-1 protease region that confer drug resistance to boosted protease inhibitor (PIs) are rarely detected at the time of virological failure. Mutations in the HIV-1 subtype B gag-pol cleavage sites are thought to be compensatory mutations which arise as a result of PI use. This study investigated the presence of compensatory mutations in the HIV-1 subtype C gag-pol cleavage sites and matched pol genotypes from South African patients failing a boosted PI-based regimen, as compared to antiretroviral drug naïve patients. A new amplification protocol encompassing the near full-length gag, PR and partial RT was established and used to sequence the HIV-1 gag-pol cleavage sites from 23 proviral DNA samples (p24 antigen cultured peripheral blood mononuclear cells; PBMCs), and 51 patient samples (23 antiretroviral drug-naïve, 26 failing second-line lopinavir/ritonavir containing regimens), all attending the Charlotte Maxeke Johannesburg Hospital. Nucleotide sequences were aligned and codon positions S373Q, A431V, I437T/V, L449P or P453L associated with known gag-pol cleavage site mutations were analysed and compared. The pol genotypes were established using an in house assay. Antiretroviral drug resistant primary virus isolates were grown from samples from patients enrolled on the CIPRA-SA study, and propagated in coculture with PHA-activated, IL-2 stimulated PBMCs. HIV-1 gag-pol cleavage sites and pol genotypes for all primary virus isolates were established as described above. Fifty one of 74 patient samples, used to establish the in-house gag-pol cleavage site assay, were successfully amplified and sequenced. Detailed analysis of the five known gag-pol cleavage sites revealed that 5 patient samples (4 PI-exposed, 1 unknown regimen) encoded for the previously described mutations that impact on gag-pol cleavage in the absence of any major PR mutations. A further five samples from patients on the failing PI-based regimen had major PR mutations. No known mutations in the gag-pol region were identified in patients failing a first line regimen. The pol mutations described in this study were similar to the findings reported for treatment failures in South African HIV-1 subtype C infected patients. Primary virus was grown from only 25 of the 91 PBMC CIPRA samples. None of the 25 CIPRA-SA primary virus isolates had gag-pol cleavage site mutations, and only 9 harboured known RT antiretroviral drug resistant mutations. Overall, the presence of HIV-1 gag-pol cleavage site mutations may account for virological treatment failure in 5 of the South African patient samples analysed. Although the gag-pol cleavage site mutations detected in the current study are only present in a small proportion of treatment-experienced South African patients, this may increase due to more patients accessing second line PI-containing regimens. Thus, future genotyping work incorporating the analysis of the gag-pol cleavage sites in addition to the PR and RT regions is warranted. The antiretroviral drug resistant primary viruses obtained provide valuable reagents for future phenotyping studies.

Chronic renal failure patients develop a coagulopathy primarily due to reversible platelet dysfunction. This coagulopathy makes certain anaesthetic techniques and procedures such as neuraxial anaesthesia and invasive line placement possibly contra-indicated or risky. There is no evidence to suggest that the degree of platelet dysfunction is proportional to the degree of renal dysfunction. In this research project the platelet function of 39 end stage renal failure patients, who received regular dialysis and who presented to theatre for vascular access, was assessed using the thromboelastogram. A bleeding time was also performed pre-operatively. A linear regression model was used to determine if the bleeding time, plasma urea, plasma creatinine or creatinine clearance could predict maximum amplitude (and therefore clot strength) on the thromboelastogram. No such regression could be found. The clinical implication of this result is that there exists no "safe" plasma urea or creatinine, below which it is safe to perform procedures which are contra-indicated in coagulopathies. The degree of renal dysfunction did not predict the degree of platelet dysfunction. Since dialysis reverses the platelet dysfunction, the question that should be asked before performing such a procedure is not "how severe is the renal dysfunction?" but rather "has the patient been receiving regular dialysis?"

Perceived benefits and burdens encountered by relatives caring for person on long-term haemodialysis in Johannesburg. This study examines the perceived benefits and burdens of family members caring for persons on long term Haemodialysis. The caregiver burden scale by Elmastahl, Malmeberg and Annerstedtl (1996) was used for the purposes of the study. The participants were selected by Census (total) sampling. The sample consisted of family caregivers who were 18 years and above who were selected from three haemodialysis units in Johannesburg. Permission to conduct the study was requested and granted from all relevant authorities. One hundred and fifty questionnaires were distributed amongst the three haemodialysis units of which seventy nine participants responded to the study. Data were analysed using the statistical package STATA version 12. Demographic data and the caregiver burden scale were analysed through frequency counts, percentages and graphs were constructed from the collected data and analysed. Cross tabulations, using Fisher’s exact test were performed to determine the relationship between the demographic information and factors of the caregiver burden scale. The results are presented in the form of tables and graphs. Semi structured questionnaire with an option for elaboration were analysed using content analysis to enumerate a deeper understanding of the perceived burdens and benefits of caring for a person on Haemodialysis. Findings from the study concluded that family caregivers have encountered both benefits and burdens when caring for a person on Haemodialysis. The following factors have emerged namely demographics which include age, gender, relation to patient, highest education level, employment, ethnicity and duration of care and the factors surrounding general strain, isolation, disappointment, emotional involvement and environment. The factors, whether good or poor, are not always a predictor of perceived benefits and burdens of caring for persons on long term haemodialysis. The overall caregiver burden score, inclusive of all factors, showed a median score of 46.59% of all family caregivers’ experienced burden in caring for their relative on haemodialysis. Health education and support for the family caregivers proved to be a need in improving and reducing the caregiver burden. Caregiver health is quickly becoming a public health care issue that requires a more focused attention from health professionals, policy makers and caregivers themselves to ensure the health and safety of those dedicating their lives to the care of their relatives on haemodialysis.

Heart failure (HF) is a common cause of hospitalisation and mortality across industrialised countries. The number of hospitalisations and deaths attributed to heart failure is increasing, and this trend is predicted to continue. Numerical and in-vitro simulations of the human cardiovascular system constitute the basic tools for enhancing diagnostic and therapeutic technologies for HF and this would in turn, have significant effects on morbidity,mortality, and healthcare expenditure. Mechanical Circulatory Support (MCS) as a destination therapy for HF is rising significantly as it provides a cost-effective alternative to long-term treatment and cardiac transplantation. However, long-term versatility is far from ideal and incidence of transient and permanent neurological events is still high. To this end, evolution of MCS devices calls for more sophisticated design and evaluation methods. The purpose of this work is to develop a numerical model and to implemented a novel in-vitro model of the cardiovascular system with the intention of evaluating the performance characteristics of a purposely selected centrifugal pump impeller for the treatment of both Class III and IV HF conditions when placed in series with the heart at two different anatomic locations: Ascending Aorta and Descending Aorta. An existing lumped-parameter model of the CV system, that included models for the heart, the pulmonary and the systemic circulatory loops by adapting a modified version of the fourth-element Windkessel model was enhanced by dividing the systemic circulation into six parallel vascular beds, and by including an autoregulatory system to control both pressures and volumes throughout the system. As part of the novelty of the present work, a volume reflex loop was included with the purpose of simulating volume overload conditions, as commonly found in HF conditions, and obtaining a more realistic analysis of volume displacement, while using a MCS device. The in-vitro model implemented in this work adopted most of the features included in the mathematical counterpart with the purpose of validating the numerical results. As a result of the combination of models and proper optimisation of the system parameters, predictions of pathophysiological trends and MCS usage are satisfactorily obtained. The models implemented in this work offer a valuable tool for the selection and performance evaluation of MCS devices for the treatment of HF conditions.

Heart failure is the leading cause of morbidity and mortality in the world. It is an incurable disease and most treatment strategies aim to treat the symptoms or slow the progression of the condition. Cardiac contractility is governed by calcium homeostasis within cardiac myocytes and is modulated by the sympathetic nervous system. Both mechanisms are detrimentally altered in heart failure. An important group of enzymes, phosphodiesterases, are fundamental to the sympathetic (beta-adrenergic) modulation of calcium cycling in cardiac myocytes. The selective inhibition of phosphodiesterase 5 (PDE5) has recently been considered as a potential therapy for heart failure; having beneficial effects in human and animal models of the disease. The present study employs a large animal model of tachypacing induced heart failure to test the effect of PDE5 inhibition on myocyte and whole heart contractility and beta-adrenergic function, to assess the molecular mechanisms by which PDE5 inhibition is beneficial to the failing myocardium. In initial experiments the PDE5 inhibitor sildenafil was applied acutely to voltage clamped ventricular myocytes from uninstrumented sheep. PDE5 inhibition reduced baseline L-type calcium current and systolic calcium transient amplitude, suggesting it is negatively inotropic. Furthermore, the positive inotropic effects of beta-adrenergic stimulation were somewhat reversed by acute PDE5 inhibition. Interestingly, such negative inotropic effects of acute PDE5 inhibition were not observed in failing ventricular myocytes, which have dysfunctional calcium homeostasis and beta-adrenergic reserve. When delivered chronically over 3 weeks to tachypaced animals, PDE5 inhibition restored and augmented the systolic calcium transient and beta-adrenergic responsiveness at both the whole heart and myocyte level. These effects were associated with changes to the expression and phosphorylation status of the proteins that control calcium homeostasis in left ventricular tissue. In vivo, PDE5 inhibition prolonged longevity and reduced the onset of clinical signs of heart failure in sheep, as well as arresting cardiac dilatation and wall thinning. Chronic PDE5 inhibition however had no effect on cardiac contractility or heart failure induced changes in cardiac electrophysiology. This study presents a novel mechanism by which PDE5 inhibition may be beneficial in a large animal model of heart failure by restoring calcium homeostasis and beta-adrenergic responsiveness. This study may have important implications for the management of heart failure in clinical practice.

In eukaryotes the coding regions of most genes are interrupted by introns that must be removed by splicing to form a coding mRNA. However, while the splicing mechanism has received a lot of attention, much less is known about the metabolism of introns. This is partly due to the difficulties in studying introns as both aberrantly spliced transcripts and spliced introns are rapidly degraded. In this study, I have analysed intron metabolism in two respects: first I have investigated how introns are degraded following the completion of splicing. Second, I investigate the fate of transcripts, in which introns are retained due to splicing failure. In order to study the degradation of introns following splicing, I performed siRNA mediated knock down of the debrancing enzyme (Dbr1). Following splicing, introns are present in a circular lariat structure and Dbr1 is the enzyme thought to be responsible for opening this. Indeed, I found that knockdown of Dbr1 increased the amount of stabilised introns. Interestingly, introns were found to be stabilised in the cytoplasm and not in the nucleus as expected, even though immunofluoresence showed that Dbr1 is clearly nuclear. However, western blot analysis localised Dbr1 in the cytoplasm. Further investigation showed widely used methods to separate nuclear and cytoplasmic fractions are prone to generating artefacts which result in nucleoplasmic proteins delocalised to the cytoplasm. This finding may prevent future misinterpretation of data obtained by these methods. To investigate splicing failure, it was necessary to generated a sufficiently large pool of unspliced transcripts. To do this I used antisense morpholinos (AMOs) that bind to specific snRNAs (small nuclear RNAs). They are designed to block interaction surfaces that are important for splicing. Using this approach, I investigated the localisation of RNA transcripts and selected RNA processing and degradation factors in normal conditions and where splicing was inhibited. When splicing is inhibited I found splicing factors and unspliced, polyadenylated RNA localising to nuclear, splicing speckle marker SC35 positive speckles. I further discovered that for RNA to localise to nuclear speckles, polyadenylation and RNA cleavage are essential, indicating that SC-35 speckles might sequester unspliced transcripts preventing translation of potentially harmful transcripts. These transcripts remain functional however, and can be spliced where functional spliceosomes can be assembled.

Failure mechanisms observed in electromigration (EM) stressed dual damascene Cu/SiO₂ interconnects trees were studied and simulated. Failure sites with ‘melt patch’ or ‘crater’ are common for test structures in the top metal layer, though the occurrence of such failure modes probably depends on the passivation layer thickness. Interconnects that were EM stressed for a short time and then stressed with increasing current to induce Joule heating in the line had similar failure sites to lines that were stressed to failure under standard EM conditions. This shows that some failure mechanisms during EM could be assisted by Joule heating effect. / Singapore-MIT Alliance (SMA)

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 48-54).