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Heart failure (HF) is a pathological state indicating insufficient blood supply to the peripheral tissues from the heart. The pathophysiology of HF is multifactorial like cardiac remodeling including cardiac hypertrophy, perivascular fibrosis and apoptosis to compensate for the heart’s inability to pump enough blood. Cardiac hypertrophy is initially adaptive to hemodynamic overload; however, it chronically contributes to heart failure and sudden cardiac death. The extracellular regulatory factors and intracellular signaling pathways involved in the cardiac remodeling are not yet fully clear. PI3-kinase is an important intracellular kinase in organ size control. Cardiac overexpression of Class I PI3-kinase caused heart enlargement in transgenic mice. Autophagy as a dynamic process involving the degradation of damaged mitochondria prevents ROS overproduction which leads to the cardiac remodeling. Therefore, our aim was to study the relationship between PI3-kinases and Ang II-induced cardiac remodeling via an autophagy-dependent mechanism. Ang II significantly increased autophagy with two distinctive phases: an increasing phase at low doses and a decreasing phase at high doses in cardiomyocytes. The Ang II-induced autophagic depression was attenuated by a Class I PI3-kinase inhibitor and potentiated by Class III PI3-kinase inhibitor. Besides, Ang II-induced cardiac hypertrophy and mitochondria ROS generation were attenuated via blockade of Class I PI3-kinase or mTOR. To further validate our in vitro data, we studied the role of Class I PI3-kinase in Ang II-induced cardiac remodeling in vivo. We successfully transferred Lv-DNp85 (Class I PI3-kinase blockade) and Lv-GFP (control) into adult rat hearts and found that cardiac transfer of Lv-DNp85 did not alter Ang II-induced pressor effect, but attenuated Ang II-induced cardiac hypertrophy, perivascular fibrosis and cardiac dysfunction. Ang II-induced cardiac remodeling was associated with impaired autophagy and mitochondrial ROS overproduction, which were significantly attenuated by Lv-DNp85-induced blockade of Class I PI3-kinase. Taken together, these data suggest that Class I PI3-kinase is involved in Ang II-induced impairment of autophagy via Akt/mTOR pathway, leading to mitochondrial ROS overproduction and cardiac remodeling. These results are not only highly significant from a pathophysiological perspective, but also have important pharmacological implications in the control of cardiac hypertrophy to prevent decompensation and failure in cardiac function. / National Institute of Neurological Disorders and Stroke / National Institutes of Health (NIH, NS55008)

MSc (Med), School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 2009 / Excess adiposity may increase the risk of heart failure through interactions with conventional risk factors. As cardiomyocyte apoptosis may be an important mechanism responsible for the development of heart failure the aim of the present study was to determine whether obesity enhances a) the increased cardiomyocyte apoptosis that accompanies pressure-overload hypertrophy and b) sympathetic-induced cardiomyocyte apoptosis. The impact of dietary-induced obesity on cardiomyocyte apoptosis was studied in elderly spontaneously hypertensive rats (SHR) and age-matched (8-9 months of age at the beginning of the study) Wistar Kyoto rats (WKY) after a 5 month feeding period and in young WKY rats (1 month of age at the beginning of the study) receiving either isoproterenol (ISO) or the vehicle (saline) for 5 days at the end of the feeding period. To induce obesity rats were fed a diet that promotes hyperphagia. At the end of the feeding period echocardiography was performed. Cardiac myocyte apoptosis was assessed using a TUNEL staining technique. Rats receiving the obesity-inducing diet had increases in body weight and visceral fat content. No further changes in systolic blood pressure were observed in rats during the feeding period. SHRs on the obesity-inducing diet had an increased left ventricular end-diastolic diameter and a decreased endocardial fractional shortening. As compared to lean rats, dietary-induced obesity resulted in an increase in the percentage of cardiomyocytes that were apoptotic in SHRs (3.4±0.5%, p<0.005 vs all other groups) and in WKYs receiving ISO (0.35±0.05%, p<0.05 vs Control-ISO and p<0.01 vs Control-saline and Diet-saline groups). In conclusion, obesity was associated with cardiomyocyte apoptosis through an interaction with pressure-overload hypertrophy v and excessive sympathetic activation. These findings provide insights into the potential mechanisms through which obesity may promote the development of heart failure.

Submitted in fulfillment for the requirements of the Degree of Master of Education in the Department of Didactics in the Faculty of Education at the University of Zululand, 1996. / The aims of this study were: • to investigate the didactic causes of scholastic failure in primary schools; and • to suggest, in the light of findings obtained, didactically justifiable guidelines for reducing the failure rate in primary schools. To address these concerns the investigation was underpinned by the following hypothesis: the principal didactic causes of scholastic failure in primary schools centre upon the ineffective application of socialisation, individuaiisation, perception, motivation and evaluation as didactic principles. In order to combat the problem of fragmentation caused by an overemphasis on empirical research while theoretically engaging concepts as revealed in recent research findings are often disregarded, this investigation concentrated entirely on literary research. A comprehensive study was conducted of recent primary and secondary sources related to didactic causes of scholastic failure. Data collated from different types of research which were conducted, tried out and tested by other researchers were blended, integrated and analyzed according to didactic criteria articulated in the hypothesis. The findings revealed that scholastic failure in primary schools revolved around five major causes. First: inadequate situation analysis prevents effective psychological and educational diagnosis of (earning disabilities; temporary poor scholastic achievement of average learners are sometimes erroneously diagnosed by the teachers or orthodidacticians as being caused by permanent learning disabilities. Second: inattention to language skills causes many primary school children to be at a learning disadvantage; definite connections have been shown to exist between scholasticfaiiureand speech deficiencies, defective hand writing, spelling disabilities as well as reading and writing limitations. Third: inefficient teaching styles result in inadequacies in the integral, interactive parts which the child and his or her teacher play in the education situation. Fourth: weak classroom management generates disruptive behaviour, distraction, hyper-activity resulting in corporal punishment which in turn lead to scholastic failure. Lastly: lack of teacher self-evaluation creates a situation in which classroom actions are often not guided by accountable personal teaching theories and didactic principles. In the light of the above findings, the recommendations flowing from the research include, inter alia: that bridging module readiness classes be established for children turning five years of age and that professionally qualified educators be pfaced in charge of these children; • that more emphasis should be placed on peer group teaching in primary schools; • that teachers and parents work closer together to help, guide and shape the child's attitude towards school and that self-improvement among teachers should be promoted through in-service education.

Submitted in partial fulfilment of the requirements for the degree of Master of Education in the Department of Planning and Administration in the University of Zululand, 1990. / This study looks into the problem of failure in Matric in Black schools in KwaZulu. Some researchers have focused on causes for academic failure before. Some of these researchers are: Souper, (1976); Bryant, (1978); Havinghurst, (1979); Donald, (1980); Simons, (1980). Failure is rarely, if ever, attributable to one simple cause. There are likely to be a multiplicity of interrelated causes. Some' of these causes are : family disorganisation; family size and education; poor study facilities at home and teacher-pupil ratio. Failure at school may imply that one may fail in life. Society believes that school subjects are the means of i equipping pupils with the knowledge of understanding certain socio-economic and political demands. School subjects, it is believed, reveal the r, ealities that they should know in their society. It is through these school subjects that the child will know how to live comfortable with other people (Social Studies); how to look after his/her body, (Physiology and Hygiene); how other organisms are important in her/his life, (Biology/ Ecology; (Geography) .

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No / This paper is part of a research theme to develop methods that enhance risk assessment studies by the use of 'automated' failure analysis. The paper presents an approach to mechanical failure analysis and introduces a mechanical failure analysis module that can be used in a virtual reality (VR) environment. The module is used to analyse and predict failures in mechanical assemblies; it considers stress related failures within components, as well as failures due to component interactions. Mechanical failures are divided into two categories in this paper: material failures and interference failures. The former occur in components and the latter happen at the interface between components. Individual component failures can be analysed readily; a contribution of the mechanical failure analysis module is to predict interference failures. A mechanical failure analysis system that analyses and visualizes mechanical failures in a virtual environment has been developed. Two case studies demonstrate how the system carries out failure analysis and visualization as design parameters are changed.

A reliability-based optimization (RBO) methodology was developed and applied to fiber-reinforced polymer (FRP) bridge decks. Commercially available software was used to optimize a FRP bridge deck panel by weight with structural reliability, stress, and deflection constraints. A methodology using optimization software, finite element analysis, and probabilistic analysis software was developed to examine the effects of load and resistance uncertainties in FRP bridge deck optimization. Eight modular deck designs were considered for use in the RBO methodology. Investigations into random variable sensitivities, design variable sensitivities, wheel positions, and buckling were conducted to minimize computational effort. Five models were eventually optimized with deterministic methods and the RBO methodology. Ply thicknesses were treated as design variables. Material parameters, design variables, and load were taken as random variables in the reliability calculations. A comparison of RBO designs was made with the best candidate chosen based on deck panel weight.

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