thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree Doctor of Philosophy. Johannesburg, 2013 / Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLM) are common neurological disorders for which the underlying aetiology is not fully understood. Currently RLS and PLM are thought to be caused by a central deficiency of dopamine or other functional abnormalities of the central nervous system. The work included in this thesis investigated different new methods of assessing the sensory and motor features of RLS and PLM, in an attempt to extend our understanding of their aetiology and improve the accuracy of diagnosis of these conditions. The first two studies in the thesis described and characterized the sensations of RLS symptoms, and whether they are influenced by the presence of pain, in an English speaking South African population. The most frequently cited descriptors were different to those used in the current RLS diagnostic criteria. Inclusion of the most commonly used RLS descriptors in the diagnostic criteria may help to improve the accuracy of RLS diagnosis. Patients who experienced painful RLS had greater McGill Pain Questionnaire scores and used different terms to describe their RLS to those that did not have painful RLS sensations. The third project quantified the responses of the Hoffman and patellar reflexes in RLS patients using electromyography and kinematics. The RLS patients exhibited hyporeflexia in the evening compared to the morning, and compared to control participants. This data suggests that RLS is not the result of a global state of hyperexcitability, as the literature suggests, but may reflect more discrete functional abnormalities of the spinal cord. A diurnal variation in the patellar reflex was found, supporting the notion of circadian variations of spinal excitability in RLS patients. The final investigation assessed the sensory qualities (discomfort and pain) of RLS in conjunction with motor activity evoked by using the Suggested Immobilization Test. Despite rating significant levels of discomfort, the majority of the RLS patients did not exhibit PLM; possibly suggesting a disconnect between the sensory and motor components of RLS. In conclusion, it is the major finding of this thesis that inclusion of new assessment techniques for the measurement of sensory and motor features of RLS and PLM provides both new insights and potential clinical tools enhancing our understanding of these disorders.

No description available.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

Injury now surpasses disease as the leading global cause of premature death and disability, claiming over 5.8 millions lives each year. However, unlike disease, which has been subjected to a rigorous epidemiologic approach, the field of injury prevention and control has been a relative newcomer to scientific investigation. With the distribution of injury now well described (i.e. ???who???, ???what???, ???where??? and ???when???), the underlying hypothesis is that progress in understanding ???how??? and ???why??? lies in classifying injury occurrences aetiologically. The advancement of a means of classifying injury aetiology has so far been inhibited by two related limitations: 1. Structural limitation: The absence of a cohesive and validated aetiological taxonomy for injury, and; 2. Methodological limitation: The need to manually classify large numbers of injury cases to determine aetiological patterns. This work is directed at overcoming these impediments to injury research. An aetiological taxonomy for injury was developed consistent with epidemiologic principles, along with clear conventions and a defined three-tier hierarchical structure. Validation testing revealed that the taxonomy could be applied with a high degree of accuracy (coder/gold standard agreement was 92.5-95.0%), and with high inter- and intra- coder reliability (93.0-96.3% and 93.5-96.3%). Practical application demonstrated the emergence of strong aetiological patterns which provided insight into causative sequences leading to injury, and led to the identification of effective control measures to reduce injury frequency and severity. However, limitations related to the inefficient and error-prone manual classification process (i.e. average 4.75 minute/case processing time and 5.0-7.5% error rate), revealed the need for an automated approach. To overcome these limitations, a knowledge acquisition (KA) software tool was developed, tested and applied, based on an expertsystems technique known as ripple down rules (RDR). It was found that the KA system was able acquire tacit knowledge from a human expert and apply learned rules to efficiently and accurately classify large numbers of injury cases. Ultimately, coding error rates dropped to 3.1%, which, along with an average 2.50 minute processing time, compared favourably with results from manual classification. As such, the developed taxonomy and KA tool offer significant advantages to injury researchers who have a need to deduce useful patterns from injury data and test hypotheses regarding causation and prevention.

Reprints of the author's previously published articles included as an appendix. Bibliography: leaves 165-188. "This thesis describes a series of experiments that aimed to investigate the effects of folic acid deficiency and defects in folate metabolism on chromosome damage rates in human lymphocytes. The accumulation of chromosome damage over time is an important issue because it is thought to contribute to the mechanism of ageing and the aetiology of diseases of age such as cancer and Alzheimer's disease."

The primary intervention for injury in children traveling in cars in Australia has involved the mandatory use of a restraint while traveling in a vehicle. This intervention has been successful as evidenced by high restraint usage rates by Australian children and substantial casualty reductions since the 1970’s. However casualty rates have been relatively stagnant over the last couple of decades. Currently more than 3,000 child occupants are seriously injured in Australia every year. There is a need to examine the scope for further preventing injury among restrained child occupants. This thesis presents four interrelated studies examining the factors and mechanisms involved when Australian children are seriously injured while using some form of restraint in a crash. Methods used include retrospective medical record review, in-depth crash investigation and analysis of mass in-depth crash data. Both descriptive and nonparametric statistical analysis techniques, including those that allow for the control of potential confounders, were used. Observations and results indicate there is substantial scope for further reducing serious injury in children traveling in cars in Australia. To realize this reduction there is a need to address the quality of restraint use by children through the development of strategies that not only encourage restraint use, but encourage the correct use of the most appropriate forms of restraint. There is also a need to address the protection provided by restraint systems and vehicles to child occupants in high severity crashes, and in crashes that involve impacts with fixed roadside objects such as trees and poles.

Reprints of the author's previously published articles included as an appendix. / Bibliography: leaves 165-188. / xiv, 189 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / "This thesis describes a series of experiments that aimed to investigate the effects of folic acid deficiency and defects in folate metabolism on chromosome damage rates in human lymphocytes. The accumulation of chromosome damage over time is an important issue because it is thought to contribute to the mechanism of ageing and the aetiology of diseases of age such as cancer and Alzheimer's disease." / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2002?

The primary intervention for injury in children traveling in cars in Australia has involved the mandatory use of a restraint while traveling in a vehicle. This intervention has been successful as evidenced by high restraint usage rates by Australian children and substantial casualty reductions since the 1970’s. However casualty rates have been relatively stagnant over the last couple of decades. Currently more than 3,000 child occupants are seriously injured in Australia every year. There is a need to examine the scope for further preventing injury among restrained child occupants. This thesis presents four interrelated studies examining the factors and mechanisms involved when Australian children are seriously injured while using some form of restraint in a crash. Methods used include retrospective medical record review, in-depth crash investigation and analysis of mass in-depth crash data. Both descriptive and nonparametric statistical analysis techniques, including those that allow for the control of potential confounders, were used. Observations and results indicate there is substantial scope for further reducing serious injury in children traveling in cars in Australia. To realize this reduction there is a need to address the quality of restraint use by children through the development of strategies that not only encourage restraint use, but encourage the correct use of the most appropriate forms of restraint. There is also a need to address the protection provided by restraint systems and vehicles to child occupants in high severity crashes, and in crashes that involve impacts with fixed roadside objects such as trees and poles.

Injury now surpasses disease as the leading global cause of premature death and disability, claiming over 5.8 millions lives each year. However, unlike disease, which has been subjected to a rigorous epidemiologic approach, the field of injury prevention and control has been a relative newcomer to scientific investigation. With the distribution of injury now well described (i.e. ???who???, ???what???, ???where??? and ???when???), the underlying hypothesis is that progress in understanding ???how??? and ???why??? lies in classifying injury occurrences aetiologically. The advancement of a means of classifying injury aetiology has so far been inhibited by two related limitations: 1. Structural limitation: The absence of a cohesive and validated aetiological taxonomy for injury, and; 2. Methodological limitation: The need to manually classify large numbers of injury cases to determine aetiological patterns. This work is directed at overcoming these impediments to injury research. An aetiological taxonomy for injury was developed consistent with epidemiologic principles, along with clear conventions and a defined three-tier hierarchical structure. Validation testing revealed that the taxonomy could be applied with a high degree of accuracy (coder/gold standard agreement was 92.5-95.0%), and with high inter- and intra- coder reliability (93.0-96.3% and 93.5-96.3%). Practical application demonstrated the emergence of strong aetiological patterns which provided insight into causative sequences leading to injury, and led to the identification of effective control measures to reduce injury frequency and severity. However, limitations related to the inefficient and error-prone manual classification process (i.e. average 4.75 minute/case processing time and 5.0-7.5% error rate), revealed the need for an automated approach. To overcome these limitations, a knowledge acquisition (KA) software tool was developed, tested and applied, based on an expertsystems technique known as ripple down rules (RDR). It was found that the KA system was able acquire tacit knowledge from a human expert and apply learned rules to efficiently and accurately classify large numbers of injury cases. Ultimately, coding error rates dropped to 3.1%, which, along with an average 2.50 minute processing time, compared favourably with results from manual classification. As such, the developed taxonomy and KA tool offer significant advantages to injury researchers who have a need to deduce useful patterns from injury data and test hypotheses regarding causation and prevention.

Congenital heart disease (CHD) is characterized by structural defects of the heart and great vessels. It is the most common birth defect, affecting an estimated 1% of live births, and is the leading cause of mortality among birth defects. Despite recent progress in genetic research, more than 50% of CHD cases remain unexplained. An estimated 23% are due to aneuploidies and copy number variants and up to 30% has been attributed to de novo variation, though that number ranges between 3-30% depending on CHD complexity. The contribution of somatic mosaicism, or de novo genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood due to limitations in sample size, detection method, and validation rate. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. We developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic accurately detected 309 mosaic mutations in blood, with 85 of 94 (90%) candidates tested independently confirmed. We found twenty-five likely damaging mosaics in plausible CHD-risk genes, affecting 1% of our cohort. Variants in these genes predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The frequency of protein-coding mosaic variants detectable in blood was 0.122 or roughly 1 in 8 individuals. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. CHD patients often present with comorbid cardiac and extracardiac anomalies that further their impact quality of life. Neurodevelopmental disorders (NDDs) are especially prevalent in CHD cases compared to the general population, yet the underlying genetic causes remain poorly explained. Further, patients with single ventricle defects undergoing surgery often later develop arrhythmias and experience worsening ventricular function. We used a statistical approach to dissect the association between de novo variation and these clinical outcomes and found that pleiotropic mutations contribute a large fraction of the risk of acquiring NDD and abnormal ventricular function phenotypes in CHD patients. We developed a proof-of-concept rare variant risk score that combines information from de novo, rare transmitted, and copy- number variants and show that prediction of outcomes such as NDD can be improved, especially in complex CHD cases.