Stress-related functional bowel disease is a common, often incapacitating, problem in humans; the symptomatology of stress-related intestinal dysfunction is: (1) impaired small intestinal transit and motility, and (2) increased large intestinal transit and, commonly, diarrhea. The etiology of stress-induced intestinal dysfunction is completely unresolved, and the lack of an appropriate animal model has hindered studies of causality. We compared a number of stressors and their resultant effects on intestinal transit, a measure of the propulsive motor activity of the gut, in the rat. We found that the response of the intestine to stress, and the neural systems activated by stress, were dependent on the type and duration of stress, as well as the animal strain, and gender. We developed a model, acute wrapping restraint stress, to fully characterize the effects of stress on intestinal transit. Wrap restraint stress is a nonulcerogenic model in which rats are subjected to acute restraint by wrapping them in a harness of paper tape to restrict, but not prevent movement of the upper body and forelimbs. Transit was evaluated by the geometric center method, in which a radiomarker (⁵¹Cr) is instilled directly into the proximal duodenum and proximal colon via a surgically placed intestinal cannula, in fasted, adult female Sprague Dawley rats (150-200g). Subjecting animals to 35 min. of wrap restraint stress resulted in (1) inhibition of small intestinal transit, and (2) increased large intestinal transit and increased fecal output. The effects of stress on intestinal transit in rats resembled symptoms associated with stress in humans, suggesting that wrap restraint stress may be suitable as a model of stress-induced intestinal dysfunction. We found a close correlation between stress-induced intestinal dysfunction and stress-activation of endocrine systems. Stress-induced changes in intestinal function was strongly influenced by circadian variations in endocrine levels, suggesting that stress-induced intestinal dysfunction may be hormonally mediated. However, neither pituitary nor adrenal factors mediated the effects of stress on the gut. To evaluate the role of corticotropin-releasing factor (CRF), the major hypothalamic factor released in response to stress, in stress-induced intestinal dysfunction, we studied the effects of exogenous CRF on intestinal transit. CRF resulted in (1) a potent, dose-dependent inhibition of small intestinal transit, (2) a dose-dependent increase in large intestinal transit, and (3) increased fecal excretion. The effects of exogenously administered CRF closely paralleled the effects of stress on intestinal transit and on ACTH secretion in the rat. Blockade of CRF receptors by means of an antagonist, α helical CRF (9-41), prevented the effects of stress on colonic transit and fecal excretion. These data strongly suggest that endogenous CRF may mediate the effects of wrap restraint stress on intestinal motor activity and coordination in the rat.

Taurine (2-aminoethane sulfonic acid) is one of the most abundant inhibitory amino acids in the mammalian central nervous system (CNS). Substantial evidence exists to suggest that this amino acid is a physiological modulator of neuronal excitability. Taurine is also a potent anticonvulsant in a variety of animal epilepsies and in certain human epileptics. The mechanisms of these neuromodulatory and anticonvulsant actions of taurine are not known. I have investigated a proposed relationship between altered amino acid metabolism, seizure-susceptibility and the anticonvulsant action of taurine. The findings of the work presented in this dissertation indicate that in the genetically seizure-susceptible rat there are alterations in the subcellular concentration and transport of taurine. Furthermore, the data presented here indicate that these alterations in the CNS handling of taurine are not a consequence of seizure activity but rather may be contributing to the seizure-susceptibility. This supports the hypothesis that taurine is a physiological modulator of neuronal excitability and that defects in this neuromodulatory process may contribute to seizure-susceptibility. The action of taurine was found to not be mediated by a redistribution of glutamate in the brain but instead may be by increasing the conversion of glutamate to GABA.

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A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Physiotherapy. Johannesburg, 2014 / Cycling has grown in popularity as a sport and is rated as one of the top 15 most popular sports in South Africa with more than 420 000 participants. Cyclists spend long continuous hours on the bicycle in an awkward position, which leads to unique overuse injuries. Overuse injuries in cyclists have been estimated to be as high as 85% with lower back and pelvis pain (LBPP) among the most common. The lower back and pelvis is the foundation the cyclist use for powering and controlling the bicycle and optimal functioning thereof is essential for optimal comfort and performance in cycling. The prolonged forward flexed position of the cyclist on the bicycle is regarded as one of the main contributors to LBPP in cyclists. Cyclists with LBPP are known to assume a position of greater lumbar flexion compared to those without but the reason for this has not been extensively explored. The purpose of this study was therefore to not only establish the prevalence of LBPP in cyclists in South Africa, but also identify factors associated with it in cyclists. The factors were considered in three broad categories: (1) training methods used, (2) intrinsic functioning of the cyclist and (3) bicycle set-up. Intrinsic and bicycle set-up factors included were those proposed to influence the forward-backward and side-to-side position of the cyclist on the bicycle and thereby lead to the development of LBPP in cyclists. The study had a cross-sectional descriptive design and comprised of two parts: a questionnaire (survey) investigating the prevalence of LBPP in cyclists together with the training methods used, and a physical assessment of the factors proposed to be associated with LBPP in cyclists. All cyclists belonging to cycling clubs registered with Cycling South Africa were invited to complete the online survey. From there, cyclists could indicate willingness to undergo a physical assessment which was done in the greater Gauteng area. The physical assessment included the following measurements: the lumbar curvature on the bicycle in all three handlebar positions, strength of gluteus maximus and gluteus medius, extensibility of the hamstring muscle group, control of lumbar movement in the direction of flexion, neurodynamics, active straight leg raise for load transfer, one leg stance test for lateral shift of the pelvis, leg-length discrepancy and bicycle set-up (saddle height, set-back and angle, handlebar height, forward reach, cleat position). The study revealed a lifetime prevalence of 65% for LBPP among cyclists in South Africa. Of the factors assessed, only the lumbar curvature in the brake lever position i.e. flexion of the lumbar spine (p=0.03) and the weakness of gluteus medius (Gmed) (p=0.05) were significantly related to LBPP in cyclists. This study was the first to assess the relationship between so many different factors and LBPP in cyclists, and the largest of its kind in cycling. Understanding the relationship between these factors and LBPP in cyclists can guide the development of preventative strategies and interventions with the aim of reducing the occurrence and recurrence of LBPP in cyclists and limiting the impact thereof.

by Francis Ka-leung Chan. / Thesis (M.D.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (p. 187-210). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

The aim of this work was to study the environmental and genetic factors for Parkinson???s disease (PD) in Chinese and Australian. Using a case-control method, environmental factors for PD were studied in a Chinese population (n=528) in Hong Kong. Current smoking (OR=0.437; p=0.013) and infrequent tea drinking (OR=1.51; p=0.02) were found to be protective factors, whereas family history and pesticide exposure during farming in females were found to be risk factors in the univariate analysis. In the multivariate analysis, current smoking reached borderline significance at the 5% level and the variables, years exposed to pesticides and family history were significant at the 10% level. Similarly, a case-control study involving 534 subjects was conducted in Australia. A positive family history was the strongest risk factor (OR=3.4; p&lt0.001). In addition, rural residency was found to be another risk factor (OR=1.8; p&lt0.001). Hypertension, stroke and well water ingestion were inversely correlated with PD (OR=0.2; p&lt0.001, OR=0.2; p&lt0.001 and OR=0.7; p&lt0.03 respectively). When genetic factors were examined in the Chinese population, no association to PD were found for the polymorphisms of the following candidate genes: CYP-2D6 debrisoquine hydroxyalse gene, dopamine transporter gene and monamine oxidase B (MAOB) gene. Furthermore, the Ala53Thr and Ala30Pro mutations of the alpha-synuclein gene were not found amongst this large Chinese population, indicating that variations of this gene are probably rare in Chinese. When candidate genes were studied amongst Caucasian Australians, the poor metaboliser genotype of CYP-2D6 was found to be weaky associated with PD (OR=1.36) in a meta-analysis. The length of the GT repeat alleles of MAOB gene were found to be significantly associated with PD (&gt188 base pair and 186 base pair) while angiotensin converting enzyme gene polymorphism was not found to be associated with PD. A pilot study was then conducted in Randwick, New South Wales to find out the latest prevalence of PD as well as putative risk factors in a random population. A validation study was carried out for a screening tool (questionnaire) for PD, which was then used for the main study. A total of 730 subjects were involved (527 in the community and 203 in institutions). The survey found that PD prevalence was between 3.6% and 4.9% (higher in aged care facilities). The putative risk factors positively identified were ???family history???(p&lt0.01) and ???exposure to chemicals at work or in surrounding environment??? (p&lt0.05). The age adjusted prevalence rate of PD revealed at least 42.5 % increase in the disease compared to 1966. We conclude that there may be an increase in the disease in Australia due to aging and other risk factors.

The role of dieting in the etiology and maintenance of bulimia nervosa remains unclear, and current treatments, which primarily aim to eliminate dieting behaviors, demonstrate limited efficacy. The purpose of this study was to conduct a randomized treatment trial to test whether healthy dieting maintains bulimic symptoms or effectively reduces this eating disturbance. Female participants (N=85) with full and subthreshold bulimia nervosa were randomly assigned to a 6-session healthy dieting intervention or waitlist condition and assessed through 3-month follow-up. Relative to control participants, intervention participants showed modest weight loss during treatment and demonstrated significant improvements in bulimic symptoms that persisted through follow-up. These preliminary results suggest that this intervention shows potential for the treatment for bulimia nervosa and may be worthy of future refinement and evaluation. Results also provide experimental evidence that dieting behaviors do not maintain bulimia nervosa, suggesting the need to reconsider maintenance models for this eating disorder. / text

Hirschsprung’s (HSCR) disease is a congenital disorder in which some enteric ganglion cells are absent in the colon due to incomplete colonization of neural crest cells (NCCs) in the hindgut, causing chronic constipation. A significant number of HSCR patients also clinically present with other NC- associated disorders, such as ventricular and atrial septal defects (VSD/ASD). A hypomorphic allele or SNP of a major gene, RET, causes or imparts susceptibility to HSCR. In particular, SNP (rs2435357) residing in the intron 1 of RET gene was found to be highly associated with HSCR and lead to reduced RET expression. However, the molecular basis of syndromic HSCR with VSD/ASD is largely unclear. In our project, with the use of the induced pluripotent stem cell (iPSC) technology, we aim to establish a patient-specific model unravel the etiology of HSCR and the associated disorders. To this end, 3 iPSC clones from a syndromic HSCR patient with VSD/ASD, carrying the RET risk allele in rs2435357 were generated. We attempted to use different protocols to directly differentiate iPSCs into NCCs with unique HOX expression patterns, corresponding to anterior cranial/vagal or posterior vagal/trunk NCCs. Consistently, the patient iPSCs displayed similar capacities in generating NCCs at all axial levels, marked by HNK-1 and 〖p75〗^NTR. Nevertheless, the patient NCCs and their derivatives exhibited severe migration and/ or differentiation defects in making neurons and smooth muscle cells. In particular, HNK-1+〖p75〗^NTR+ HOX+ (vagal/trunk) NCCs derived from patient-iPSCs were less migratory compared to the control NCCs, while no obvious migration defect was observed in their cranial counterpart, indicating that the migration defect was only restricted to the more posterior NCCs. In addition, these patient NCCs were less capable in generating neurons and readily biased toward generating glial cells. Intriguingly, the neural differentiation defects were restricted to NC lineage. The capacity of patient iPSCs to make various types of CNS progenitors and neurons was comparable to that of the control iPSCs, nicely recapitulating the patient’s phenotype where only enteric neurons, but not CNS progenitors were affected. Subsequent expression analysis revealed that patient NCCs express lower level of RET which is known to be regulating enteric NCC migration and differentiation. Whole transcriptome RNA sequencing analysis also revealed an enhanced expression of genes associated with gliogenesis and a reduced expression in genes associated with neurogenesis and migration. Moreover, the expression of a new candidate gene ALDH3B1 was shown to be significantly reduced in the HSCR-iPSC-derived NCCs that might contribute to the disease pathogenesis. In summary, these data suggests that reduced RET expression in HSCR patient NCCs may at least partly account for the disease phenotypes. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

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