published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

Methylenetetrahydrofolate reductase catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for the remethylation of homocysteine to methionine. Patients with severe MTHFR deficiency have $<$20% residual enzyme activity, moderate hyperhomocysteinemia, vascular lesions and neurological dysfunction. Mildly-deficient individuals with a thermolabile enzyme are at increased risk for developing cardiovascular disease. / Two MTHFR sequence changes were identified. The first was a C to T transition at bp 764 altering a proline to a leucine codon; this change was found in one severely-deficient patient. The second was a C to T transition at bp 677, substituting a valine for a highly-conserved alanine codon. The $ rm A to V$ substitution was identified on 35-40% of chromosomes. Expression of the $ rm A to V$ mutation in prokaryotic cells revealed increased thermolability over the wild-type enzyme. Genotyping for the $ rm A to V$ mutation in three vascular disease studies showed that it was associated with mild hyperhomocysteinemia, a risk factor for vascular disease. / The preventative effects of folate supplementation on the occurrence and recurrence of neural tube defects (NTDs) have been repeatedly demonstrated. The curly-tail (ct) mouse model for NTDs was used to investigate the involvement of MTHFR in these defects. Ct mice had significantly increased homocysteine levels although differences in MTHFR activity were not demonstrated. The mouse MTHFR gene was mapped to distal chromosome 4, close to the major gene for NTDs in ct. MTHFR is suggested as a candidate locus for the ct defect.

People with diabetes are at a greater risk of burn injuries than those without diabetes. This stems from the epidemiological profiles of the conditions and the effects of morbidities associated with diabetes. Both conditions share some similarities in terms of metabolic alterations and suboptimal immune functions which may result in poor outcomes for patients. For that reason, it is reasonable to deduce that patients with diabetes are a challenging group to manage in burns units. However, this deduction should be taken cautiously because of lack of supporting evidence. Accordingly and after consulting with clinical experts, the research in this portfolio investigated the association between diabetes and burn injuries. In particular, two different aspects of this association were investigated in two individual quantitative and descriptive inquiries. The first was a case note review of patients hospitalised with a principal diagnosis of a foot burn injury in a large tertiary hospital in South Australia from 1999 to 2004. The second study investigated management of diabetes in burns units treating adults. This study is an e-mail survey of clinical leaders of burns units in Australia, New Zealand, Hong Kong and the United Kingdom. The clinical leaders were approached indirectly through key liaison persons in each identified unit. In the first study, outcomes for twelve subjects with and fifty-two without diabetes were described using descriptive and non-parametric statistics. In the second study, descriptive frequencies and content analysis were adopted to analyse twenty-nine responses from seventeen out of thirty burns units which participated in the study. Supporting findings in the literature, the first study showed that burn injuries among subjects with diabetes were mainly resulted from household devices. There were no statistically significant differences between subjects with and without diabetes in terms of size and depth of burn injuries and treatment received. In spite of this, there was a statistically significant association between diabetes and the experience of local post-burn complications and longer duration of hospitalisation. The second study indicated that more than twenty-five percent of the respondents believed that multidisciplinary centres should only occasionally be involved in the process of care. Participants reported that the individual profile of each patient plays a major role in determining the management of diabetes. Additionally, it was found that the insulin sliding scale was commonly used in the management of diabetes in burns units. The association between diabetes and a burn injury is a serious issue in terms of health and cost. This association need be addressed firstly and most importantly at the prevention level; secondly through proper management of both diabetes and burns. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1285462 / Thesis (D.Nurs.)--Population Health and Clinical Practice, 2007.

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Angiogenesis is a process of new blood vessels sprouting from the pre-existing vasculature, and mediated by multiple angiogenic and anti-angiogenic factors. Disturbance of the balance often leads to development of neovascular diseases. Neovascularization affecting the eye is a common cause of visual impairment and even blindness, particularly when corneal or choroidal neovascularization (NV) is involved. While there are effective treatment modes for ocular neovascularization, they are expensive and only inhibit disease progress. Since herbal medicine has been applied for anti-angiogenesis and anti-carcinogenesis therapies, we investigate the anti-angiogenic effect of selected herbal molecules: isoliquiritigenin (ISL), a flavonoid from licorice; epigallocatechin gallate (EGCG), a polyphenol from green tea; and resveratrol (Rst), a polyphenol phytoalexin derived from grapes. / In conclusion, by in vitro and in vivo studies, we showed that ISL, EGCG and Rst contributed to anti-angiogenesis via different biological mechanisms. We propose that these three herbal molecules (ISL, EGCG and Rst) are candidate anti-angiogenic agents for the treatment of ocular angiogenesis diseases. Their distribution profiles and pharmacokinetic properties should be investigated. / Results showed that sub-toxic levels of ISL (10 microM), EGCG (50 microM) and Rst (10microM) effectively suppressed endothelial cell proliferation and migration in the scratch-wound assay. Treatment with ISL was found to significantly up-regulate PEDF, which is known as a potent angiostatic factor. EGCG and Rst downregulate VEGF signaling cascade by suppressing Akt and FAK activation and affecting MMP-2, MMP-9 expression. In vivo angiogenesis assays further showed the suppressive effect of ISL, EGCG and Rst on neovascularization in three different animal models. Application of ISL at 1 microM showed the suppressive effect on chick CAM assay, corneal NV and choroidal NV assays consistently, the most effective dosage was close to 10 microM. EGCG at 1 microM showed the effect to reduce chick CAM vessel formation and corneal NV, and at 10 microM (the lowest tested concentration) to suppress choroidal NV in mice. Variable effects were observed in Rst treatment. Rst at 10 microM prohibited vessel growth in chick CAM, and 1 microM suppressed corneal NV formation and 2 microM deterred choroidal NV development. / This thesis contains two major parts. The first in vitro cell-based analysis investigated the toxicity of these herbal chemicals and their effect on endothelial cell growth and migration. The expression profile of vascular endothelial growth factor (VEGF) signaling cascade events, including Akt and focal adhesion kinase (FAK) activation, VEGF, pigment epithelium-derived factor (PEDF) and matrix metalloproteinases (MMPs) were examined by Western blotting. Then three in vivo models were established to study the effect of these herbal chemicals on angiogenesis. They were (1) developmental angiogenesis in chick chorioallantoic membrane (CAM), (2) pathological angiogenesis in silver nitrate cauterization-induced corneal neovascularization in BALB/c mice and, (3) laser photocoagulation-induced choroidal neovascularization in C57BL/6 mice. Changes of vascularization were determined by qualification of vessel number changes on the edge of gelatin sponge in 24 hours (chick CAM assay), measurement of vascularized area, live imaging of vessel leakage (fundus fluorescence angiography, FFA) and immunochemistry using antibodies specific for endothelial cells (corneal & choroidal NV assays) respectively. / Liu, Huanming. / Adviser: Chi Pui Pang. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 155-180). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Atherosclerosis is a vascular degenerative disease leading to progressive thickening in the intima of large and medium sized arteries through the formation of plaque that is very rich with cholesterol. The cholesterol is carried by LDL (low density lipoprotein) particles which pass through the endothelium and accumulate in the intima. The passage of LDL is influenced by wall shear stress which activates physiological responses of the endothelium. However, the causal relationship between the physiological responses and their effect on LDL mass transport is not fully understood. To obtain blood flow patterns in human carotid arteries, a fluid structure interaction (FSI) computational approach is employed, based on the in-vivo arterial geometry constructed from black blood magnetic resonance images (BBMRI) and flow rate boundary conditions obtained from phase contrast images (PC). Wall shear stress (WSS) on the luminal surface is computed, and this variable is related to the formation of leaky junctions, which is a major transendothelial pathway for LDL. A model for the fraction of leaky junction at a surface is incorporated into the overall computational scheme for mass transport, along with pore theory. The theoretical model is applied to images from three human carotid arteries in which the degree of disease ranges from mild to moderate. Maximum mass flux is predicted to be in the downstream region of stenoses where WSS is low, and this result is consistent with the clinical observation of plaque progression downstream of the stenosis. The hypothesis that the majority of LDL enters into the intima through leaky junctions is supported by observation of similar distributions between the pattern of volume flux via leaky junctions and mass flux. These studies suggest that mass flux of LDL can be a predictor to indicate areas with potential for plaque formation and progression in human carotid artery disease.

The thesis explores chronic leg ulceration experienced by young people who inject drugs (PWID). The applied health research study, in two phases, used a sequential explanatory mixed methods design. Phase 1 involved a survey of 200 people who injected drugs to investigate the prevalence of skin problems and leg ulceration, together with the identification of risk factors for ulceration. Phase 2 involved a series of fifteen qualitative semi-structured interviews that explored the results relating to risk factors with a sample of PWID who had experienced leg ulceration, and investigated participants’ perceptions of appropriate harm reduction methods. Main findings There were three research questions in this study: 1) What is the extent of skin problems and chronic leg ulceration in young people who inject drugs? The study identified a high prevalence of leg ulceration as 15%. 60% of the sample had experienced a skin problem. Each reported skin complication is clearly defined. 2) What causes chronic leg ulceration in young people who inject drugs? Leg ulceration experienced by PWID in this study was directly linked to deep vein thrombosis (DVT), as well as injecting in the groin and the leg. DVT was strongly associated with groin and leg injecting. The acceptance amongst injectors of the groin and leg as a site of choice has occurred with a lack of awareness of the long-term consequences of damage to the limb. 3) What are appropriate harm reduction measures in young people who inject drugs? Harm reduction methods related to the development of leg ulceration have been absent across schools and drug services. Training for healthcare workers which enables them to identify risk factors should be developed, and harm reduction information related to leg ulceration should be included in drug education within schools, and instigated within drugs services. This applied health research has led to a number of practice-focused recommendations surrounding clinical care including early detection of venous insufficiency and accessible services to prevent, assess, and treat venous disease in PWID. The original contribution to knowledge is three-fold: 1. Leg ulcers have been found to be highly prevalent in young people who inject drugs. 2. Ulceration is predominantly caused by venous thrombosis due to injecting in the legs or groin. 3. Harm reduction related to the development of venous disease has lacked impact and effect.

Finally, the system of vascular interventional radiology simulator is discussed by integrating all presented techniques and designing a trackball mouse based hardware sensors. Training experiments demonstrate that the presented techniques benefit rapid development of realistic and interactive vascular interventional radiology simulators. / Fourth, in order to clearly visualize vascular networks and the placement of instruments while treating the lesion, a physics-based simulation for angiography procedure is presented based on navier-stokes equation and semi-lagrangian method. The multi-scale vessel grid is reconstructed for flow distribution, and point sprites based rendering is adopted to preserve real-time visualization of the procedure. The experiments demonstrate that our results are more realistic compared to previous methods and are closer to the real angiography procedure. / In order to build a high fidelity interventional simulator for physician training and surgery planning, accurate reconstruction of three dimensional vascular network, real-time simulation of angiographic medium propagation and physics-based simulation of interaction between surgical instruments and vessel wall are absolutely indispensable. Thus, first, a methodology for geometric vascular modeling is proposed. As the reconstructed models are essential for many subsequent applications such as deformable modeling and visualization, a series of methods are proposed based on the parallel transport frames in order to maintain high mesh quality of these models. An improved bifurcation modeling method and two novel trifurcation modeling methods are developed based on 3D Bezier curve segments in order to ensure the continuous surface transition at furcations. To solve the twisting problem caused by frame mismatch of two successive furcations, a frame blending scheme is implemented. A curvature based adaptive sampling scheme combined with a mesh quality guided frame tilting algorithm is developed to construct an evenly distributed, non-concave and self-intersection free surface mesh. In terms of surface mesh quality criteria, our methodology can generate vascular models with better mesh quality than previous methods. / Second, we extend our geometric modeling method for illustrative visualization of vasculature, which is an indispensable component in medical education and training. Illustration of vasculature accentuates depth perception and provides a specific manner to identify the branching pattern and topology of vascular structure, which is crucial for therapy planning and real surgery in order to give an effective treatment. With advanced GPU acceleration techniques including render to texture (RTT) , framebuffer object (FBO) and fast image convolution, a real-time visualization can be achieved. / Third, an interactive simulation of angioplasty procedure is reported. To achieve an efficient modeling of soft tissue deformation and virtual device mechanics, mass spring models are adopted to construct the deformable models of vessel wall and stent. By designing a quasi-equilateral triangular mesh model of blood vessel and stent, a linear spring coefficients setting method is adopted to achieve the same accuracy compared with finite element method. With the employment of Physics Processing Unit (PPU), a real-time simulation of the interaction between blood vessel wall and surgical device is developed for vascular interventional radiology simulation. / Vascular diseases have been the leading cause of death worldwide. Interventional procedures are an increasingly promising therapy for treating vascular diseases, which are usually done by a guidewire-catheter combination under the fluoroscopic guidance. However, due to the complicated vascular network, bending of surgical instruments and the risk of vessel injury, these techniques need to be performed by highly trained and experienced specialists. Virtual reality based training of these procedures offers high flexibility and cost effective alternative. Furthermore, it allows training evaluation and accelerates learning process without risk to patients, therefore has distinct advantages than traditional training methods on animals or cadavers. / Guo, Jixiang. / Advisers: Pheng-Ann Heng; Tien-Tsin Wong. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 97-111). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

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Objectives: To date little is known of the interaction between diabetes and sex hormones in the vasculature. A number of studies suggest that premenopausal diabetic women loose their gender based cardiovascular protection. However, there is insufficient evidence to explain the mechanism underlying the loss of this gender based cardioprotection in premenopausal diabetic women. The objectives of this study were to investigate whether there is a gender difference in the aortic endothelial function in · streptozotocin (STZ, 58 mg/kg, iv)-induced diabetic rats, and the potential role of superoxide and cyclooxygenase (COX) metabolites in diabetes-induced vascular dysfunction.