A complete understanding of the pathogenesis of diabetic neuropathy continues to be elusive and as a result, progress in developing effective therapies has been disappointing. In particular, there is only limited understanding of why some patients suffer severe chronic pain, whilst others have painless symptoms. Assessment of the peripheral nerves frequently shows no differences between painful and painless diabetic peripheral neuropathy (DPN). There is growing evidence that the nerve damage in DPN is more generalized, involving the entire nervous system including the central nervous system (CNS). The advent of new radiological techniques, such as magnetic resonance spectroscopy (MRS) provides us with non-invasive modalities to study pathophysiological processes in greater detail. In addition, although a clear link between DPN and cardiac autonomic neuropathy (CAN) is recognised, the relationship of autonomic neuropathy with sub-types of DPN is less clear. The development of novel and sensitive measures of CAN, such as spectral analysis of heart rate variability (HRV), may allow the detection of subclinical abnormalities not detected by conventional autonomic function tests (AFT). The principal aim of this thesis was to better understand the nature of the relationship between painful and painless DPN with other parts of the nervous system, namely the CNS and the autonomic nervous system. In the first study the central processing of sensation in people with diabetes was assessed to determine whether central mechanisms have an important role in the perception of pain. In the second study, short-term HRV analysis was used to help define the nature of the relationship between CAN and painful and painless DPN more clearly. A secondary aim was to develop and validate a model incorporating HRV parameters as a sensitive measure of autonomic dysfunction. In the first study, 110 subjects with type 1 diabetes (20 no DPN, 30 subclinical DPN, 30 painful DPN and 30 painless DPN) and 20 healthy volunteers (HV) underwent detailed clinical and neurophysiological assessments (Dyck's NIS(LL)+7 staging criteria). They all underwent proton magnetic resonance spectroscopy of the left thalamic nucleus and somatosensory cortex to measure established markers of neuronal function using long echo time (LET) and neuronal integrity using short echo time (SET) spectroscopic sequences. The results demonstrated significant differences between painful and painless DPN. In the thalamus, at LET, subjects with painless DPN had significantly lower N-acetylaspartate (NAA) compared to other groups (ANOVA p<0.001). No differences were seen at SET. In contrast, in the somatosensory cortex, no inter-group differences were seen at LET, but at SET, the painless DPN group had lower NAA, compared to HV and subjects with diabetes but no DPN, whilst subjects with painful DPN had intermediate levels (ANOVA p<0.001). Various other differences were also seen between painful and painless DPN in other cerebral neurochemicals (particularly myo-inositol and glutamate), despite no differences between the groups in detailed peripheral nerve assessments. These results suggest that astrocyte dysfunction within a hyperglutaminergic state within the thalamus may be a key factor in the development of painful DPN. In a second study, a subset of these patients (20 HV, 20 no DPN, 20 painful DPN and 20 painless DPN) underwent short-term HRV analysis, to assess sympathovagal modulation of the heart rate. Various frequency domain and time domain parameters were assessed. The results showed that despite no differences in conventional AFT, subjects with painful DPN had greater autonomic abnormalities when assessed using HRV analysis, suggesting that it is a more sensitive tool to detect autonomic dysfunction. The greater autonomic dysfunction seen in painful DPN may reflect more predominant small fibre involvement and adds to the growing evidence of its role in the pathophysiology of painful DPN. In the third study, we demonstrated that this method of HRV analysis can be used to develop a sensitive tool to detect early autonomic dysfunction. Using discriminant function analysis, a model was developed which incorporated 8 HRV parameters as well as basic demographic data. It demonstrated a high degree of sensitivity and specificity. From the above studies it can be inferred that changes in neuronal physiology and function may be important in the perception of pain in DPN. They have demonstrated that DPN is a disease that affects the entire nervous system, including the CNS which should trigger a critical rethinking of the disorder.

An accurate estimation of physiological buffer capacity and total titratable buffer concentration of blood can give a great deal of insight into the physiological stability of a patient and yet it remains an undervalued diagnostic marker. This thesis highlights the need for a lab-on-chip device to quantify buffer capacity of whole blood samples by estimating the total titratable buffer concentration. Buffer capacity is quantified by titrating the buffer to its end point using monoprotic acids. More sophisticated ways include electrolytic titration, i.e. producing a proton flux using electrodes in a controlled environment. This thesis looks at a novel approach to electrolytic (coulometric) titration by inhibiting the production of OH ions during electrolysis and titrating the sample due to the proton flux from the anode. By definition, is the amount of acid or base added to change the pH of 1 litre of buffer by 1 pH unit. The carbonic acid bicarbonate buffer system is the most important buffer that maintains the body's pH within a stable range. To quantify this buffer's total buffering concentration, it is important to know and indicate its titration end point which signifies the total exhaustion of all buffering constituents. Colorimetric indicators have been used to indicate this end point which can be quantified through cameras or spectrophotometric techniques. Using this novel coulometric titrator and the colorimetric end point detector, this thesis presents a portable lab-on-chip prototype to spectrophotometrically quantify total titratable buffer concentration. Clinically, this device could benefit patients with sickle cell disease, nephritic disease and those admitted in accident and emergency wards. This research work is aimed at presenting a proof-of-concept for a device that can titrate nano-litre samples and be able to detect the end point of a titration in a controlled way.

This thesis aimed to explore the use of the Common Sense Model (Levanthal, 1980) in cardiovascular populations. The literature review critically evaluates the application of clinical interventions developed using the Common Sense Model (CSM), in a cardiovascular disease population. The research report used a cross-sectional design to investigate the relationship between illness representations using the CSM, coping, and psychological and functional outcomes in a post-stroke population.

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The dissertation is divided into two separate experiments that explore the effects of visual-spatial learning on PSD-95 dorsal hippocampal expression. Specifically, the aim of these studies was to explore the effect of learning an assay, the Hebb-Williams mazes, on the protein expression of PSD-95 in Fmr1 KO mice. PSD-95 is an important scaffolding protein hypothesized to be involved in learning and memory. In cellular models of Fragile X Syndrome it has been shown to be dysregulated but it has never been measured following behavioural learning. Establishment of a deficit using an ecologically valid behavioural assay could lead to the development of novel interventions. Study one employed a subset of the Hebb-Williams mazes of various levels of difficulty to evaluate PSD-95 protein expression in Fmrp intact and Fmr1 KO mice following learning. The results revealed significant increases in PSD-95 protein expression in control runners when compared to Fmr1 KO mice. There was a negative correlation between PSD-95 protein levels and mean total errors on the mazes meaning that as expression was increased, errors were decreased. The goals of study two were to reverse the molecular and behavioural deficits using pharmacological antagonist treatment shown to be effective in cellular models of Fragile X Syndrome. Fmr1 KO mice were treated with either saline or 20 mg/kg of a metabotropic glutamate receptor antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP). Relative to saline treated controls, drug treated Fmr1 KO mice made fewer errors on the same subset of Hebb-Williams mazes used in study one. Latency to complete these mazes did not differ between groups, indicating that MPEP treatment does not adversely affect motor functioning. Protein assessment revealed that PSD-95 was selectively rescued in MPEP treated mice and not saline controls. Similar to study one, a negative correlation between PSD-95 protein levels and mean total errors was observed. When taken together, these studies indicate that protein deficits are associated with a deficit of learning that can be reversed with a selective glutamate receptor antagonist. One of the strengths of the Hebb-Williams mazes is that performance is measurable without floor or ceiling effects, which plague other common behavioural assays. These data further suggest that pharmacological antagonist treatments may be promising in correcting the learning deficits in human Fragile X Syndrome patients.

As customer demands become more stringent for canbody stock, it becomes essential to understand the complex interaction between the processing conditions and resulting product properties. This research focused on investigating the influence of homogenization process parameters (heat-up rate, soak temperature and time) on the microstructural evolution of an AA3104 aluminum alloy used for canbody stock. Experiments were conducted on samples taken from an industrial D.C. cast ingot and homogenized in a programmable temperature controlled laboratory furnace under various thermal profiles (i.e. homogenization temperatures 550°C, 580°C and 610°C at various heating rates and homogenization soak times of up to ten hours). The samples were then characterized in terms of their microstructure (retained manganese in solid solution, percentage a-phase, and size distribution and density of dispersoids). The homogenization process parameters were found to affect the evolving microstructure profoundly with: • An increase in heat-up rate favoring a reduction in the number of evolving dispersoids. • An increase in soak temperature increasing the Mn in solid solution, and decreasing the number of dispersoids that form. • An increase in soak time up to 3 hrs increasing the volume percent of α- Al₁₂(Fe,Mn)₃Si. Based on this work, a homogenization profile for optimum microstructure and texture development would include a fast heat-up rate to a high soak temperature (610°C) with moderate soak times (up to 3 hrs). / Applied Science, Faculty of / Materials Engineering, Department of / Graduate

Purpose of the Study: The primary aim of this research is to demonstrate the safety and efficacy, or lack thereof, of percutaneous cholecystostomy placement as a management option in patients with acute cholecystitis (AC), not suitable for cholecystectomy and not responding to best medical management. The secondary aim of this research is to investigate the feasibility and complexities of interval cholecystectomy in this cohort of patients, with respect to the conversion rate to open, operating time and performing a subtotal cholecystectomy. Background: Acute cholecystitis is a complication of cholelithiasis (gallstones) and one of the most common admission diagnoses in Acute Care Surgery Units. The standard of care, according to the Tokyo Guidelines (1-4), for the management of acute cholecystitis, includes the immediate use of empiric antimicrobial drugs and index-admission laparoscopic cholecystectomy. A (>72 hour) delay between the onset of symptoms and presentation and initiation of medical care, as well as high operative risk patients are the two main reasons for diversion from this protocol of care. In the case of delay, the guidelines suggest the use of interval (six week) cholecystectomy as appropriate care. Index admission cholecystectomy in the setting of delayed presentation has been associated with increased morbidity. As inflammation of the gallbladder progresses, the tissues become more oedematous, with anatomic distortion and therefore increased difficulty in identifying important structural landmarks during LC. This difficulty increases the risk of operative complications, including bleeding and common bile duct injury, the most feared complication of LC. In addition to this distortion, adjacent surrounding organs may be involved in this inflammatory complex, thereby also being placed at risk of injury during dissection. In such circumstances, alternative methods of controlling disease progression may be necessary. 7 According to the Tokyo guidelines (1-4), AC can be classified into three grades of severity, namely mild (grade I), moderate (grade II) and severe (grade III). The grading system takes into account clinical and laboratory parameters, with organ dysfunction representing more advanced disease. Percutaneous cholecystostomy tube placement has been described as a method to achieve sepsis control in patients with severe AC, in which case LC may not be safe, owing to operative and high anaesthetic risk. The use of percutaneous cholecystostomy is well established in critically ill patients with acalculous cholecystitis and its safety and efficacy have been reported in many studies (5-11). Early LC has recently been shown to reduce the rate of major complications as compared to PC, even in high risk patients (15) The management of one subset of patients with acute cholecystitis remains unclear. This group comprises those with delayed presentation, in whom index-admission surgery is not advised, but who subsequently do not respond to best medical therapy. They have traditionally undergone urgent cholecystectomy but suffer higher rates of both morbidity and mortality (12- 14). In the current setting, patients often present with a delay since the onset of symptoms, rendering index-admission cholecystectomy unsafe. This problem is exacerbated by the lack of urgent operating theatre time, often with more urgent cases taking preference, thus delaying operative care beyond what is deemed safe by the Tokyo guidelines. The vast majority of patients are managed by interval cholecystectomy, leaving only the mentioned unresponsive subset. Recent reports have established the safety of the use of percutaneous cholecystostomy tube placement in patient groups that include this subset (severe sepsis, septic shock, local gallbladder rupture, progressive intolerant pain and persistent fever) (5-11).

In this thesis, we compute minimal presentations in terms of generators and relations for the oriented cohomology rings of several semisimple linear algebraic groups of ranks 1 and 2 over algebraically closed fields of characteristic 0. The main tools we use in this thesis are the combinatorics of Coxeter groups and formal group laws, and recent results of Calm\`es, Gille, Petrov, Zainoulline, and Zhong, which relate the oriented cohomology rings of flag varieties and semisimple linear algebraic groups to the dual of the formal affine Demazure algebra.