Indwelling urethral catheters are the most commonly used medical devices and catheter associated urinary tract infections (CAUTIs) are one of the most common hospital acquired infections. Over 40% of CAUTIs in long-term catheterised patients may be caused by the bacterium Proteus mirabilis. Urease produced by this bacterium generates alkaline conditions by breaking down urea, leading to the formation of dense crystalline biofilm structures on catheter surfaces. This crystalline biofilm makes infections hard to treat and causes the blockage of the catheter lumen, resulting in the retention of infected urine leading to episodes of ascending urinary tract infections. The aim of this study was to identify genes and pathways involved in crystalline biofilm formation by P. mirabilis, in order to inform the development of novel strategies for prevention of catheter blockage. To accomplish this, a bank of random mini-Tn5 transposon mutants was constructed in the clinical isolate P. mirabilis B4. A total of 3840 transposon mutants were screened for phenotypic alterations in biofilm formation. A total of 575 mutants isolated exhibited altered biofilm formation, but comparable rates of growth to P. mirabilis B4 under assay conditions (310 biofilm enhanced; 265 biofilm deficient). The disrupted genes of a subset of 35 transposon mutants were successfully identified. After further phenotypic characterisation 12 transposon mutants were selected and their ability to encrust and block urethral catheters analysed using an in vitro model of the catheterised urinary tract (the bladder model). The bladder models yielded 4 transposon mutants with significant differences in the time taken to block catheters when compared to P. mirabilis B4. Two blocking deficient mutants were further analysed because these types of mutations are most likely to give insights relevant to the prevention of crystalline biofilm formation. Mutants STS8.1D7 and NHBFF9 were disrupted in aspects of the nitrogen metabolism and MFS family transport systems respectively. Timed bladder model experiments and chemical analysis of catheters of these mutants and the wild type B4 were then carried out to further evaluate the differences in crystalline biofilm formation. Overall, transposon mutants that took longer to block catheters displayed a lower level of encrustation after 10 h bladder model experiments. This was confirmed quantitatively by a significant reduction in calcium and biomass deposited onto catheters. Scanning electron microscopy (SEM) and environmental SEM (ESEM) further substantiated the quantitative methods illustrating clear differences in crystalline biofilm distribution for mutants that took longer to block catheters when compared to P. mirabilis B4. ESEM analysis optimized for this purpose allowed the examination of the crystalline biofilm ultrastructure in fine detail in its native, hydrated state and identified delicate calcium based crystal sheets which had not been visualised before. Additional flow chamber experiments confirmed that the ability of the two mutants to adhere to catheter biomaterials was not impaired, highlighting that the initial stages of biofilm formation were not associated with the genes disrupted for these mutants. Overall, the research conducted during this study identified 4 mutants differing in the time taken to block catheters, elucidating 4 genes that are involved in this complex phenotypic trait. Mutants with significant reductions in the ability to block urinary catheters displayed disruptions of the nitrogen metabolism and efflux systems which are believed to be involved in waste management in this bacterium. The inhibition of efflux systems in particular could be of potential value in the treatment or prevention of P. mirabilis crystalline biofilm formation by increasing its susceptibility to antimicrobials, and further investigation of these genes in the future could lead to the development of novel treatments for P. mirabilis CAUTIs.

The primary aim of this thesis was to assess the differences in response to a 3 x 1 minute SLR tensioner treatment between 3 sub-groups of individuals with spinally referred leg pain (somatic referred pain, radicular pain and radlculopathy). · Preliminary studies of the 3 outcome measures were required prior to the main study. These were: validity ofthe method to measure nerve excursion using ultrasound imaging (VI) which was assessed in pig nerves; repeatability of sciatic nerve excursion during a side-lying modified SLR measured with UI in the posterior thigh, and repeatability of pressure pain thresholds (PPT) and vibration thresholds (VT). The 3 outcome measures were repeatable and the sciatic nerve excursion technique was valid. Sixty seven participants were placed into one of the 3 sub-groups and further assessed to identify the presence of central sensitisation (CS). Five questionnaires were completed by participants to assess disability and psychological characteristics. Sciatic nerve excursion, PPT and VT were measured prior to and after a 3 x 1 minute SLR tensioner technique. No significant differences (p>O.05) were found for any of the 3 outcome measures between the 3 groups. Slight improvements in VT were seen in the radiculopathy group after treatment, which were not significant, but indicated that even in individuals with conduction loss, no detrimental changes to nerve conduction occurred after treatment. A varied response to nerve excursion was seen. Longitudinal nerve excursion at the posterior thigh decreased after treatment in individuals with pain below the knee; this location of pain being more common in the radiculopathy and radicular groups. The decrease in nerve excursion suggests regional changes to nerve compliance after treatment, which may have occurred at the nerve root. Since it was n.ot possible to measure nerve root excursion, these findings are speculative. Only 2 participants were identified with CS, suggesting a low prevalence of the condition in individuals with spinaUy referred leg pain. This may be-Clue to individuals with CS choosing not to participate in the study, or a limitation of the method used to identify CS. Disability and psychological factors were not significantly different at baseline between the 3 sub-groups, and were not correlated with the outcome measures. A 3 x 1 minute SLR tensioner technique in individuals with spinally referred leg pain of greater than 3 months of duration is not effective in improving pain or nerve conduction. However, it is not harmful, even in individuals with loss of nerve conduction. Changes to nerve excursion after treatment may be related to individual differences in nerve compliance, and possibly restriction of the nerve root.

The thiazolidinedione Rosiglitazone can protect pancreatic beta cells from the detrimental effects of free fatty acids. The aim of this study was to determine the differential effects of saturated fatty acids on beta cells and to identify the mechanisms through which Rosiglitazone can protect beta cell viability. Utilising the mouse beta cell line MIN6, transmission electron microscopy (TEM) was used to determine the effects of palmitate and Rosiglitazone on lipid uptake and cell ultra-structure. H/PI staining and MTT assays were used to determine cell viability.

Cytapheresis is an extracorporeal separation technique widely used in medicine for elimination of specific classes of blood cells from circulating blood. It has been shown recently to have clinical efficacy in various disease states, such as leukaemia, autoimmune disorders, rheumatoid arthritis, renal allograft rejection and sickle–cell anaemia. There are two major methods of extracorporeal leukocyte removal therapy in use in the clinical field, these are the centrifugal method, and the adsorptive method with fibre or beads. Leukocytapheresis using the leukocyte filter Cellsorba and granulocytapheresis using an Adacolumn has been proven to reduce leukocyte load in patients with rheumatoid arthritis and inflammatory bowel disease, but still has major limitations of specificity and selectivity. An ideal extracorporeal technique with non-thrombogenic materials and selective adsorption matrix is still in demand. Extracorporeal separation techniques can be improved by a combination of properties, such as mechanical properties of the column, an appropriate porosity of the matrix, biocompatibility of the polymer and chemical modification of the surface by immobilization of a ligand with an affinity towards target molecules or cells.

Pathways of care are available for people with cerebral palsy (CP) including various conservative and surgical interventions. A common aim of these interventions is to improve functional ability and prevent or reduce the prevalence of pain. There is currently no research evidence that demonstrates whether a surgical approach is more effective in achieving these aims than conservative treatment. Moreover, there is also no available research that explores the experiences of young people and their satisfaction with life in relation to the clinical management of their CP. The aim of this research was, retrospectively, to establish whether young people with CP who had experienced surgery as children to their lower extremities had better long term functional outcomes, less pain and a greater satisfaction of life than young people who had not experienced surgery as children. It also aimed to gain an understanding about their lives with CP and about experiences of the pathways of care that they had received.

This thesis examines the challenges for professional practice, socialisation, and identity in Physiotherapy. The government‘s modernisation agenda and society‘s increasing expectations of healthcare require physiotherapists to update their role, location, and identity. Physiotherapy has viewed identity as a fixed entity emphasizing coherence, continuity and distinctiveness. Socialisation has required the acquisition of a professional identity as one among several necessary assets‘ for novices. Yet how do physiotherapists come to be the physiotherapists they are?

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Accumulating evidence suggests that Positive Affect (PA) is beneficial in determining health-outcomes. Defined as ‘feelings that reflect a level of pleasurable engagement with the environment, such as happiness, joy and excitement’, PA has been associated with social and physiological factors as well as health practices. The work undertaken in this thesis aimed to investigate the relationship between PA and health-outcomes in people living with and without diabetes mellitus, independent of negative affect (NA).

A number of pathological conditions are associated with the build up of toxic substances within the systemic circulation. For example, renal and hepatic failure can lead to the accumulation of metabolites which are usually processed by these organs. There has been much interest over a number of years in techniques such as haemoperfusion that could help clear these toxins from the body and improve patient outcome. Haemoperfusion is an extracorporeal blood purification technique in which a patient’s blood is passed over a column containing a material designed to adsorb a board spectrum of biological toxic molecules. Direct blood contact with the adsorbent requires a material that is able to display good haemocompatibility whilst maintaining adsorption efficiency. Activated carbons (AC) have great adsorption capacity and have previously been used as haemoadsorbents. However the haemocompatibility of carbons has been questioned and they are often coated with biocompatible polymers that increase their haemocompatibility but also act as a barrier to the removal of larger toxins and middle molecules.

Patients with differentiated thyroid cancer (DTC) are usually managed with total thyroidectomy and subsequent radioiodine ablation of the remnant thyroid tissue. Since these patients become athyrotic, L-throxine (L-T4) therapy is required for life, in order to replace the thyroid hormones and also to suppress the endogenous thyroid stimulating hormone (TSH) which may have a growth-promoting effect on any residual thyroid cancer cells. The approximate dose required to achieve this suppression is about 2 g/kg. However, there is wide variation between patients in their L-T4 requirement. Although factors such as the timing of the dose, compliance, weight and age play important roles, genetic factors are also thought to be important in this dose variability. Therefore, the aims of this study are to identify and evaluate the association of polymorphisms in six genes [(iodothyronine deiodinases (DIO) 1, 2 and 3, paired box gene 8 (PAX8), thyroid stimulating hormone subunit β (TSHβ), and sodium iodide symporter (NIS)], involved in thyroid hormone metabolic and functional pathways with DTC risk and L-T4 dose requirement.