The work presented in this thesis concentrates on the local generation of AII. Preliminary experiments using wire myography were performed in human resistance arteries from normal subjects, obtained by subcutaneous gluteal at biopsy. In these vessels, AI stimulated a contractile repose that was dependent on activation of the AII type 1 receptor (ATIR). Thus, conversion of AI to AII can occur within the vasculature. This conversion was resistant to inhibition of ACE with enalaprilat in human tissue. In contrast, AI responses in rabbit arteries were almost completely inhibited by enalaprilat. Further investigation demonstrated that the combination of enalaprilat and the chymase inhibitor, chymostatin (but neither agent alone), inhibited the response to AI in human resistance arteries. Thus, a dual pathway for AII generation exists in human arteries, probably mediated by ACE and chymase. Since the significance of non-ACE AII generation may be greatest in patients taking ACE-inhibitors, further studies were conducted on resistance arteries from patients with chronic heart failure (CHF) who were receiving such medication, compared to patients with coronary heart disease (CHD). In patients with CHD a similar dual pathway to that observed in normal volunteers appeared to be present. However, in arteries from patients with CHF, the contribution of chymase to AII generation - as inferred from the effect of inhibiting ACE - appeared to be less. Thus, the activity of the enzymes responsible for AII generation may be modulated by either the syndrome, or its treatment.

The aim of this study was to define new quantitative parameters of dynamic Pelvic Floor Muscle (PFM) function using 2D transperineal (TP) ultrasound imaging combined with image processing methods (IPM). Ultrasound and digital vaginal data were obtained from a volunteer convenience sample of 23 continent and 9 Stress Urinary Incontinent (SUI) women recruited from the San Francisco Bay Area community, California, U.S.A. Two methods of IPM were used; speckle tracking for measuring displacement of the ano-rectal angle (ARA) and symphysis pubis (SP); and segmentation IPM for measuring displacement of the urethra. Good to excellent inter and intra observer reliability was established for processing the ultrasound images on stored audio-visual imaging files (AVI). Intraclass correlation coefficient (ICC) values: 0.61 to 0.99; 95% confidence intervals (CI) 0.08→0.84 to 0.97→0.99; standard error of measurement (SEM) 0.01to 0.25 cm. There was good agreement between measures on Bland and Altman analysis: mean difference 0.06 to -0.21 cm; 95% CI 0.02→0.45cm to -0.01→0.20cm. Validity of the IPM was confirmed with digital palpation, and furthermore indicated good sensitivity and specificity. Technical and methodological limitations of the IPM, and suggestions for future studies were discussed. Several research questions were addressed using TP ultrasound combined with IPM that enabled the dynamic evaluation of pelvic floor (PF) displacement throughout an entire manoeuvre, rather than limiting the quantification from static images at rest to the end of the manoeuvre. In this way, IPM determined unique quantitative data regarding the automatic displacement, velocity and acceleration of the ARA and urethra during a cough, Valsalva, voluntary PFM contraction, The Knack and a Transversus Abdominis contraction. During automatic events that raised intra-abdominal pressure (IAP), normal PFM function produced timely compression of the PF and additional external support to the urethra, reducing the displacement, velocity, and acceleration. In women with SUI, who have weaker urethral attachments, this shortening contraction did not occur; consequently, the urethra of women with SUI moved further and faster for a longer duration. Caution regarding the generalisability of this study is warranted due to the small number of women in the SUI group and the significant difference in parity between groups. However this non-invasive physiological measurement tool demonstrated a new way of assessing the PFM. It is envisaged that this study will provide the foundation for future studies with larger parity matched populations and eventually improve the rehabilitation of women with SUI and other PF disorders.

Total joint replacement is one of the most successful surgical procedures and is a proven treatment for arthritis. Despite low failure rates, the wide application of the treatment means that large numbers of prostheses fail and must be revised. Improved pre-clinical testing methods for these orthopaedic devices may assist in developing new prostheses with improved clinical results. Computational modelling of biological systems is becoming increasingly accurate and is a much quicker and cheaper alternative to physical testing, but continued development is necessary to ensure computational models produce accurate and reliable predictions of implant behaviour. Acrylic bone cements have been used as a method of fixation for over 50 years but despite improvements in cement handling techniques and numerous attempts to improve the mechanical properties of the cement in other ways, the cement is often highlighted as the weak link in the joint replacement system. Aseptic loosening is cited as the cause for the majority of revision operations and cement degradation has been shown to be a contributor to the loosening process. In-vivo, cement is subject to cyclic loads and these are the primary cause of cement damage. Residual stresses generated during the polymerisation of the cement are now thought to play a significant role in cement failure. This thesis examines the development of residual stresses as a result of thermal and chemical changes during polymerisation of the cement. Experimental techniques for characterising the evolution of materials properties during the polymerisation reaction are discussed. Differential scanning calorimetry was used to measure the reaction variables such as the activation energy of polymerisation. The development of an ultrasonic rheometry technique for monitoring the mechanical property evolution within a bone cement specimen is discussed. Computational models were generated to predict the reaction behaviour of the cement in terms of the heat produced and the evolution of the physical properties of the curing mass. Some advantages and disadvantages of candidate mathematical models have been evaluated and are discussed, along with applications in several implant fixation scenarios. The model compared well with experimental data and was used to predict thermal necrosis in the bone surrounding both a hip resurfacing implant and a knee replacement. Using the output reaction path produced by the thermal model a mechanical model was also produced simulating the shrinkage and mechanical property evolution exhibited by the polymerising cement. Two material models were compared with and without the effects of plasticity. Residual stress magnitudes were assessed in comparison with published values and showed better agreement when plasticity was included. Peak stresses were observed to occur during polymerisation. The location of the peak stresses were compared with experimental data on pre-load crack locations in the literature and showed good agreement.