Schistosomiasis is one of the most important helminth infections in man, infecting an estimated 200 million people worldwide leaving 20 million people with severe morbidity and causing 20,000 deaths a year. Of chronically infected patients approximately 8 per cent develop the periportal fibrosis first described by Symmer in 1908 known as clay-pipe-stem fibrosis. Little research has been carried out in the disease with regards to fibrosis alone. The main cell within the liver responsible for fibrosis in a number of liver conditions is the hepatic stellate cell (HSC). This cell is located in the liver sinusoid and is responsible for matrix maintenance and storage of vitamin A within the liver. Upon insult to the liver this cell undergoes a process of transdifferentiation into a myofibroblast responsible for production of a scar like matrix observed in liver fibrosis. This thesis investigates interactions between viable and non-viable schistosome eggs with this cell in an in vitro model developed within this investigation. This model makes use of the HSC human cell line, LX-2. HSC demonstrate dose and time-dependent reduced expression of fibrogenic genes for a-smooth muscle actin, connective tissue growth factor and type I collagen but increased expression of adipogenic peroxisome proliferator-activated receptor y. HSC exhibited elongated fine processes and reduced size, increased accumulation of lipid droplets and reduced expression of a-smooth muscle actin and F-actin stress fibres. Additionally, schistosome eggs prevented the HSC fibrogenic response to exogenous transforming growth factor-p. This supports previous research to suggest that fibrosis observed in schistosomiasis is TGF-3 independent and may additionally explain why myofibroblasts are observed towards the edge of granulomas and not in the immediate vicinity of the eggs themselves. In summary, viable and non- eggs blocked fibrogenesis in HSC, a finding which may have implications for our understanding of the fibrotic pathology in S.mansoni infections.

Standard surgical training consists of the acquisition of theoretical knowledge complemented with practical observation during surgery and, at some advanced stage, performing the surgical procedures on live patients under the supervision of qualified surgeon. Also, experienced surgeons still require training to perform rare and complex cases. However, a potentially contradictory situation exists whereby patients' expectations of surgical experience are obviously high, whereas clinical governance requires surgeons' track records to be established before they move to operate on live patients. There is increasing fear of litigation among healthcare professionals, along with worktime legislation which limits the hours available for training. Therefore there is a need for surgical simulation systems for training to overcome the initial lack of experience and for planning of rare and complex procedures. In this thesis we have developed a Cataract Eye Surgery Simulation system (CESS) with the capability to simulate, in addition to the basic surgical interaction, the main steps of cataract eye surgery, and which can be used as a teaching and training method to train medical students in a realistic environment. The CESS, in its present form, provides users with an interactive, affordable, easy to learn, risk-free, reusable and adaptable means for training in cataract eye surgery procedures. In this thesis we have presented and examined different modelling techniques that have been used for soft tissue simulations. In particular, we have been interested in the computation complexity of the models, numerical stability, and physical realism. Within this context, we proposed the Circular Wave Model (CWM) which is capable of modelling homogeneous, surface objects and is fast enough for applications such as surgery simulations. The CWM algorithm is derived using the analogy of water waves produced when water is hitby stone. Two dimensional (2D) and three dimensional (3D) objects can interactively be deformed with the CWM. We have put forward a new technique to assign stiffness and damping coefficients to springs of the mesh being manipulated and the spring that connects the virtual surgical instrument to its manipulated mesh.

The number of surgical procedures is increasing worldwide. The Audit Commission set a target that only 5% of patients should experience severe post-operative pain. Major abdominal surgery is a cause of severe post-operative pain. Epidural analgesia is regarded as the "gold standard" for treating this category of post-operative pain. A randomised controlled trial conducted by the author suggested that it was possible to have 95% of patients pain controlled, but with a high incidence of hypotension. Hypotension can restrict rather than enhance a patient's recovery after surgery. Building on this work, this thesis will explore whether it is possible to provide good analgesia without serious side effects in the workplace. Methods This study reports the results of a prospective observational study (n = 480) designed to both describe the technique and examine the association of various factors with pain scores and the incidence of hypotension. Classical statistics and statistical process control methods, a unique feature of the study, were employed to analyse and learn from the data. Results Twenty-eight percent of patients reported severe pain. Lower pain scores were associated with female gender and elective surgery. An association exists between increasing age and decreasing pain scores on the first day. The incidence of hypotension was 56%. Low pain scores strongly correlated with hypotension. Many failures occurred due to technical problems. Recommendations It is important for nursing professionals to know the true risk/benefit profile of postoperative epidural analgesia as it is ward nursing staff who are primarily responsible for monitoring the effectiveness of the technique, the patients' safety, and intervening to improve poor quality pain control. The results of this study suggest that epidural analgesia is far from the gold standard for postoperative analgesia. An urgent debate needs to take place to establish its true place in the management of postoperative pain.

Ischaemia reperfusion injury of skeletal muscle is a major cause of morbidity and mortality in various surgical specialities. Developing a protective method or pharmacological agent that will limit this damage will be of considerable benefit to both patients and doctors. I have used potassium channel openers and calcium as preconditioning agents. The results show that potassium channel openers are a viable option whereas the use of calcium can exacerbate muscle damage. I looked at various protocols of ischaemic and pharmacological preconditioning. The results from both ischaemic and pharmacological preconditioning have shown a comparable decrease with some pharmacological agents in the extent of skeletal muscle infarction both in the early and late period of reperfusion. This decrease in the extent of muscle infarction is associated with changes in the levels of nitric oxide in the circulation. There was preservation of skeletal muscle oxygenation in preconditioned muscle. I have shown that preconditioning of skeletal muscle is a viable option in trying to reduce the amount of damage caused by ischaemia reperfusion injury.

Since its introduction by Inoue in 1984, percutaneous balloon mitral valvotomy (BMV) has been widely used as an alternative to surgery for the treatment of rheumatic mitral stenosis. The success of BMV relies on heavily on the presence of value morphology suitable for balloon dilation and cardiac ultrasound has become the cornerstone for assessment of patients undergoing this procedure. In young patients with pliant valves and predominant commissural fusion, the success of BMV has been well documented and for such patients this is the treatment of choice. However, with the disappearance of rheumatic fever in developed countries, patients presenting with mitral stenosis to centres such as ours are typically elderly. They often have anatomy less suitable for balloon dilation but surgical risk is also much higher. Experience of BMV in this population is limited, results are less predictable and the selection of patients less straightforward. In a centre with the largest experience of BMV in the UK, I have reported on a series of 405 consecutive patients, mean age 60.7 years, 27.7% over 70 years old. Longer term outcome was recorded in 300 patients over 10 years. I studied the anatomical and clinical characteristics of this diverse group of patients. I evaluated the role of BMV as a definitive treatment where echocardiography showed valve anatomy to be suitable for balloon dilation and as a palliative option in older patients with severe degenerative valve disease but high surgical risk. I identified factors predicting immediate haemodynamic and longer term functional success. I studied in detail the strengths and limitations of two-dimensional transthoracic, transoesophageal and three-dimensional echocardiography for the assessment of patients undergoing BMV. Importantly, I have been able to show that specific evaluation of mitral commissural morphology, a feature not included in current knowledge scoring systems, was a powerful predictor of outcome and could improve the selection of patients referred for BMV in this older population.

The procedure of open perforator ligation was popularised by Linton and Cockett but became less favoured as it was associated with frequent wound complications, prolonged stay in hospital and mixed results in reported series. Two technological advances have resulted in the impetus to reappraise the indications for surgical interruption of calf perforating veins. Duplex ultrasound is a non-invasive investigation that has allowed anatomical and functional information on blood vessels and flow to be gathered safely and painlessly. Secondly, minimal invasive surgical instrument technology allows interruption of the medial calf perforating veins with expectation of reduced complication rates. The aim of the present work therefore, is to define the role of calf perforating veins in the development of the complications of chronic venous insufficiency. Deteriorating clinical status of the limb was associated with increasing number and maximum diameter of medial calf perforating veins. The number and proportion of these vessels demonstrating bidirectional flow (incompetence) also increased with deteriorating clinical findings. Incompetent calf perforating veins were found to be associated with main stem venous reflux in the superficial and deep systems, but were rarely found as the sole venous abnormality. Surgical correction of the main stem venous reflux resulted in the correction of the physiology in the majority of incompetent perforating veins (IPV). The minimally invasive approach to the interruption of IPV showed several advantages over the open approach in terms of documented complications and post-operative stay in hospital. The present work demonstrates associative evidence of a link between the presence of IPV and the development of the complications of chronic venous insufficiency, evidence that saphenous surgery alone will correct IPV physiology without direct intervention to perforators, if the deep system is normal, and also evidence that minimally invasive perforator surgery is associated with few complications over and above those expected for routine varicose vein surgery.

Pigs transgenic for hDAF were created by microinjection of human DNA into fertilized pig oocytes. Ten control hearts, eight heterozygous hDAF transgenic hearts and one homozygous hDAF transgenic heart, were transplanted heterotopically into the abdomen of non-immunosuppressed cynomolgus monkeys. Fifteen heterozygous transgenic and five control hearts were then transplanted heterotopically into the abdomen of immunosuppressed cynomolgus monkeys. Of the transgenic hearts ten were immunosuppressed with a high cyclophosphamide (CyP) regimen (group I) and five were immunosuppressed with a low CyP regimen (group 2). All control hearts were immunosuppressed with the high CyP regimen. The hDAF transgenic hearts in the high CyP group had a median beating time of 40 days (range 6-62 days) compared with 9 days (range 8-34 days) for those in the low CyP group. This difference was statistically significant (p <0.05). The control grafts had a median beating time of 55 minutes (range 2-180 minutes). The difference between the control grafts and the high CyP transgenics was statistically highly significant (p <0.001). The difference between the control grafts and the low CyP transgenics was also statistically significant (p <0.05). All control hearts were hyperacutely rejected. Only two hearts in the high CyP group were lost due to AVR, on days 6 and 62: all other hearts showed no evidence of rejection. All hDAF transgenic hearts in the low CyP group underwent AVR. These results confirm that HAR can be abrogated with the hDAF transgene in this pig-to-primate model and that prolonged survival can be achieved. Perioperative CyP would appear to be an essential component of this regimen, without which, graft loss due to antibody-mediated AVR is encountered. Finally, hDAF transgenic pig hearts were transplanted both heterotopically, and orthotopically into immunosuppressed baboons. No graft underwent HAR and survival of heterotopic pig-to-baboon heart xenografts for up to 21 days was achieved.

Quality assessment in healthcare is an essential part of governance culture. Clinical outcomes and research output are routinely assessed with national and global comparisons commonplace in a bid to continually drive up standards. While the subject of surgical training has received greater exposure in recent years, there remains no rigorous assessment of surgical training quality in the same way as clinical and research outcomes. To improve surgical training quality, high quality training must first be defined to permit evaluation of training and facilitate identification of methods to raise standards. Variability of global surgical training programs is first identified by comparing the national surgical curricula of a sample of countries against defined standards for curricula. A questionnaire study further explores the variations between the two nations with the most contrasting surgical curricula. Qualitative methodologies, including semi-structured interviews and a global Delphi consensus study, are subsequently employed to define high quality surgical training. The results have enabled the development of a surgical training quality assessment tool (S-QAT). The S-QAT has been piloted in the North West London training region where variability in surgical training quality has been confirmed. Defining high quality training has facilitated the development and piloting of interventions to improve surgical training quality. The first intervention employs video-based coaching to improve surgical skills. The second intervention is an intensive, immersive week of simulation training to ease the transition from medical student to Foundation Doctor. These interventions demonstrate that improvements in training quality can be made without the need to rely on increasing the quantity or time in training. The foundations for robust evaluation of surgical training quality have been constructed. Evidence-based medicine is the gold standard for patients; evidence-based training of surgeons will ensure standards are maintained for the next generation of patients.

Carotid intervention for stroke prevention in the form of carotid artery stenting has been performed in clinical trials since the beginning of the 1980's. Improvements in the operative technique and pharmacology used during the procedure have reduced complication rates since stenting began. Long term follow up of the Sheffield data set has shown that patient selection has the most impact on reducing adverse outcomes from the procedure. Multivariable analysis of the Sheffield database detailed in this thesis has shown that retinal events have a lower risk of adverse outcomes than cerebral events, and clopidogrel use at the time of stenting prevents adverse events. Recurrent stenosis of more than 50% also increases risk for recurrent stroke in the long term and therefore warrants a long term surveillance programmes in stented patients. It was possible to show from the same analysis that stenting patients as a routine procedure prior to cardiac surgery had no immediate benefit in reducing operative stroke risk from the procedure. The EPICAS study was developed from these initial observations to investigate the effects of variability in response to clopidogrel on outcomes. Using transcranial Doppler detected embolic events as a clinical endpoint for comparison with the clopidogrel dependant pathways of platelet activation the study hoped to show a direct effect of the degree of platelet inhibition on the number of emboli detected. This was not shown to be the case in the patients studied as part of this work. Patients classified as non responders to clopidogrel had no difference in emboli counts before and after the stenting procedure (p = 0.24). The results suggest that a variance in response to clopidogrel is unlikely to be clinically significant even in larger cohorts of patients.

Percutaneous pulmonary valve implantation is an innovative technique for the treatment of right ventricular outflow tract dysfunction. This procedure is available for a limited group of patients with very specific anatomy. Finite element analyses, together with computer aided design technology and imaging processing software, were used in this study to broaden the range of patients who might benefit from this procedure. Three-dimensional reconstruction of patient right ventricular outflow tracts, derived from magnetic resonance data, was performed by image elaboration to assess the implantation site anatomy. A morphological classification was created to analyse the criteria for percutaneous pulmonary valve implantation subject selection. Physical models of the right ventricular outflow tracts from patients with borderline anatomy for percutaneous procedure were built using the rapid prototyping technique. These models provided a complete appreciation of the three-dimensional anatomy and aided patient selection for percutaneous pulmonary valve implantation more accurately than magnetic resonance images. Moreover, they enabled trial implantation of devices to test their deployment and anchoring force into the right ventricular outflow tract. Computer aided design models of different stents were created: the early generation device employed for percutaneous pulmonary valve implantation, the device currently in use and a new possible stent design made of nitinol. Virtual simulation of the inflation of these devices was performed using the finite element method to study the mechanical behaviour and risk of fracture in these devices. The stress and strain distributions were evaluated to numerically compare the performance of the first generation device, with the current stent. A finite element model of a selected patient right ventricular outflow tract was created to computationally investigate the stent/implantation site interaction. Finite element analyses aided the optimisation of a nitinol ring to be employed in the next generation stent.