Microwave thermography has been used for the objective assessment of inflammation in the knee joints and wrist and finger joints of patients suffering with rheumatoid arthritis by comparison with similar information obtained from a control group of subjects. Combined microwave and thermal modelling has been used to estimate the effective blood supply to the anterior intra-articular region of the patella, and the perfusion of the quadriceps muscle in both groups. 2-D numerical modelling was compared with results obtained using 1-D modelling. Microwave thermography has also been used for the detection of breast cancer. However, problems such as high false positive detection rates have occurred due to natural cyclical breast temperature changes. The thermal behaviour of the normal breast throughout the menstrual cycle has been investigated and it is shown that microwave thermography is capable of detecting temperature variations in the female breast corresponding to the ovulatory and luteal phase of the menstrual cycle. Combined microwave and thermal modelling estimated the effective perfusion of the normal breast to be in the range 0.2 - ˜ 2 kg m-3s-1. This is consistent with previous work. Microwave thermography is a quick, simple technique which clinicians can easily use. It is non-invasive, passive and causes the patient no distress. By using combined microwave and thermal modelling it is possible to estimate tissue blood perfusions and water contents and compare them with expected values. The technique has many potential applications and will hopefully find a secure niche in clinical medicine.

Building on Reynolds' and Gutman's (1988) assumption that is possible to categorise consumers with respect to their values orientation, we argued that it is possible to categorise Portuguese GPs according to their clinical values. The exploratory phase of this research was therefore developed in accordance with Means-End Chain Theory (Gutman, 1982) and the related Laddering technique (Reynolds and Gutman, 1988). These tools were useful in assessing Portuguese GPs' therapeutic cognitive structures. Resulting hierarchical maps (which summarise the most frequently evoked therapeutic means-end paths) were obtained with newly available software (Ladder Map) (Gengler and Reynolds, 1995). The results suggested that Portuguese GPs' prescribing behaviour was based on different patient typologies. These cognitive schemas were used to develop the patient typology model (PTM). Subsequently, a self-administered questionnaire was sent to 1,500 Portuguese GPs. Factor analysis and multiple logistic regression were the statistical techniques chosen for the analysis of the 309 responses. This empirical phase of the research confirmed that the PTM is a useful theoretical framework to categorise Portuguese GPs according to the stepped-care approach and the liberal approach. The former uses diuretics and -blockers, while the latter prefers angiotensin-converting-enzyme (ACE) inhibitors for the management of hypertension.

Moderate physical activity and snack intake suppress the appetite of obese and lean women acutely. The associations between circulating leptin and appetite-satiety ratings suggest that there is some physiological involvement of leptin in short-term appetite regulation in response to physical activity-induced factors but only in obese women. The exercise-related factors considered in this thesis as possible mediators of leptin action were catecholamines, fatty acids, glucose and insulin. Adrenaline is unlikely to be the exercise factor responsible for the coupling between leptin and satiety since adrenaline infusion stimulated an increase in subsequent energy intake in obese women. Labetalol decreased circulating FFA and increased glucose concentrations, which confirms at least b-adrenoceptor blockade. Any conclusion with respect to the a- adrenoceptor blockade should be drawn with caution since labetalol, an a/b blocker, has greater affinity for b- than a-adrenoceptors. No differences in appetite/satiety sensations were found following exercise with adrenoceptor blockade compared to exercise alone. This indicates that the observed anorexic effect of exercise on appetite in obese women was not mediated by b-adrenoceptors. Noradrenaline is another possible exercise factor that could mediate the coupling between leptin and appetite in obese women since it is known that leptin and noradrenaline (NA) have common hypothalamic targets (e.g. NPY) and their effects are mediated by a-1 adrenoceptors. Labetalol probably was not a sufficiently strong a-adrenoceptor blocker to investigate such effects. A study of a more selective a1-adrenoceptor antagonist might be helpful in the investigation of the interaction between leptin and NA in the regulation of eating. Study 4: In endurance-trained athletes a short term detraining increases postprandial plasmin leptin, induces insulin resistance but has no effect on appetite/satiety ratings. The results of the present studies implicate leptin, insulin, insulin resistance and noradrenergic factors in the control of eating following exercise and detraining.

Aim of this thesis was to evaluate mixtures of indigestible carbohydrates in vitro to predict their effects on gut function. In this study, I investigate the effect of combining carbohydrates with different fermentative properties and their interactive influences, reflected in the end products from in vitro fermentation. The study focused on the rate of fermentation and fermentability of such mixtures and the SCFA produced to gain an index of the likely site of fermentation in the colon. The main aim of the thesis was to produce a mixture of carbohydrates which would delay but preserve butyrate production from rapidly fermenting carbohydrates such as raftilose. This was achieved in several mixtures but mostly those containing raftilose and ispaghula. In general, mixtures of carbohydrates were fermented more slowly than raftilose alone. Overall, ispaghula was the most effective in slowing the rate of fermentation compared with pectin or gums. Mixing raftilose with ispaghula or guar gum gave the best preservation of n-butyrate and propionate production. The rate of n-butyrate production was less rapid in mixed cultures of three carbohydrates (raftilose, ispaghula and pectin) than cultures of 100mg raftilose but production of n-butyrate was preserved. In summary, ispaghula and raftilose in two-carbohydrate mixtures and ispaghula, pectin and raftilose in three-carbohydrate mixtures delayed the release of butyrate with no loss in butyrate production and may move butyrate further round the colon, at the same time reducing the potential adverse effects of raftilose. Moreover, the addition of pectin (or guar gum) may add the therapeutic effect of delaying nutrient absorption in the small intestine was well. These studies have identified at least two mixtures (raftilose & ispaghula; raftilose, ispaghula & pectin) worthy of study in more detail in man.

This thesis begins by considering that modern medicine as a profession has tremendous scope for both good and ill, and as an enterprise consumes a vast amount of the national wealth. Against this background, the thesis considers how and why medicine is regulated, and what the effects of this regulation are. The study aims to assess the regulation of the medical profession against the interests of the state, the profession, and the consumers of health care, to see whether the regulatory mechanisms adopted adequately safeguard the interests of all parties concerned with the practice of medicine. The methodology chapter spells out the analytical techniques which the bulk of the thesis utilises and delimits the scope of the research to cover only bodies having a legal genesis and which are universal in application. A series of "core evaluation criteria" are identified against which the four regulatory mechanisms are assessed. Chapters 3 to 6 contain the bulk of the actual research into the four main areas of regulatory endeavour which the study considers; each is analysed in turn in terms of the purpose, mechanism and effect of the regulatory machinery being considered and then assessed against the core evaluation criteria. Finally, the conclusions chapter draws together the different threads which the sector-specific analyses have identified as being points of concern, and the system as a whole is evaluated to see whether the interests of the relevant stakeholders are adequately safeguarded, to identify any regulatory gaps which exist in the present system, and to point out the direction which anyone seeking to improve the system should consider

In children and newborn babies on intensive care, information regarding blood oxygen saturation (SpO2) is determined non-invasively by a device called a pulse oximeter. Sensors are usually placed on a hand or foot where their operation relies on the presence of pulsatile arterial blood. Light shines at two or more wavelengths (usually red and infrared) into the tissue where the pulsatile blood modulates, absorbs and scatters the different wavelengths of light in varying amounts and is detected by a photo-detector as a photoplethysmograph (PPG). The spectral information received is then processed electronically and digitally to determine the amount of haemoglobin present. In the sickest of children blood supply can become compromised to these sensor locations and the pulsatile component of the blood may diminish and pulse oximeter readings may become unreliable, especially at times when accurate blood oxygen information would be vital. Currently the alternative is to take blood from an arterial line and run a relatively lengthy analysis (pulse oximeters are near-instantaneous in their operation) that may be unnecessary if the pulse oximeter could be relied upon at these critical moments. In the smallest of babies invasive sampling of blood becomes even more of an issue as any blood loss could lead to hypovolaemia and introduce extra sites of infection plus it causes a lot of stress to the neonate. Since central blood flow may be preferentially preserved, the anterior fontanelle was investigated as an alternative monitoring site. Custom reflectance fontanelle and reference PPG sensors have been designed and built to investigate the fontanelle in those children at risk of peripheral supply compromise. Dedicated instrumentation and software has also been successfully developed for the control of the sensor electronics and the data-logging of PPG signals for retrospective analysis. Sixteen neonates were recruited for fontanelle monitoring; all were ASA 1 – 3 (ASA ranges from 1 to 5 where 1 is the least sick and 5 is the most critically ill). As part of the approved protocol the delivered oxygen to the patients was artificially altered to look for corresponding changes in PPG signal amplitudes. Amplitude results reveal strong correlations (R > 0.5) between the reference sensor (placed on the foot) and the fontanelle sensor. This suggests that the fontanelle sensor is sensitive to changes in amplitude when oxygen in the blood alters. Correlation of the health of the child, using the ASA score, and the difference in amplitudes of PPGs between the sensors reveals that the fontanelle sensor does detect increasing fontanelle PPG amplitudes when compared to the PPGs from the reference sensor the sicker the child is, confirming that pulsatile flow is being preferentially preserved at the fontanelle in those children who are the most at risk from peripheral supply compromise. SpO2 estimation at the fontanelle reveals a mean difference of 2.2 % to the SpO2 as read by the commercial device and a 1.7 % difference to the blood gas results. These results confirm that the anterior fontanelle may be used as an alternative location for SpO2 measurement in those who are at most risk of peripheral supply compromise.

Epilepsy affects 50 million people world-wide. Since 1982, the Western Infirmary Epilepsy Unit has provided a specialist service for over 6900 people with suspected and established seizure disorders. The twelve studies detailed in this thesis discuss the management of epilepsy in different patient populations, and explore beneficial and adverse effects of antiepileptic drugs (AEDs). AED development has allowed advances in pharmacological treatment of localisation-related epilepsies. Thus, outcomes were investigated in 550 such patients followed-up at the epilepsy clinic over 13 years (Paper i). Of these, 312 (57%) became seizure-free on medication. Those with hippocampal sclerosis had the poorest outcome (p<0.01), and a higher incidence of febrile convulsions (p<0.001). Although many patients benefited from AED therapy, results may be biased, given this cross-sectional study analysed data from both newly diagnosed patients, and those with drug-resistant seizures. Many people with epilepsy take more than one AED, although supportive evidence is sparse. Hence, polytherapy outcomes in 2881 patients registered with the Epilepsy Unit database were examined (Paper ii). Of these, 1617 (56%) were seizure-free, with 332 (21%) taking more than one AED (287 on two, 86%; 42 on three, 13%; 3 on four, 1%). There were 40 duotherapy and 28 triple therapy combinations resulting in seizure freedom. Therefore, combining two or three, but rarely four AEDs may be useful for patients not responding to monotherapy. Because this was a retrospective analysis of newly treated patients and those with refractory epilepsy, the analysis was subject to bias. Lack of a control group was also a weakness. Epilepsy Unit staff are therefore now examining similar outcomes in a large population of newly treated patients only. To establish the place of recently marketed AEDs in clinical practice, four studies examined prospectively the efficacy and tolerability of the novel agent, topiramate, in uncontrolled epilepsy. Adjunctive topiramate was administered in 170 patients with refractory seizures (Paper iii). Seizure frequency and adverse events were monitored. Patients were followed-up until seizure freedom for ≥ 6 months, ≥ 50% or <50% seizure reduction, intolerable side-effects, or lack of efficacy occurred. Seizure freedom was achieved in 39 (23%) patients. A ≥50% reduction in seizure frequency was reported in 80 (47%) others. Doses were often lower than those in regulatory studies. Efficacy as monotherapy was also demonstrated. Using the same end-points, topiramate was added to AED regimens of 64 patients with learning disabilities and epilepsy (Paper iv). Remission from seizures was established in 16 (25%). In similar fashion, levetiracetam was started in 156 patients with uncontrolled epilepsy (Paper v). Of these, 40 (26%) became seizure-free, many on low doses. When the drug was added to AED regimens in 64 patients with learning disabilities, 24 (38%) became seizure-free for at least 6 months (Paper vi). Caregiver quality-of-life scores improved significantly with levetiracetam (p<0.001). It is important to recognise that for all four audits results may be biased due to their observational nature, and the fact that they were undertaken at a single centre, with no control group. For patients with learning disabilities, small numbers, and retrospective baseline recordings for some could also have introduced bias. In Papers vii, viii and ix, findings from longitudinal studies in teenagers, people with learning disabilities and epilepsy, and newly diagnosed elderly patients attending the Epilepsy Unit, are reported. At the Teenager Clinic, 301 adolescents were reviewed over four years (Paper vii). Epilepsy was excluded in 135 (45%), five taking AEDs. A single seizure occurred in 22 others. In the 144 with epilepsy, seizure freedom for ≥ 12 months was attained in 76 (53%), but outcomes were poorer than expected. Neuroimaging was abnormal in 27 (43%). Newly diagnosed patients fared better than those taking treatment (p<0.05). More teenagers with primary generalised seizures (60%) attained remission, compared to those with focal-onset seizures (46%) (p<0.02). The retrospective natures of the analysis, and lack of control group may have biased results, thus making statistical conclusions inaccurate. Findings suggested the need for improved services. Over four years, 214 patients with learning disabilities and refractory epilepsy were followed-up (Paper viii). Although it is generally thought these individuals’ seizures are difficult to control, 59 (43%) became seizure-free for ≥ 12 months with AEDs. There was no change in quality-of-life scoring during this time, and no relationship between extent of learning disability and seizure control. The observational nature of the audit, and lack of control group may have biased results. Currently, there are few data on elderly people with epilepsy. Thus, outcomes over a 20-year period in 117 newly diagnosed senior citizens were examined (Paper ix). After starting AED treatment, 93 (79%) became seizure-free for ≥ 12 months, 73 (62%) with their first drug. Prognosis was better than in younger patients, and for those with fewer pre-treatment seizures (p=0.0078). Again bias may have been introduced because of the study’s observational nature and lack of control group. The final studies concentrate on AED-related adverse effects (Papers x, xi and xii). Bone changes have been reported with AED use. Hence, the relationship between bone mineral density, and long-term AED treatment in 78 older adults (47 post-menopausal women, 31 men), taking hepatic enzyme-inducing or non-inducing AEDs, was explored in a case-controlled study (Paper x). Men had significantly lower bone mineral density than controls at the lumbar spine (p<0.01), and neck of femur (p<0.005). Women had statistically reduced bone mineral density at the femoral neck (p<0.05). It was concluded that long-term AED treatment is an independent risk factor for reduced bone mineral density in people with epilepsy. As sodium valproate may be associated with metabolic changes and polycystic ovarian syndrome, hormone profiles were compared in 76 young men and women taking sodium valproate or lamotrigine monotherapy, to assess whether a pharmacological effect of valproate was responsible (Paper xi). Results revealed only four obese females exhibiting biochemical characteristics of polycystic ovarian syndrome (p=0.05), with obese patients of both sexes (p=0.01), and valproate-treated men (p=0.03) having higher insulin concentrations. Results are not significant when corrected for multiple comparisons. It can therefore be concluded that no differences in metabolic indices between patients taking sodium valproate or lamotrigine existed. To examine further effects on androgenic hormones, and the efficacy and tolerability of sodium valproate and lamotrigine monotherapy, a randomised, prospective study in 225 patients was performed (Paper xii). Patients were recruited if they presented with a minimum of two unprovoked seizures of any type, or a single seizure and underlying neuropathology. Of patients with partial-onset seizures, 81 received sodium valproate and 80 were randomised to receive lamotrigine. Of those with idiopathic generalised epilepsies, 30 received sodium valproate and 34 took lamotrigine. Seizure-free rates were identical in both arms at twelve months between the valproate and lamotrigine cohorts. There was a trend towards superiority for valproate (57% seizure-free) over lamotrigine (35% seizure-free) for patients with idiopathic generalised epilepsies (p=0.09), but a converse separation of outcomes for localisation-related epilepsies (43% seizure-free with valproate, 53% seizure-free with lamotrigine, p=0.24). More patients taking sodium valproate withdrew due to adverse events (p=0.046), eight because of weight gain.

Cell migration and invasion is a central process in embryonic development, wound healing and immune responses. Errors during this process have serious consequences, including mental retardation, vascular disease, tumor formation and metastasis. An understanding of the mechanism by which cells migrate and invade may lead to the development of novel therapeutic strategies for controlling, for example, cancer metastasis. Fascin is an actin-bundling protein involved in filopodia assembly and cancer invasion and metastasis of multiple epithelial cancer types. In this thesis, I have investigated the role of fascin in invadopodia formation, which are invasive finger-like protrusions that cancer cells use to invade into and degrade extracellular matrix. I demonstrated that fascin and its actin bundling activity are required for the assembly of the actin cytoskeleton at invadopodia as well as for the degradation of matrix. Fascin is a very stable component of invadopodia and its presence enhance the stability of actin structures at invadopodia. Furthermore, fascin is required for invasive migration into collagen I-Matrigel gels particularly in cell types that use an elongated mesenchymal type of motility in 3D. These data provide a potential molecular mechanism for how fascin increases the invasiveness of cancer cells. During embryogenesis, melanoblasts proliferate and migrate ventrally through the developing dermis and epidermis as single cells. In the second part of this thesis, I examined the importance of small Rho GTPase Rac1 on melanoblast migration during development. I demonstrate that targeted deletion of Rac1 in the melanoblasts of developing mice causes defects in migration, cell cycle progression and cytokinesis. Rac1 null cells migrate markedly less efficiently, but surprisingly global steering, crossing the dermal/epidermal junction andhoming to hair follicles are normal. Melanoblasts navigate in the epidermis using two classes of protrusion: short stubs and long pseudopods. Short stubs are driven by actin assembly, but unexpectedly are independent of Rac1, Arp2/3 complex, myosin or microtubules. Rac1 positively regulates the frequency of initiation of long pseudopods, which promote migration speed and directional flexibility. Scar/WAVE and Arp2/3 complex drive actin assembly for long pseudopod extension, which is also microtubule dependent. Myosin contractility balances the extension of long pseudopods by effecting retraction and allowing force generation for movement through the complex 3D epidermal environment. In addition, I demonstrated that expression of activated N-Ras did not affect migration and proliferation of melanoblast during embryogensis. However, Rac1 is required for constitutively active N- Ras induced dermal melanocytes survival in mice.

Cardiovascular disease (CVD) is the leading cause of death in the UK, accounting for more than a third of all deaths, with atherosclerotic coronary artery disease (CAD) being the commonest type of CVD. Recently, it has become recognised that in addition to traditional cardiovascular (CV) risk factors such as dyslipidaemia, hypertension, smoking, and diabetes, inflammation plays an important role in the development and progression of atherosclerosis. A concept has emerged that atherosclerosis to some extent can be viewed as a chronic inflammatory autoimmune disease in which the adaptive immune system is targeted against vascular self-antigens modified by hypercholesterolaemia, involving both the innate and adaptive immune response. Much work has been done in determining how the immune system is involved, however relatively little is known about natural killer (NK) cells – an important component of the innate immune system which acts against virally infected cells and neoplastic transformation. In addition NK cells possess cytolytic ability and provide an early source of immunoregulatory cytokines. Recently, there has been increasing evidence to support a role for NK cells in the development of atherosclerosis. The work in this thesis examines NK cell function with the aim of determining whether any changes in the function of this immune cell could have a role in the development of CVD. In order to do this, we chose two patient populations at high CV risk and compared NK cell subsets and function to healthy controls. Firstly, 66 patients with dyslipidaemia on a variety of lipid lowering treatments attending a lipid clinic, and secondly 143 patients with chronic kidney disease (CKD) including 11 with end-stage renal disease (ESRD) on hospital haemodialysis (HD). It is known that CVD is the leading cause of death in patients with CKD, and in ESRD patients have a 20-100 fold risk of premature CV death compared to age matched controls from the general population. The increased CV risk results from additional risk factors that are unique to this patient population, but in particular, these patients have an immune dysfunction that is not completely understood and a resultant inflammatory state. We determined T-cell, NKT-cell, and NK cell subsets from peripheral blood mononuclear cells (PBMCs) by flow cytometry. We then isolated NK cells from PBMCs and assessed NK cell function using a 51-Chromium release assay. These results were then correlated with clinical and laboratory results. In the patients with dyslipidaemia, we did not find any correlations between lipid levels and NK cell numbers, subsets, or cytoxicity. The presence of statin therapy or any other lipid lowering treatment did not result in a reduction in NK cell cytotoxicity. In the CKD patient group, we found a correlation between NK cell cytotoxicity and creatinine, although this did not retain significance after multivariate analysis. Interestingly, we also found a correlation between NK cell cytotoxicity and serum phosphate level, which did remain significant after multivariate regression. We are the first to report a relationship between phosphate and NK cytotoxicity. This is an interesting finding as there is increasing evidence supporting a role for hyperphosphataemia in CVD and increased mortality in both the general population and particularly in patients with ESRD. Phosphate has been shown in some studies to be an independent predictor of inflammation, and may provide the link between the high risk of CVD and CKD. The next part of this thesis was an in vitro study of membrane cholesterol in NK cells. The cell membrane supports cholesterol-rich microdomains termed “lipid rafts”, which concentrate receptors and signal transduction molecules to facilitate high efficiency signal transduction. Statins have a number of pleiotropic effects which have been explained by reduced production of isoprenoid intermediates, and depletion of cell membrane rafts. This study aimed to investigate the effects of membrane cholesterol manipulation on NK cell function, and specifically, whether the actions of statins on NK cells are due to depletion of membrane cholesterol or inhibition of isoprenylation. The NK92MI cell line was used. Cells were either cholesterol loaded, or cholesterol depleted using statins, and NK cell function assessed using a 51-Chromium release assay. Cholesterol was successfully incorporated into the membrane and rafts and was concentration dependent. The addition of cholesterol to statin treated cells restored the cholesterol content in the cell membrane and in rafts. NK cell cytotoxicity decreased with statin treatment in correspondence with raft levels, however in contrast with the increased raft levels of cells which were cholesterol loaded, NK cytotoxicity was also decreased. Measurement of active Ras (a small G-protein that is localised by isoprenylation in membrane rafts when activated), showed that statin treatment reduced Ras within the raft which was not rescued by the addition of cholesterol, suggesting that statins deplete membrane cholesterol and rafts as well as inhibiting isoprenylation. Replenishment of membrane cholesterol restores non-isoprenylated, raft-associated proteins, but does not correct the functional effects of statins. The final part of this thesis aimed to evaluate the relationship between NK cells and potential CV risk biomarkers in these two patient populations at high risk of CVD. High sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), pentraxin-3 (PTX-3), adiponectin, and soluble ST2 (sST2) levels were determined by ELISA, and correlated with NK cell numbers, phenotype, and function, as well as other routine biochemical and haematological parameters. We were not able to determine any definite relationships between the biomarkers studied and NK cell function, although there was an association between PTX-3 and NK cytotoxicity that was only found in inflamed (hsCRP>2mg/L) patients. In conclusion, these studies have provided further insight into the role of NK cells in a group of patients that have not previously been studied: patients with a range of CKD, in addition to patients with dyslipidaemia. This study is the first to associate NK cell cytotoxicity with serum phosphate levels which may have clinical implications. Further studies are needed to clarify whether other immune abnormalities occur in the context of hyperphosphataemia, and the causes and consequences of this. We have also demonstrated that statins deplete membrane lipid rafts as well as inhibit isoprenylation, suggesting a novel dual mechanism of action which merits further investigation.

Major vascular surgery is associated with a substantial risk of cardiovascular events and death. This risk is of increased importance in prophylactic elective open Abdominal Aortic Aneurysm (AAA) repair, where a balance of risk of rupture and postoperative outcome is assessed prior to management decisions. Further, the UK Small Aneurysm Trial has shown that prophylactic repair of an AAA has no survival benefit for the first three years due to the major adverse cardiac event (MACE) rate of 5-15%. There is however no ideal method of predicting this risk. Cardiac Troponin I (cTnI) is a contractile protein that is a highly sensitive and specific marker of myocardial necrosis. A few case reports have commented on the finding of preoperative asymptomatic elevated cTnI levels and poor outcome in a small number of patients undergoing major vascular surgery. There are however no studies looking at its incidence in the vascular surgical population or its utility as a preoperative marker. Several studies have noted that B-type natriuretic peptide (BNP), a diagnostic and prognostic marker of heart failure, may have a role in predicting MACE in settings including major vascular surgery. There are no studies that have investigated this role in AAA repair alone. The aim of this thesis is to investigate the incidence of, and to determine a possible role for, preoperative elevated cTnI in major vascular surgery. The further aim is to determine if a single preoperative BNP level correlated with MACE and all-cause mortality in elective open AAA repair in both the short and long-term. Comparisons to current accepted risk indices in AAA, and a possible role for BNP in EndoVascular Aneurysm Repair (EVAR) will also be investigated. Patients were recruited in two cohorts: Firstly, a prospective, 2 year observational single centre cohort study of all patients undergoing a vascular procedure, with an expected cardiac event rate >5%, recruited patients who had no clinical or ECG evidence of myocardial ischaemia. Preoperative cTnI was performed in all and postoperative screening (clinical assessment, ECG and cTnI) for cardiac events was performed at days 2, 5 and 30. 213 patient were recruited, of whom 11 (5.2%) had an asymptomatic elevated preoperative cTnI (>0.02 ng/ml). Eight of these patients proceeded directly to theatre, and 2 were delayed but later underwent surgery with a persistently elevated cTnI. Of these 10 patients, 5 (50%) died and 4 (40%) suffered MACE. The remaining patient was delayed due to the poor outcome of the preceding patients, and later underwent an uncomplicated aortic bifurcation graft with a normal cTnI level which had been preceded by coronary intervention. Secondly, a prospective, 2 year observational multi-centre cohort study in the 3 largest vascular units in Glasgow (Gartnavel General Hospital, Glasgow Royal Infirmary and Southern General Hospital) was performed between August 2005 and August 2007, recruiting all patients who were admitted for both elective open AAA repair and EVAR. Preoperative BNP levels were performed and batch analysed at the end of the study. Postoperative screening for cardiac events was performed as described above. Data was collected to allow calculation of risk indices associated with outcome in AAA repair (Glasgow Aneurysm Score [GAS], Vascular physiology only Physiological and Operative Severity Score for enUmeration of Mortality [V{p}-POSSUM], Vascular Biochemical and Haematological Outcome Model [VBHOM], Revised Cardiac Risk Index [RCRI] and Preoperative Risk Score of the Estimation of Physiological Ability and Surgical Stress Score [PRS of E-PASS]). Follow-up was continued to a minimum of 3 years, where possible, with cause of death recorded. 106 of 111 patients were recruited. The median [interquartile range] BNP concentrations in the 16 patients (15%) who suffered immediate postoperative MACE was 206 [118-454] vs 35 [17-61] pg/ml in the remainder (p=0.001). ROC analysis indicated a BNP concentration of 99.5 pg/ml best predicted MACE (area under the curve 0.927), with sensitivity of 88% and specificity of 89%. The BNP in patients who suffered cardiac death was significantly higher than in those that did not (median BNP 496 [280-881] vs 38 [18-84] pg/ml, p=0.043). ROC analysis revealed a cut-off of 448 pg/ml (AUC 0.963), with sensitivity 80%, specificity 100%, positive predictive value 100% and negative predictive value 99%. Not only did higher values of BNP predict MACE, but it was also found to predict all-cause mortality in the immediate (median BNP 100 [84-521] vs 35 [17-81], p=0.028), intermediate (median BNP 201 [97-496] vs 35 [17-73], p<0.001) and long-term (median BNP 98.5 [58-285] vs 32 [17-71.5], p<0.001) postoperative periods. ROC analysis revealed decreasing BNP levels to predict outcome over time, with a BNP of >60.5 pg/ml (AUC 0.761) found to best predict death at 3 years. Whilst BNP was found to predict outcome, most risk indices performed poorly. The GAS, VBHOM and RCRI performed poorly and did not predict any outcome measure. V(p)-POSSUM was, however, found to predict all outcome measures (p=0.028, p=0.030, p=0.038 for MACE, cardiac death and all-cause mortality respectively). The PRS component of E-PASS was found to predict MACE (p=0.019) and cardiac death (p=0.017). BNP performed better than any risk index. During the study period only 40 of 42 patients admitted for elective EVAR were recruited. Of these 40, only 3 suffered a non-fatal MI and 1 died of respiratory failure. BNP was not found to predict MACE or death in this cohort, and due to the small number of patients, and events, no strong conclusions could be drawn. Whilst preoperative elevated cTnI was found to identify patients that were at an increased risk of both postoperative MACE and death following their major vascular surgical procedure, its use in elective open AAA repair is limited due to infrequent occurrence. Preoperative serum BNP concentration, however, predicted postoperative MACE, cardiac death and all-cause mortality in patients undergoing elective open AAA repair on immediate, intermediate and long term follow-up. Further, BNP performed better than any current risk index for elective open AAA surgery. This simple blood test, therefore, offers valuable information regarding risk stratification of prospective surgical patients and should be considered a part of routine preoperative assessment in this prophylactic procedure.