More young people are participating in organised sport, due to growing physical activity promotion programmes. This may increase the risk of injury in adolescents. The rate of injury in football, in particular at a professional level has increased. There is a lack of literature in Scottish youth football in different aspects of sports injuries. There is a need in sports medicine for a static and dynamic standing balance and proprioception tests to quantify balance ability in adolescents. Although there are many studies focussing on the risk of falls in the elderly there are few studies of balance and measures of proprioception and muscle strength in young and adolescent sports participants. Young football players were selected as the target population of these studies, because of the growing number of young participants in this popular sport, as well as the vulnerability of this group to sports injury during their growth. Knee injuries commonly occur during sports activity. The consequences of ACL injury, in particular, are more serious and costly compared to the injuries of other joints. Football players suffer from an increased of knee injuries. In various stages of rehabilitation of the injured athlete after ACL injury a sensitive method of evaluation is required to identify neuromuscular impairment. This thesis reflects the results of four studies on different aspects of sports injury. The first study, the retrospective epidemiology section, looked at the prevalence of sports injury in youth football players, using a self administered questionnaire as the data collection instrument. The focus of the research was football related injuries, which happened during the season 2002-2003. The subjects of this study were 221 young Scottish football players aged between 12 and 19 years old. The second or reproducibility study was designed to examine whether the results from one of the main equipment tools utilised in this study were reproducible and consistent. This part of the study aimed to determine the test-retest reliability of one tester dynamic unipedal and bipedal balance in two groups of youth football players and young active adults. A group of healthy active adults (over 19 years old) participated in the first part and a group of younger adults (under 19 years old) participated in the second part of the reproducibility study. The extension to the second study was designed to compare balance and strength in professional and non-professional players and non-football players.

In ubiquitin (Ub) system, E3 ligases have a central role in mediating substrate ubiquitination and triggering substrate degradation or other signalling transductions. RING E3s are the largest family of E3s and they promote direct Ub transfer from E2’s active site to substrate. Some RING E3s require dimerization for their activity, but structural evidence on the importance of dimerization and the mechanism of Ub transfer are lacking. I report the structure of the human dimeric RING domain from BIRC7 (also called MLIAP or Livin) in complex with the E2 UbcH5B covalently linked to Ub (UbcH5B~Ub; ~ refers to thioester or oxyester linkage). This 2.18 Å complex structure reveals extensive Ub interactions with UbcH5B and both subunits of the RING domain dimer that stabilize the globular body and C-terminal tail of Ub. Mutations that disrupt these noncovalent interactions or RING dimerization reduce E2~Ub binding affinity and ubiquitination activity. My results provide structural insights into how dimeric RING E3s recruit E2~Ub and optimize the donor Ub configuration for transfer. CBL family proteins (CBLs) are monomeric RING E3s that negatively regulate receptor tyrosine kinase (RTK) signalling pathway. Precise control of CBLs E3 activity is crucial for many cellular functions. My structural and biochemical data show that the RING domain of c-CBL adopts an autoinhibited conformation, where the E2-binding surface of the RING domain is blocked by the tyrosine kinase-binding domain (TKBD). CBLs can be activated by phosphorylation of a conserved tyrosine residue on the linker helix region (LHR; Tyr371 in c-CBL and Tyr363 in CBL-B). This activation is required for RTK ubiquitination. I report a crystal structure of Tyr363-phosphorylated human CBL-B, bound to a stabilized Ub-linked E2 (UbcH5B–Ub; – is used to separate componets of a complex, in this case, also refers to isopeptide linkage). This 2.21 Å complex structure reveals that the pTyr363 of CBL-B contacts Ub’s Ile36 surface. Using kinetic analyses, I demonstrate that this interaction is crucial in Ub transfer. Together, my results suggest that both monomeric and dimeric RING E3s use a similar mechanism in optimizing the Ub conformation and activating E2~Ub thioester for transfer, although the Ub-stabilizing components may vary in different RING E3s.

The principles of Evidence-Based Medicine (EBM) have been well documented in the medical literature, with many examples of the successful application of these principles to the clinical environment. Despite this widespread acceptance of these principles throughout the medical profession, there has been resistance to adopt such an approach in the veterinary profession. To date, there are. few examples in the literature of the application of the principles of evidence-based medicine to either clinical or scientific research. The aim of this study was to design a series of investigations of equine diseases, and implement them at three private equine hospitals. A variety of study designs were used, providing different classes of evidence when using the classification system proposed by Yusuf et al. (1998). The main focus of this investigation was to ascertain whether it was possible to apply the ethos of EBM to the veterinary profession, and provide good quality research and evidence form private practice. It was found that 85.6% of horses (95% c.l. 81.3 to 89.3) treated for septic arthritis were successfully discharged from the hospital, with 65% of these horses (95% C.l. 57.9 to 71.6) able to return to their previous level of athletic function. When considering those horses treated for septic digital tenosynovitis, 87.8% survived to be discharged from the hospital. However, the prognosis for future soundness was poorer than that achieved following resolution of septic arthritis, with only 50% of horses treated for septic digital tenosynovitis able to return to their previous level of athletic function. Racing Thoroughbreds, both neonates and mature horses, were identified as an important subset of the population. It was found that the occurrence of septic arthritis in neonatal Thoroughbreds significantly reduced the likelihood of those foals going on to make at least one start on a racecourse, with those foals being 3.5 times less likely to start on a racecourse when compared to their siblings. In contrast, when considering mature Thoroughbred racehorses it was found that the occurrence of septic arthritis did not affect the likelihood that they would make at least one start on a racecourse when compared to their siblings, or be able to achieve an Official Rating awarded by the British Horseracing Board's handicappers equal to, or higher than, either the highest rating achieved prior to the onset of sepsis in cases in which horses had raced previously, or equal to the highest rating achieved by their siblings. In a controlled, randomised trial it was found that 31.6% (95% c.l. 17.5 to 48.7) of horses wearing a belly band following an exploratory laparotomy developed incisional complications, compared with 76.6% (95% c.I. 62.0 to 87.7) of horses where no belly band was used. If a belly band was used following an exploratory laparotomy, the risk of developing post-operative incisional complications was reduced by 45% compared to those cases where no belly band was used. Following a clinical audit of elective surgical procedures at three private equine hospitals, there was found to be a higher rate of post-operative complications, when compared to results reported in both the medical and small animal veterinary literature. It was concluded that it was possible to apply the ethos of EBM to the veterinary profession, and provide good quality research and evidence from research performed in private practice. However, in order to be able to achieve sufficient case numbers to provide answers that are directly relevant to practice-based clinical situations, multi-centre studies are likely to be the best way forward.

Successful haemodialysis depends on the availability of safe, efficient, and durable access to the vascular tree. This can be provided by creation of an arteriovenous fistula, insertion of a synthetic vascular graft or insertion of a central venous catheter. Established haemodialysis vascular access is associated with a number of important complications which can impact significantly on both the quality of life and survival of haemodialysis patients. The primary aim of this thesis was to perform a detailed evaluation of the risks to health conferred by haemodialysis vascular access and its maintenance in patients with advanced renal failure. The work described in this thesis describes the relative strength and independence of association between haemodialysis vascular access type and risk of mortality, bacteraemia and catheter thrombosis. Greater clarity is demonstrated on the relative effect of heparin-based haemodialysis catheter lock solutions on markers of systemic coagulation in vivo, whilst the in-vitro variability of antimicrobial activity against planktonic and biofilm-embedded staphylococci achieved with catheter lock solutions containing heparin and vancomycin, alone and in combination, is clearly shown. New insights are gained into the benefits of contrast magnetic resonance venography as a tool for demonstrating thrombosis and stenosis of the central veins in the assessment of vascular access in haemodialysis patients. Similarly, the emergence of a new disease, nephrogenic systemic fibrosis was found and its association with gadolinium-enhanced magnetic resonance imaging was explored in detail.

Introduction: Obesity, metabolic syndrome and Type 2 diabetes are clinical states associated with insulin resistance and an increased risk of vascular disease. The prevalence of Type 2 diabetes is reaching epidemic proportions and there is a growing need for new therapeutic targets. There is a significant body of research that demonstrates an association between obesity, insulin resistance, endothelial dysfunction and accelerated atherosclerosis, but the molecular mechanisms underlying this link are incompletely understood. Biguanides and thiazolidinediones are widely used in the treatment of Type 2 diabetes to improve glycaemia but the precise site, mode and extent of their actions remain uncertain. For example, in the United Kingdom Prospective Diabetes Study (UKPDS), metformin treatment reduced the incidence of myocardial infarction by 39% in comparison with conventional treatment which is more than would have been predicted by the difference in achieved HbA1c (0.6%). In addition, when the metformin group was compared with a group treated with sulphonylurea or insulin, to control for glycaemia, there was still a significant reduction in the incidence of stroke and any other diabetes-related end-point. The enzyme AMPK is a novel therapeutic target in Type 2 diabetes and the development of specific tissue specific AMPK activators is an attractive prospect for the future. We therefore investigated the role of AMPK in the action of biguanides and thiazolidinediones. Accordingly, the aims of this project were to first determine if metformin improves vascular endothelial function and large artery stiffness in patients with Type 2 diabetes. In parallel, the thesis examines if metformin exerts its beneficial effects in patients with Type 2 diabetes in association with altered AMPK activity in human adipose. Finally, the thesis determines if insulin sensitizers such as metformin and the thiazolidinediones, acting directly on vascular endothelial cells, increase NO production by increasing AMPK activity thus accounting for beneficial effects on endothelial function and, in metformin’s case, cardiovascular outcome. Methods: Twenty men with Type 2 diabetes were randomised to metformin (500 milligrams three times daily for ten weeks) and gliclazide (80 milligrams twice daily for ten weeks) in a double-blinded, glycaemia controlled, cross-over design. There was a six week run in and washout period. At the end of each ten week phase of therapy routine and non routine blood sampling (including plasma ADMA), PWV and an adipose biopsy were performed to determine resistance artery function and adipose AMPK activity. The effects of metformin, its closely related analogue phenformin and rosiglitazone were characterised in cultured human aortic endothelial cells (HAECs). AMPK activity was assessed using a peptide kinase assay and the quantification of phosphorylation of the AMPK substrate, acetyl-CoA carboxylase (ACC) in HAECs incubated in rosiglitazone, phenformin or metformin. Nitric oxide (NO) release was evaluated with a Sievers NO meter. Results: The mean age and BMI of subjects in the clinical study was 56.5 years and 31kg/m2. Mean HbA1c after metformin therapy was 8.3% compared with 7.8% following gliclazide therapy. There was no significant difference between resistance artery function and PWV. ADMA was marginally lower following metformin therapy (p=0.019). AMPK activity was 2 fold higher following metformin therapy when compared with gliclazide therapy (p=0.002). Stimulation of human aortic endothelial cells with phenformin and rosiglitazone resulted in the time- and dose-dependent stimulation of AMP-activated protein kinase activity and NO production with concomitant phosphorylation of endothelial NO synthase at Ser1177. Infection of endothelial cells with a virus encoding a dominant negative AMPK mutant attenuated both phenformin and rosiglitazone-stimulated Ser1177 phosphorylation and NO production. Furthermore, the stimulation of AMPK and NO synthesis by rosiglitazone was unaffected by the peroxisome proliferator-activated-receptor-inhibitor, GW9662. Incubation of HAECs with metformin, however, had no effect on AMPK activity or NO synthesis. Conclusion: Taken together, the data in this thesis provides further insight into the molecular mechanisms underlying the interactions between insulin sensitizing drugs, the enzyme AMPK and both the human vascular endothelium and adipose. Further work leading to an increased understanding of the molecular mechanisms by which anti-diabetic drugs activate AMPK in both the vascular endothelium and adipose tissue may identify novel therapeutic targets in patients with Type 2 diabetes.

Premature cardiovascular (CV) death is the commonest cause of death in patients with end stage renal disease (ESRD), which includes those receiving or close to requiring renal replacement therapy. In ESRD patients, CV deaths are most commonly caused by cardiac arrhythmia and sudden cardiac death compared to the general population where myocardial ischaemia and infarction predominate. Higher CV disease burden is due to accumulation of “conventional” risk factors (e.g. hypertension, diabetes mellitus, smoking) and “novel” risk factors (e.g. oxidative stress, proteinuria, anaemia, inflammation) in ESRD patients. In addition, risk factors specific to patients with renal disease have been identified including alteration in left ventricular (LV) structure, called uraemic cardiomyopathy. These structural abnormalities are common in patients with ESRD (between 60-80% of subjects upon initiation of dialysis) and include left ventricular hypertrophy (LVH), systolic dysfunction (LVSD) and dilatation. These changes in LV structure confer adverse CV outcome in ESRD patients and have proven difficult to reverse. Detection of these abnormalities is usually performed using echocardiography, however this technique is inaccurate in ESRD patients due to significant alterations in LV shape and geometric assumptions made during calculation of myocardial mass. Cardiovascular MRI (CMR) negates these assumptions and is the most accurate, reproducible and reliable method of assessing LV dimensions independent of intravascular volume, particularly in patients with altered myocardial architecture. Furthermore, maximal left atrial volume can be measured using CMR. The principle aims of the studies presented in this thesis were to elucidate prognostic and pathophysiological features of uraemic cardiomyopathy using CMR. In a large study (n=246) of haemodialysis patients, the determinants of each LV abnormality of uraemic cardiomyopathy were identified from past clinical history, haemodialysis and blood parameters and other LV measurements. For LV changes, major determinants were clinical features associated with advanced renal disease, namely expansion of intravascular/ extracellular fluid compartment, abnormal bone mineral biochemistry and hypertension. Furthermore, presence of one LV abnormality was one of the strongest predictors of presence of another, perhaps indicating differing stages of uraemic cardiomyopathy development. In a subsequent prognostic study including these patients (n=446), presence of LVSD and LV dilatation on CMR were significantly associated with poorer all cause and CV mortality. Presence of LVH, which is by far the most common structural change, was associated with poorer cardiovascular survival only. In addition, presence of two or three abnormalities (commonly LVH with another abnormality) had a significantly poorer prognosis and independently predicted CV and all cause mortality. This has implications for therapeutic strategies which should aim to slow or reverse cardiac changes of ESRD and prevent progression from one cardiac abnormality to 2 or more. In a further study (n=201) investigating additional prognostic features of ESRD patients with LVH, maximal left atrial volume (LAV) was measured using the bi-plane area length method at end LV systole. Elevated LAV and presence of LVSD were significantly associated with poorer all cause survival and were independent predictors of death. The most likely causes of elevated LAV in ESRD patients are LV diastolic dysfunction and expanded extracellular compartment and may provide a target for therapeutic intervention. The electrophysiological features of uraemic cardiomyopathy were assessed using microvolt T wave alternans (MTWA) which is a novel, non-invasive method of measuring small variations in surface electrocardiogram (ECG) T wave morphology and thus ventricular repolarisation. This technique has been used to stratify other cohorts at elevated risk of sudden cardiac death (such as ischaemic and non ischaemic cardiomyopathy, hypertensive LVH). A study presented in this thesis, compared MTWA results between ESRD (n=200) and hypertensive patients with LVH on echocardiography (n=30). Abnormal MTWA result was significantly more common in ESRD patients compared to hypertensive patients with LVH. Furthermore, abnormal MTWA result was significantly associated with myocardial abnormalities of uraemic cardiomyopathy and a history of macrovascular atheromatous disease in ESRD patients. Despite preservation of LV function on CMR, the frequency of abnormal MTWA result in ESRD patients was similar to previous studies in subjects with heart failure. 31Phosphorus magnetic resonance spectroscopy is a novel, non-invasive technique of estimating cardiac energetic status and high energy phosphate (HEP) metabolism in a myocardial area of interest and has previously been used to assess patients with global myocardial disease (dilated cardiomyopathy, hypertensive LVH). High energy phosphate metabolism was compared between patients with ESRD (n=53) and hypertensive LVH (n=30) and despite similar LV mass between both groups, PCr: ATP (an indicator of HEP metabolism) was significantly reduced in ESRD patients. These findings are most likely due to cardiac interstitial fibrosis and the alteration of tissue composition within the area of interest, and changes in metabolic function within cardiomyocytes of uraemic hearts. Finally, a small study (n=50) investigated the effect of successful renal transplantation on LV mass measured by CMR. On comparison of patients who remained on the renal transplant waiting list, there was no significant difference in LV mass in patients who received a renal transplant. It is likely that previous echocardiography studies that demonstrated significant regression of LVH, measured improvement in fluid control rather that actual reduction in myocardial mass. Future studies investigating benefit of therapeutic intervention may require identification of individuals at higher CV risk and the results of studies presented in this thesis aim to provide information for selecting such ESRD patients. With these results in mind, further prospective studies will be able to carefully select groups of ESRD patients with differing left ventricular, left atrial, electrophysiological and biochemical properties to demonstrate survival benefit with interventional agents. In this way, future therapies for ESRD patients can be tailored to improve cardiovascular survival.

The aim of this study is to gain a comprehensive illustration of the experience of non-serious, non-chronic, general aches and pains, and their associated risk factors in the workplace. A cross-sectional questionnaire survey was carried out in 23 different workplaces in Scotland, inviting individuals to comment on their pain prevalence, pain responses, and pain experience in relation to the Glasgow Pain Questionnaire (GPQ; Thomas et al., 1996). The GPQ provides an index of total pain experience, Pain Frequency, Pain Intensity, Ability to Cope with Pain, Pain Emotion and Pain impact. Although response rates were low (24%), 1888 workers participated in the final study, representing a variety of ten different industry groups. Results showed that the prevalence of general aches and pains was high (70%), for which workers were most likely to either present to a primary care professional (doctor or dentist), or to take a medication that they had close at hand. One third of those suffering for general aches and pains did not act on them at all. Prevalence of non-troublesome general aches and pains varied marginally in relation to risk factors, although an adjusted association was found between the likelihood of pain and some demographic groups (female sex, having a chronic condition). An association was also found between pain prevalence and higher work stress. Adjusted responses to pain differed in relation to pain site and pain cause, although demographic and work variables show little association, after adjustment, with the decision to act on or consult for pain. The more negative the pain experience, the more likely workers were to act or consult, although ‘Ability to Cope with Pain’ showed no association with either acting or consulting. After adjustment for age and gender, the experience of pain was relatively similar across pain sites, although it was more negative in long-term conditions, or where medical intervention was required.

Up to 50% of patients with the clinical syndrome of heart failure have preserved left ventricular systolic function (HF-PSF). Invasive studies utilising cardiac catheterisation have demonstrated that patients with HF-PSF have abnormalities of left ventricular (LV) relaxation and filling, or LV diastolic dysfunction. As a result, it has been proposed that LV diastolic dysfunction is the primary pathophysiological process in HF-PSF. However, population-based studies have shown that there is poor correlation between the presence of LV diastolic dysfunction and the presence of heart failure. This controversy has led to a search for alternative pathophysiological processes which could potentially cause HF-PSF. There are some data to suggest that patients with HF-PSF have a combination of LV diastolic dysfunction, or ‘LV stiffness’, and large artery stiffness, when compared with normal subjects and patients with systemic hypertension. This implies that the interaction between the left ventricle and the vasculature is dysfunctional and a potential cause of HF-PSF. Although there are limited data on arterial stiffness in HF-PSF, there have been no studies examining other parameters of vascular function in HF-PSF and vascular function has never been formally compared in cohorts of patients with HF-PSF and heart failure due to reduced LV systolic function (HF-RSF). The studies presented in this thesis were designed to further characterise vascular function in HF-PSF and to compare vascular function between patients with HF-PSF, patients with HF-RSF and control subjects. I used non-invasive techniques to assess parameters of arterial function, such as arterial stiffness and arterial endothelial function. I also evaluated parameters of venous function, namely venous capacitance and venous endothelial function. Arterial stiffness, measured by aortic pulse wave velocity (PWV), was significantly elevated in HF-PSF compared to both HF-RSF and control groups, implying that HF-PSF is indeed associated with greater arterial stiffness. In contrast, arterial diastolic waveform analysis failed to show any significant differences in derived parameters of arterial compliance between the three study groups, which may be due to the fact that all three groups were matched for underlying coronary heart disease, reducing the ability of the technique to differentiate between groups. Using Laser Doppler iontophoresis, I demonstrated that HF-PSF and HF-RSF subjects have impaired microvascular responses to both acetylcholine and sodium nitroprusside. This suggests that, rather than being solely a primary disorder of endothelial function, impaired control of vascular tone in HF-PSF reflects significant vascular smooth muscle dysfunction. It is not certain if arterial smooth muscle and/or endothelial dysfunction is secondary to the inflammatory and neurohumoral activation associated with the heart failure syndrome, or a primary pathophysiological factor in the development of either form of heart failure. As regards venous function, patients with HF-PSF had a lower venous capacitance than patients with HF-RSF (but similar venous capacitance to the controls). Increased venous capacitance may represent a compensatory response in heart failure that is less marked or absent in HF-PSF, compared to HF-RSF. Venous endothelial function was measured with the Aellig dorsal hand vein technique. It was not technically possible to complete an Aellig study in the whole patient cohort, resulting in fewer data being available for analysis. Despite this, both heart failure groups appeared to have impaired venodilatation in response to acetylcholine, compared to controls, although this apparent difference was not statistically significant. While the studies of venous capacitance and endothelial function were not conclusive, they suggest that venous function may be abnormal in HF-PSF. The finding that endothelial and smooth muscle control of arterial tone was impaired in both HF-PSF and HF-RSF may indicate a similar primary pathophysiological process, or indeed a similar response to inflammatory and neurohumoral activation in heart failure. I conclude that the data presented in this thesis supports the hypothesis that HF-PSF is associated with increased arterial stiffness, which in combination with increased LV stiffness is likely to result in impaired ventriculo-vascular coupling. This process is likely to be an important pathophysiological factor in the development of HF-PSF.

The study derived its data from semi-structured interviews with 100 relatives of patients with a primary diagnosis of dementia. At the time of the interview, the dementia sufferer lived with the carer in 61 cases, in their own home in 16 cases, and in long-term institutional care in 23 cases. The interviews were based on a `Carers' Questionnaire' which has evolved via preliminary unstructured exploratory interviews with carers, followed by a pilot study employing an initial draft of the questionnaire. The study demonstrated that caregiving relatives generally acknowledged dementia to be an illness which would result in continued deterioration and death in the sufferer; that is, as a terminal illness, bringing both current and future losses. The emotional and behavioural reactions which previous studies have labelled `anticipatory grief' were experienced - to varying degrees - by the caregiving relatives of dementia sufferers. While partly simply a response to the burdens of the caregiving situation, they could also be attributed in part as the response to the loss of the person of the dementia sufferer. The majority of carers believed they had experienced grief, and the underlying structure of their reactions was similar to that of conventional grief. The results of the study showed that taken as whole, there was considerable stability in the emotional and behavioural reactions of the caregiving relatives of dementia sufferers over time. Against this background, there was a sub-group of approximately one-third of the sample of carers whose shock, or disbelief, or hope was greater earlier on in the process of their relatives' dementia, and whose acceptance of the illness and the future had increased over time. There was, however, no evidence of a phasic emergence of a variety of discrete stages in the carers' reactions, nor of an end-point of resolution or acceptance. The different components of the emotional and behavioural reactions of caregiving relatives were associated with different caregiver and sufferer characteristics. Initial shock was associated with learning the diagnosis and prognosis suddenly. Current carer shock, denial or hope were associated with sufferers who were younger, were spouses or siblings, and were demanding, with carers who were older, with less time since onset of the dementia. Protest, questioning and guilt were more likely in younger carers, those who perceived dementia as a horrible/worst illness, and those reporting a poor relationship with the sufferer. Reactions of yearning or preoccupation were more likely in carers who perceived dementia as a horrible/worst illness, and who were not helped by a religious or other belief. Carer depression was associated with demanding sufferer behaviour, perceiving dementia as a horrible/worst illness, and reporting a poor relationship with the sufferer. Finally, carer acceptance was more likely when they perceived dementia as the consequence of aging or just an illness, and when they had greater general knowledge regarding dementia. Whilst not labelling it as such, some carers did perceive their dementing relative in terms which could be regarded as `socially dead'. Three factors comprised the underlying structure of social death. Factor one, `Anticipate Death', relating to thinking in a variety of ways about the sufferer's death, had occurred for between half and three-quarters of the sample. `Anticipate Death' was associated with variables suggesting that the dementia sufferer had lived too long, and that the carer was fed up (angry or depressed) with the situation. Factor Two, `Life Pointless', relating to elements of social death such as believing that the sufferer's death would be a blessing, had occurred - to varying degrees - for at least half the sample. This was the only social death factor to be associated with a carer's belief that they had experienced grief. It was also related to a lack of carer hope or bargaining behaviours (perhaps representing the acceptance of the inevitability of the sufferer's decline), with increased sufferer dependency, with the carer's perception of dementia as a horrible/worst illness, and their reporting a poor relationship with the sufferer. Social Death Factor Three, `Sufferer Unaware', relating to sufferer lack of awareness of, and response to, their environment, was endorsed by the vast majority of the caregiver sample. It was associated with increased impairment in the sufferer (perhaps representing `loss of the person'). Those carer emotional and behavioural reactions most clearly representing distress were associated with increased subjective burden. Belief that they had experienced grief was associated with a reduction in a carer's perceived coping ability. None of the social death factors was linked to carer subjective burden or coping. Finally, with regard to institutionalisation, there was no evidence that placement in long-term care triggered either the social death of dementia sufferers or anticipatory grief in their relatives. Among community carers, preference for institutional care was not directly related to any of the anticipatory grief reactions. It was, however, associated with social death factor `Life Pointless'. This suggests that if a carer perceives the continuation of their dementing relative's life as meaningless, then the removal of the physical presence of the sufferer to institutional care may be more acceptable, or even welcomed.

Obesity is increasing in prevalence, in both the developed and the developing worlds This is due to an increase in the availability of energy dense food and globally reduced levels of physical activity. Obesity would appear to be the driving force for increased prevalence of type 2 diabetes. The processes that lead to the development of insulin resistance and ultimately type 2 diabetes may also play a significant role in the development of endothelial function. Biological changes leading to insulin resistance may also cause impairment of endothelium-mediated vasodilatation. This is thought to be one of the first manifestations of atherosclerotic cardiovascular disease (CVD), also a major burden on individuals and health services. Endothelial dysfunction has been shown to be a surrogate marker of underlying risk for atherosclerotic cardiovascular disease. The effects of intentional weight loss on reducing the burden of cardiovascular disease remain unclear. Although it is recognised that intentional weight reduction can ameliorate insulin resistance, hypertension and abnormalities of lipoprotein metabolism, there is little evidence to suggest that weight loss reduces CVD-related morbidity. A number of studies have attempted to address this issue by assessing the effects of weight loss on endothelial function. However, few of these studies have included subjects with type 2 diabetes, and a number of them have included exercise interventions, which have been shown to have effects on vasculature over and above the effects of weight reduction. Given the increased risk of cardiovascular morbidity and mortality associated with type 2 diabetes, and the need for further strategies addressing this issue, this study aimed to assess the effects of intentional weight loss using solely dietary manipulation in a cohort of subjects with type 2 diabetes. Fifteen male and female subjects with type 2 diabetes were recruited from local diabetes clinics and advertisements in local press. A six-week period of dietary intervention in the form of a 1200kal/day liquid diet was prescribed, with subjects being closely monitored by a dietician during this period. Vascular and metabolic assessments were performed at baseline and following a one-week dietary washout period at the end of the intervention. This dietary intervention led to significant reductions in body weight, waist and hip circumferences and body fat percentage, measured by three distinct methods. Change in body weight correlated with change in waist circumference, but there were no correlations between change in body composition or any of the other anthropometric measurements. The probable reason for this was the small numbers involved. Weight reduction was associated with improvements in metabolic parameters. Significant reductions in fasting plasma glucose, glycated haemoglobin and whole body insulin sensitivity as measured by the isoglycaemic hyperinsulinaemic clamp technique were noted after the intervention. In addition, there were significant reductions in liver enzymes (surrogate markers of hepatic steatosis), and in serum total cholesterol concentrations. Changes in glycaemic control were closely correlated with changes in liver enzymes. With the exception of serum intercellular adhesion molecule-1 (ICAM-1), there were no improvements in any of the measured concentrations of adipocytokines or inflammatory markers following weight reduction. Serum concentrations of ICAM-1 were significantly reduced as a result of the intervention, with no changes in C-reactive protein, interleukin-6 or adiponectin being observed. The possible reasons for these results are multifactorial. Weight loss was associated with variable effects on vascular function. Three modalities were employed for the assessment of the vasculature; wire myography, laser Doppler inontophoresis and pulse wave analysis / velocity measurements. Significant reductions in endothelium-dependent vasodilatation as measured by both wire myography and laser Doppler iontophoresis were observed after weight reduction. In contrast, however, there was a significant improvement in pulse wave velocity measurements. In summary, weight reduction in a cohort of subjects with type 2 diabetes led to significant improvements in metabolic parameters, little change in markers of inflammation and a deterioration in endothelium-dependent vasodilatation.