This thesis describes a study of the mechanisms involved in the elimination of established, morphologically identifiable electron dense deposits from the glomeruli of rats with chronic serum sickness. The initial experiments established the experimental model and evaluated the effects of variations in the method of administration, the antigen dose and charge, and the route of administration. The model was further characterized in terms of the progression of the morphological, functional and biochemical abnormalities induced. Methods were developed to measure the amount of radio-labeled antigen in isolated glomeruli, and to measure the volume fraction of the electron dense deposits in glomeruli. Study was then limited to the first two weeks of recovery from chronic serum sickness, after injections of antigen have ceased, to ascertain the rates at which the antigen and deposits were removed. The influence of a variety of forms of intervention during this recovery period was then assessed. Manoeuvres which increased the level of circulating anti-BSA antibody were found to inhibit the removal of antigen and deposits from glomeruli. This effect was confirmed by passive immunization with immune rat serum. Manoeuvres which increased the number or activity of glomerular macrophages had no detectable effect on the removal of antigen or deposits. In the absence of plasma complement, the removal of antigen virtually ceased after four days. Cobra venom factor treated rats had lower proteinuria than controls, despite having a heavier antigen load. Manoeuvres which altered the, glomerular filtration rate and renal haemodynamics did not alter the rate of removal of antigen or deposits; nor did the administration of highly cationic molecules. The administration of large doses of heparin enhanced the rate of removal of antigen from the glomerulus, though an effect on deposit volume was not detected.

Background: Prostate cancer risk has been associated with several environmental factors but there is little information to indicate the effects of timing and of lifetime exposures that may add to the risk. This thesis aims to investigate the association of six main areas that may contribute to prostate cancer risk (1) body shape & fat distribution, (2) chronic diseases/conditions (diabetes mellitus, hypertension, ischaemic heart diseases and hypercholesterolemia), (3) statin medications (4) painkillers (NSAIDs and paracetamol), (5) skin & sunlight exposure and (6)diet (isoflavones, selenium, vitamin D & lycopene). The exposures will be investigated at different stages of life for subsequent effects on cumulative prostate cancer risk. Methodology: This study is a part of "The UK Prostate Cancer Study: Gene-Environment Interactions", which is an ongoing large scale case-control study and a collaboration between the University of Nottingham, University of Warwick and the Institute of Cancer Research UK. Data were collected using questionnaires. Subjects were recruited between the years of 1999 to 2009 as cases and controls from hospitals and GPs' referrals in England. Possible risk factors for prostate cancer are investigated through statistical analyses using unconditional logistic regression to obtain odds ratios (OR) and confidence intervals. Results: The response rate was 85.0% among cases and 74.4% among controls, with a total of 4041 males (1963 cases and 2078 controls) recruited into the study. The mean age among cases and controls was 59.6 and 59.1 years respectively. Multivariate analysis of socio-demographic factors showed education, ethnic group and family history were statistical significantly associated with prostate cancer risk and therefore are treated as confounders. Further, (1) Body fat distribution of 'apple' and 'oval' shapes were found to have protective effect towards prostate cancer when compared with a symmetrical shape with an OR of 0.69 (95% CI: 0.55- 0.87) and 0.73 (95% CI 0.53-1.00) respectively, however body shape at age 20's, 30's, 40's and last 5 years showed no statistical difference between cases and controls. (2) The cumulative duration of diabetes mellitus categorised as 5 years or more and 10 years or more when compared to non-diabetic individuals had a protective effect towards prostate cancer risk at OR 0.45 (95%CI: 0.27-0.75) and 0.44 (95% CI: 0.22-0.86) respectively while hypertension, hypercholesterolemia and ischaemic heart disease did not associate with prostate cancer risk. (3) Use of Statins for less than 5 years compared to non-users, produced an OR 0.61 (95%CI: 0.47-0.82). A dose response relationship for duration of use was also seen. (4) Paracetamol showed a protective effect for prostate cancer risk when used for 20 years to 30 years when compared to none-users, OR 0.54 (95%C1: 0.28-1.00). Similarly paracetamol showed a cumulative risk reduction against prostate cancer for all categories of use of up to 20 years or more. However aspirin and ibuprofen did not show any statistical significant associations with prostate cancer risk. (5) Higher exposure to sunlight received in non-working situations and more frequent use of suntan cream showed protective effects against prostate cancer and also when accounted for exposure at different stages of life age. (6)Dietary isoflavones and tablet supplements of selenium at higher intake quartiles levels showed a protection effect against prostate cancer risk when compared to lowest quartile intake. New surrogate indicators for body size and sunlight exposure and a proposed model for overall vitamin D levels from sunlight and dietary sources were also introduced. Conclusions: Body fat distribution of 'apple' and 'oval' body forms, diabetes mellitus, statin usage, higher exposure to sunlight and higher dietary intakes of isoflavones were shown to associate with a decreased risk for prostate cancer. The findings of this case-control study strengthen and support the current understanding of environmental factors associated with prostate cancer risk, whilst at the same time provides further evidence on the effects of exposure at different stages in life and their cumulative effect, as well identifying new surrogate indicators as parameters measurement for such exposures.

Urinary incontinence is a common health problem with not only physical, but also far-reaching psychological and social implications for the sufferer, her family and carers. Assisting patients with meeting their eliminatory needs is a fundamental part of nursing care. Incontinence is encountered in almost every sphere of clinical practice and is a problem with which nurses are often directly concerned. Nurses, in association with other members of the health care team, have considerable potential to help patients regain continence, or when this is not possible, to ensure that the individuals concerned, and their relatives or carers, can cope effectively with the problem, both physically and psychologically. This is an area of nursing care, however, which to date has attracted little research. The studies undertaken in this thesis sought to examine the nursing assessment and management of the care of patients with urinary incontinence in acute medical and care of the elderly wards. The research comprises of a sequence of studies which examined the problem from a number of perspectives. Methods of data collection included nurse and patient self-, reports, the examination of nursing and medical documentation, direct observation and self-completed questionnaires. Findings indicated that urinary incontinence was common in acute medical and care of the elderly wards, and that a considerable proportion of patients had indwelling catheters to manage the problem. Nurses were not always aware of patients' incontinence problems and their assessments concerning important aspects of the symptom were frequently unreliable. Further inadequacies in nurses' assessments, as well as in the management of the care of patients with incontinence, were identified from an examination of the nursing and medical records, and observations of verbal hand-over reports. Qualified nurses and learners appeared ill-informed about the causes of incontinence, and the majority had little knowledge of the range of factors which need to be considered to ensure that a systematic assessment of the problem is carried out. Despite considerable scope for the provision of rehabilitative care for incontinence sufferers, many nurses appeared to have a limited appreciation of their potential for initiating such care. Evidence collected from the nursing and medical records, the verbal hand-over reports and nurses' questionnaires, suggested that the management of patients with incontinence still focuses predominantly on measures which aim to contain the problem with little attention being given to rehabilitative interventions. A considerable proportion of the charge nurses, and the majority of the other qualified nursing staff, stated they had not received any continuing in-service education relevant to the promotion of continence or management of incontinence since their basic training. Nurses exhibited positive attitudes, overall, towards the management of incontinence but their responses indicated that a number of common misconceptions surrounding the problem persist. The enrolled nurses demonstrated significantly less positive attitudes towards the management of patients with incontinence than other grades of nurses. Similarly, the nursing staff who worked in the slow-stream rehabilitation care of the elderly wards showed significantly less positive attitudes towards incontinence than the nurses working in other types of wards. The implications of the findings of these studies for nursing practice, education and further research are discussed.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Malnutrition is common in acute kidney injury (AKI) patients, particularly on the ICU, where they often receive renal replacement therapy (RRT). RRT may exacerbate loss of water-soluble micronutrients (e.g. trace elements, amino acids and B-vitamins). No clinical study has quantified these losses and contrasted between types of RRT that use different methods to remove solutes i.e. by diffusion (intermittent haemodialysis, IHD) by convection (continuous veno-venous haemofiltration, CVVH) or by a combination of both (sustained low-efficiency diafiltration, SLEDf). Using a prospective, observational design patients (n=24 per modality) were consented before their first treatment session. Blood and RRT effluent (dialysate or filtrate) were sampled at baseline (pre-RRT), mid and end-RRT. Amino acids were measured by HPLC, trace elements by ICP-MS and B-vitamins (B1, B3, B6, B9, B12) by LC-MS. Plasma concentrations were corrected for dialysis dose using the urea reduction ratio (for IHD & SLEDf, but not CVVH). Micronutrient losses (mass-corrected) were calculated as concentration × RRT effluent volume, corrected for plasma concentration and RRT dose (i.e. solute removal index). Data were analysed by restricted maximum likelihood estimating equations (Genstat v16, VSNi Ltd, UK). Patients receiving CVVH had significantly higher plasma amino acids, but not plasma trace elements, at baseline (amino acids: CVVH, 3762 ± 357; IHD, 2039 ± 337; SLEDf, 2505 ± 423 µmol/L; trace elements: IHD, 4156 ± 465; SLEDf 3732 ± 521; CVVH 3982 ± 465 µg/L). At RRT end, plasma amino acids and trace elements had significantly reduced (429 ± 223 µmol/L; 600 ± 400 µg/L, respectively). No trace element was lost to a greater extent between types of RRT, but many ( > 10) individual amino acids declined to a much greater extent with SLEDf vs. HD or CVVH (e.g. effect size for lysine was -64 ± 23 µmol/L). Two significant sources of micronutrient loss were noted: to effluent and through dialyser adsorption. The latter contributed < 1g amino acids but in effluent recorded losses of up to 25g were noted with CVVH (5-10g for IHD and SLEDf, respectively). Effluent losses of trace elements varied significantly, but in all cases were greater for CVVH (e.g. effect size for copper was +850 ± 475 µg vs. HD or SLED-F). B-vitamins were not detectable in effluent. Significant loss of micronutrients during RRT, particularly for patients in ICU, is a possible aggravating factor for patients known to be at high risk of malnutrition. The type of RRT used influences the pattern of loss but not consistently for all nutrients. Adsorption of amino acids to dialysers adds a small, but cumulative loss that may become important if further treatment sessions are indicated.

Studies in health care professional (HCPs) have demonstrated a high prevalence of dehydration, which has been linked with morphological brain changes as well as cognitive impairment in other groups. Moreover, many age-related pathophysiological changes result in increased susceptibility to fluid and electrolyte imbalance, rendering older adults vulnerable to dehydration which may be associated with poor outcome. This thesis investigates the prevalence of dehydration and impact on cognitive function amongst HCPs. It also investigates the prevalence of dehydration in hospitalised older adults and the association between dehydration, acute kidney injury (AKI) and clinical outcome. Hydration status and cognition were objectively assessed in nurses and doctors working on emergency medical and surgical wards. This study demonstrated that a significant proportion of HCPs were dehydrated at the start and end of their shifts and many were oliguric. The prevalence of dehydration varied with level of experience and speciality and was associated with short-term memory impairment. Using serum osmolality, the key regulated variable in fluid homeostasis as a measure of hydration status in hospitalised older adults, prospective assessment of 200 patients demonstrated that over a third had hyperosmolar dehydration (HD) at admission, two-thirds of which were dehydrated 48 hours later. Dehydration at admission was independently associated with a six-fold increase in 30-day mortality. Subsequent retrospective assessment of 32,980 hospitalised older adults demonstrated that dehydration was diagnosed clinically in 8.9% of patients and was independently associated with a two fold increase in mortality. Nearly half of those dehydrated had a concomitant diagnosis of AKI and the median length of hospital stay (LOS) was nearly three times greater than those without the condition. Despite the widespread use of serum osmolality in human physiology studies, it is rarely used clinically to assess hydration. Analysis of published equations estimating osmolality, demonstrated that an equation by Khajuria and Krahn was 90% sensitivity and 97% specificity at diagnosing hyperosmolar dehydration. Using this equation, we demonstrated that 27.2% of 6632 older adults had HD at admission to hospital and the risk of developing AKI 12-24 hours after admission in these patients was five times those euhydrated at admission. Moreover, the 30-day mortality was nearly twice that of euhydrated patients, independent of key confounders. The median LOS in dehydrated patients was almost double. This work has highlighted the need to educate both patients and HCPs on the importance of hydration. Further work is required to prospectively assess the use of serum osmolality as a predictor of dehydration, AKI and outcomes. Given that hydration and nutrition are the hallmarks of compassionate care, there is clear room for improvement with findings from this thesis suggesting the need for further investigation and intervention in both community and hospital settings.

It is well established that patients with Chronic Kidney Disease (CKD) are more susceptible to develop cardiovascular disease in comparison to the healthy population. This thesis aims to develop and apply MRI techniques to assess the human heart and kidney in patients with chronic kidney disease (CKD). Magnetic resonance imaging (MRI) can be used to inform on structure, function, perfusion and blood flow, without the need for ionizing radiation. In order to assess blood flow using MRI, gadolinium based contrast agents are often used. Patients with compromised kidney function are contraindicated to these contrast agents and so it is necessary to develop imaging techniques that can be used without a contrast agent. Arterial spin labelling (ASL) is an MRI technique that provides a non-contrast enhanced method to assess tissue perfusion using the intrinsic signal from the water in the body. ASL is now becoming a well-established technique in the brain, however applications of ASL in the body are currently limited. In this work, a cardiac ASL technique is developed using a modified Look-Locker scheme to study the myocardium of the heart. This technique is then applied in patients with CKD Stage 3 and age-matched healthy control subjects to assess the changes in myocardial perfusion during a handgrip exercise challenge. MRI measurements of cardiac index and stroke volume index, global and regional contractile function (myocardial strain), coronary artery flow and myocardial perfusion using ASL are applied to assess changes in cardiac function in CKD Stage 5 patients during dialysis treatment. The measures are performed in a randomised design to assess the cardiovascular effects in patients undergoing both haemodialysis and haemodiafiltration. Finally, a comparison of 2D readout schemes for renal ASL is performed. Gradient and spin echo based readout schemes for multi-slice ASL of the kidney at 3 T are evaluated and directly compared in terms of temporal SNR, image SNR, spatial coverage, perfusion quantification and variability across slices/subjects. This work aims to determine the optimal readout scheme for pulsed ASL (PASL) of the kidneys at 3 T in healthy volunteers with normal renal function. In future work this could be applied to patients with compromised renal function where a robust imaging technique is needed. Finally, a summary of the key findings of this thesis and an outline of the potential future directions of this work is provided.

Bladder cancer is the one of the most common malignancies of the genitourinary system and the overwhelming majority of those cases, approximately 90% in the United States(1), are of the urothelial/transitional cell histologic type. Small cell histologic type of bladder cancer is extremely rare with a mean frequency of 0.7% (1), and due to its rarity, there have not been any large phase III clinical trials in order to establish a definitive treatment regimen. We report here one such case of this rare type of bladder cancer and our approach towards treatment. A 69-year-old man had an incidental finding of microscopic hematuria during routine annual testing performed by his primary care physician. He was referred to a urologist for further evaluation, and in the interim, he began to experience symptoms of nocturia, dysuria and gross hematuria. Cystoscopy revealed a 5 cm sessile mass within the bladder and transurethral resection of the tumor was performed. Histopathological analysis of the tumor revealed muscle invasive poorly differentiated urothelial carcinoma with neuroendocrine features suggestive of small cell carcinoma. Follow-up systemic imaging only revealed multiple lesions in the liver, with the largest solitary liver lesion measuring 4.4 x 3.4 cm and no discrete lung lesions. Patient was started on palliative systemic chemotherapy with carboplatin and etoposide and follow-up imaging demonstrated excellent response after four cycles of treatment; however, follow-up imaging after the completion of 6 cycles of treatment demonstrated disease progression. Patient was referred for consideration of enrollment into any clinical trials; however, unfortunately no trials were found to be available. Patient was subsequently offered systemic treatment with single-agent immunotherapy with pembrolizumab. Due to development of left sided hydronephrosis, nephrostomy tube placement was performed and patient was also started on palliative radiation. Primary small cell carcinoma (SCC) of the bladder is an exceedingly rare malignancy and therefore, data is not readily available in order to guide treatment decisions. The most commonly administered regimen consists of etoposide with a platinum agent, and this regimen is extrapolated from the treatment of SCC of the lung. However, as for patients like ours, who had progression of disease in a short interval and are deemed primary treatment (platinum) refractory, the prognosis certainly becomes far more grim and the treatment choices even more limited. In sharing our treatment approach, we hope to be able to provide insight towards potential future treatment choices for this most-challenging diagnosis, primary small cell carcinoma of the bladder. (1) Blomjous CE, et. al. Small cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. Cancer. 1989 Sep 15; 64(6):1347-57.

Melanosis vesicae (or bladder melanosis) is a rare, benign condition referring to the presence of dark pigmented melanin deposits usually within the bladder mucosa. The clinical presentation can be mistaken for primary or metastatic melanoma of the bladder, and thus a histologic assessment is useful for ruling out a malignant diagnosis. All documented cases of melanosis vesicae have presented with urinary symptoms, including hematuria, symptoms of cystitis, incontinence and obstruction. This is a case report presenting a 57-year-old female with complaints of incomplete bladder emptying who met criteria for urinary retention. She underwent in-office cystoscopy and was found to have suspected melanosis vesicae. The diagnosis was later confirmed on pathology following a bladder biopsy. The next phase in care for this patient is planned sacral neuromodulation for treatment of urinary retention. Previous case reports of bladder melanosis have suggested an association with melanin deposition and inflammatory mechanisms and have not demonstrated malignant transformation during follow up. This is, to our knowledge, the first report of documented bladder melanosis in conjunction with urinary retention. Further studies are required to understand the etiology, clinical significance, and clinical correlation of melanosis vesicae with urinary dysfunction.