This thesis is composed of three studies pertaining to the quality of care for radical cystectomy in Ontario between 1992 and 2004. In the first paper, the associations between provider volume and both operative and overall mortality were assessed. In the second paper, potential factors that could explain the association between volume and outcome were explored. In the final paper, the impact of waiting for cystectomy on survival outcomes was evaluated. Methods: A total of 3296 patients undergoing cystectomy for bladder cancer in Ontario between 1992 and 2004 were identified using the Canadian Institute for Health Information Discharge Abstract Database and the Ontario Cancer Registry. The effects of hospital and surgeon volume on operative mortality and overall survival were assessed using random effects logistic regression and marginal Cox Proportional Hazards modeling, respectively. To elucidate the factors underlying the volume-outcome association, the ability of a number of structure and process of care variables to attenuate the impact of volume was assessed. The effect of waiting for care, from transurethral resection to cystectomy, on overall survival was also assessed using marginal Cox models. Results: Neither hospital nor surgeon volume was significantly associated with operative mortality; however, both were associated with overall mortality. Of the measured structure/process measures, hospital factors caused the greatest attenuation of the volume hazard ratios, albeit to a limited degree. The wait time between the decision for surgery and cystectomy was also significantly associated with overall survival. The impact of delayed care was greatest for patients with lower stage disease. The data suggested a maximum wait time of 40 days for cystectomy. Conclusions: In this thesis, gaps in the quality of care for radical cystectomy in Ontario were identified. Patients treated by low volume hospitals and surgeons or those with long wait times all experienced worse outcomes. Since the underlying measures responsible for provider volume remain elusive, additional work is required to understand what these factors are. Initiatives to decrease wait times, however, are under way in Ontario. Whether these interventions decrease wait times and benefit patients remains to be seen.

Bakgrund: Urinblåsecancer finns i olika former och vid muskelinvasiv cancer är radikal operation den vanligaste behandlingen. Förutsatt att cancern inte spridit sig, då görs en cystektomi. Många människor har en naturlig förmåga att hantera kriser och skapar ny balans i tillvaron efter en påfrestande händelse i livet. Sjuksköterskan kan ge råd och stöd i situationen och bör då ha kunskap om förändringar i personens fysiska och psykiska tillstånd. Syfte: Syftet var att belysa hur personer som genomgått cystektomi på grund av urinblåsecancer upplevde att det dagliga livet påverkades. Metod: En litteraturstudie har gjorts där 15 vetenskapliga artiklar har granskats. Resultat: Personerna drabbades av olika problem efter cystektomin. Urinproblem, buk- och avföringsproblem och livsförändring var tydliga, men även problem med en förändrad kroppsuppfattning och problem med det sociala stödet kom fram. Slutsats: Det är olika faktorer som påverkar det dagliga livet efter en cystektomi. Kunskap i hur personerna kan reagera är viktig för sjuksköterskan, för att kunna bemöta problemen och ge råd och stöd om olika copingstrategier för att hantera situationen. Då kan individuell omvårdnad ges, utifrån varje persons behov. / Background: Bladder cancer exists in different forms and in muscle invasive cancer, radical surgery is the standard treatment. Assuming that the cancer has not spread, then, a cystectomy is done. Many people have a natural ability to handle crises and generate a new personal balance. A nurse can offer advice and support in the situation and should have knowledge of changes in the person's physical and mental condition. Aim: The aim was to illustrate how people who have undergone cystectomy because of bladder cancer felt that their daily lives were affected. Methods: A literature review has been done where 15 scientific papers have been reviewed. Results: The subjects suffered from various problems after cystectomy. Urinary Problems, abdominal and stool problems, and change in life were common, but also problems with an altered body image and problems with social support occurred. Conclusion: There are different factors that affect the daily lives after a cystectomy. Knowledge of how people might react is important for nurses, in order to address the problems and provide advice and support on various coping strategies to deal with the situation. When that is the case, individual care can be given, based on each person's needs.

This thesis is composed of three studies pertaining to the quality of care for radical cystectomy in Ontario between 1992 and 2004. In the first paper, the associations between provider volume and both operative and overall mortality were assessed. In the second paper, potential factors that could explain the association between volume and outcome were explored. In the final paper, the impact of waiting for cystectomy on survival outcomes was evaluated. Methods: A total of 3296 patients undergoing cystectomy for bladder cancer in Ontario between 1992 and 2004 were identified using the Canadian Institute for Health Information Discharge Abstract Database and the Ontario Cancer Registry. The effects of hospital and surgeon volume on operative mortality and overall survival were assessed using random effects logistic regression and marginal Cox Proportional Hazards modeling, respectively. To elucidate the factors underlying the volume-outcome association, the ability of a number of structure and process of care variables to attenuate the impact of volume was assessed. The effect of waiting for care, from transurethral resection to cystectomy, on overall survival was also assessed using marginal Cox models. Results: Neither hospital nor surgeon volume was significantly associated with operative mortality; however, both were associated with overall mortality. Of the measured structure/process measures, hospital factors caused the greatest attenuation of the volume hazard ratios, albeit to a limited degree. The wait time between the decision for surgery and cystectomy was also significantly associated with overall survival. The impact of delayed care was greatest for patients with lower stage disease. The data suggested a maximum wait time of 40 days for cystectomy. Conclusions: In this thesis, gaps in the quality of care for radical cystectomy in Ontario were identified. Patients treated by low volume hospitals and surgeons or those with long wait times all experienced worse outcomes. Since the underlying measures responsible for provider volume remain elusive, additional work is required to understand what these factors are. Initiatives to decrease wait times, however, are under way in Ontario. Whether these interventions decrease wait times and benefit patients remains to be seen.

Noise generated by fluid power applications can be treated using bladder-style suppressors, and an optimal operating condition for these devices is sought in this thesis. Bladder-style suppressors employ a compliant nitrogen-charged bladder to create an impedance change within the system, reflecting the noise back to the source and preventing it from propagating downstream. The noise in a hydraulic system is created by a pump, the flow source in a hydraulic system, and can be separated into three categories: fluid-borne noise, structure-borne noise and airborne noise. Fluid-borne noise places addition stress on sealing surfaces, potentially causing leaks. Airborne noise can be uncomfortable, even hazardous depending on the level. Bladder-style suppressors primarily treat fluid-borne noise; however, it is seen in the literature that fluid-borne noise is the cause of structure-borne and airborne noise. This thesis presents an optimization method for finding the optimal charge pressure for implementation with a given system operating over a broad range of system pressures. The optimization weights suppressor performance by the spectral content of the fluid-borne noise as well as the duty cycle of the system. A single charge pressure works well over a small range of system pressures, though many fluid power applications operate over a larger range of system pressure than the usable range of a suppressor. For systems operating over an extremely broad pressure range, two suppressors charged to different pressures are used to treat the noise in the entire system pressure range. To determine suppressor performance experimental measurements were performed, and models developed, of the transmission loss of this type of device. A multi-microphone method using transfer function relationships between six sensors determines the transmission loss of the suppressor under test. An equivalent fluid model modeling the wave behavior both upstream and downstream, as well as within the suppressor, was created to predict suppressor transmission loss. Optimal configurations are found for a set of system pressures, charge pressures and duty cycles. Analysis of the results shows the time weighting has a more significant impact on the optimum charge pressure than the frequency weighting, as shown by duty cycles considered in this thesis. In addition, all charge pressures selected as optimal for either single suppressor optimizations or double suppressor optimizations, exhibit the highest transmission loss for a single system pressure in the pressure duty cycle for a simulated machine.

No description available.

El cáncer de vejiga es una enfermedad heterogénea. Los tumores se distribuyen en dos vías con cierto nivel de solapamiento: la vía papilar superficial caracterizada por alteraciones de FGFR3 y pérdida del cromosoma 9 y la vía no papilar invasiva caracterizada por alteraciones en las vías de p53 y pRb. Los tumores T1G3 representan el 10% de los tumores de vejiga diagnosticados y representan un desafío clínico debido a su alto riesgo de progresión y la falta de marcadores moleculares que predigan el pronóstico de los pacientes. El objetivo de la tesis ha sido caracterizar los tumores T1G3 y asociar los marcadores evaluados con el pronóstico de los pacientes. La caracterización de los tumores T1G3 ha identificado que la vía de p53 está alterada en un 85% de los casos, que los tumors muestran altos niveles de inestabilidad genómica y que tan sólo el marcador de inestabilidad FGA predice el pronóstico de los pacientes con tumores T1G3. Un nuevo marcador del cancer de vejiga se ha identificado: PIK3CA. / Bladder cancer is a heterogeneous disease distributed into two distinct but slightly overlapping pathways: a papillary superficial pathway characterized by alterations in FGFR3 and loss of chromosome 9 and a non-papillary invasive pathway characterized by alterations in the p53 and pRb pathways. T1G3 tumors are a subgroup of bladder cancers which represent 10% of diagnosed tumors and are a clinical challenge due to their high risk of progression and the lack of molecular markers to predict the prognosis of the patients. The aim of this thesis was to characterize T1G3 tumors and associate these markers with the outcome of the patients. The characterization of T1G3 tumors have shown that the p53 pathway is inactive in 85% of patients, that they have high levels of genomic instability and that only FGA predicts outcome among patients with T1G3 tumors. A novel marker for bladder cancer has been identified: PIK3CA.

Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG. Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists. Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis. By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of < 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded. In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.

<p>Spinal cord injury (SCI) and other neurological diseases and disorders can cause urinary dysfunction that can cause serious health problems and reduce an individual's quality of life. Current methods for treating urinary dysfunction have major limitations or provide inadequate improvement in urinary symptoms. Pudendal nerve stimulation is a potential means of restoring control of bladder function in persons with neurological disease or spinal cord injury. Bladder contraction and relaxation can be evoked by pudendal afferent stimulation, and peripheral pudendal afferent branches may be ideal targets for a bladder control neural prosthesis. This dissertation investigates control of bladder function by selective activation of pudendal afferents.</p> <p>This study investigated the ability to improve both urinary continence and micturition by both direct and minimally-invasive electrical stimulation of selected pudendal afferents in &#945;-chloralose anesthetized male cats. Direct stimulation of the pudendal afferents in the dorsal nerve of the penis (DNP), percutaneous DNP stimulation, and intraurethral stimulation were used to investigate the bladder response to selective activation of pudendal afferents. Finite element modeling of the cat lower urinary tract was used to investigate the impact of intraurethral stimulation location and intraurethral electrode configuration on activation of pudendal afferents. Also, the impact of pharmacological and surgical block of sympathetic activity to the bladder on the bladder reflexes evoked by DNP stimulation was investigated to determine the role of the sympathetic bladder innervation on the mechanism of bladder activation by pudendal afferent stimulation.</p> <p>The DNP is an ideal target for restoring urinary function because stimulation at low frequencies (5-10 Hz) improves urinary continence, while stimulation at high frequencies (33-40 Hz) improves urinary voiding. Intraurethral stimulation is a valid method for clinical investigation of the ability to evoke bladder inhibition and activation via selective activation of the DNP or cranial sensory branch (CSN) of the pudendal nerve. In the cat, intraurethral stimulation can activate the bladder via two distinct neural pathways, a supraspinal pathway reflex activated by the CSN and a spinal reflex activated by the DNP. Finite element modeling revealed the importance of urethral location for selective pudendal afferent activation by intraurethral stimulation. Finally, the sympathetic bladder pathway does not play a significant role in the mechanism mediating bladder activation by DNP stimulation. These findings imply that selective pudendal afferent stimulation is a promising approach for restoring control of bladder function to individuals with SCI or other neurological disorders.</p> / Dissertation

Epidemiologic data suggest that soy consumption may protect against cancer induction in several tissues in humans, including urothelial carcinoma. Genistein have been reported to regulate genes that are involved in several cellular events. However, the molecular mechanism of genistein -induced upregulation of epithelial membrane protein 2 (EMP2), candidate urothelial tumor suppressor, is not entirely understood. At first, we found that the mRNA and protein expression levels of EMP2 were significantly greater in the normal urothelial tissues and human urothelial cells than those in urothelial bladder carcinoma tissues and urothelial cell carcinoma-derived cell lines. Second, EMP2 knockdown via RNA interference markedly enhanced cell proliferation, colony formation, migration and invasiveness. By contrast, EMP2 overexpression suppressed these malignant behaviors. Third, we showed that genistein-induced inhibition in cell proliferation is associated with an increase in EMP2 expression. Using various deleted EMP2 promoter constructs, we defined that the EMP2 core promoter is enough to observe the genistein-induced upregulation of EMP2 transcriptional activity. Using site direct mutagenesis and chromatin immunoprecipitation assays demonstrated that cyclic-AMP response element binding protein 1 (CREB1) acts as a positive regulator of EMP2 transcription by directly binding to its promoter. These results showed EMP2 suppressed urothelial cell carcinoma-derived cell growth, motility and invasion and for the first time that genistein promoted EMP2 expression in urothelial cell carcinoma-derived cells by inducing EMP2 transcriptional activity via CREB1 binding.

Methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate (CDODA-Me) is a synthetic triterpenoid that inhibits growth of Panc1 and Panc28 pancreatic cancer cell lines and activates peroxisome proliferator-activated receptor B (PPARB)-dependent transactivation in these cells. CDODA-Me has also induced p21 and p27 protein expression and downregulated cyclin D1; however, these responses were receptor-independent. CDODA-Me induced apoptosis, which was accompanied by receptor-independent induction of the proapoptotic proteins early growth response-1 (Egr-1), nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), and activating transcription factor-3 (ATF3). Induction of NAG-1 in Panc28 cells was p38-mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3-K)-dependent, but Egr-1-independent, whereas induction in Panc1 cells was associated with activation of p38-MAPK, PI3-K and p42-MAPK and was only partially Egr-1-dependent. Specificity protein (Sp) transcription factors Sp1, Sp3 & Sp4 are overexpressed in multiple tumor types and negative prognostic factors for survival. Since Sp proteins regulate genes associated with survival (survivin), angiogenesis [vascular endothelial growth factor and its receptors] and growth [cyclin D1, epidermal growth factor receptor], research in this laboratory has focused on development of anticancer drugs that decrease Sp protein expression. Arsenic trioxide, curcumin, 2-cyano-3,12-dioxoleana-1,9-dien-28-oic acid (CDDO), CDDO-Me, and celastrol exhibit antiproliferative, antiangiogenic and proapoptotic activity in many cancer cells and tumors. Treatment of cancer cells derived from urologic and gastrointestinal tumors with arsenic trioxide decreased Sp1, Sp3 and Sp4 transcription factors and cotreatment with the proteosome inhibitor MG132 did not inhibit downregulation of Sp proteins in these cancer cells. Mechanistic studies suggested that compound-dependent downregulation of Sp and Sp-dependent genes was due to decreased mitochondrial membrane potential and induction of reactive oxygen species, and the role of peroxides in mediating these responses was confirmed using hydrogen peroxide, demonstrating that the mitochondriotoxic effects of these compounds are important for their anticancer activities. Moreover, repression of Sp and Sp-dependent genes by CDDO-Me and celastrol was due to downregulation of microRNA-27a and induction of ZBTB10, an Sp repressor, and these responses were also reversed by antioxidants. Thus, the anticancer activity of CDDO-Me and celastrol is due, in part, to activation of ROS which in turn targets the microRNA-27a:ZBTB10?Sp transcription factor axis to decrease growth inhibitory, pro-apoptotic and antiangiogenic genes and responses.