Urinary incontinence, one of the most prevalent conditions in elderly living in nursing homes (NH) was shown to significantly impact patient's quality of life (QOL) and health outcomes. Bladder antimuscarinics (BAM), the main drug class to treat urinary incontinence, have limited effects in managing the condition; however, given their anticholinergic properties and the characteristics of those living in NH, BAM could potentially lead to serious health consequences in this population. We conducted a retrospective cohort study with a new-users design by linking existing Veterans Affairs (VA) data (inpatient, outpatient, pharmacy administrative files, and Minimum Data Set- MDS) between fiscal years 2003 and 2009. Potential risks (i.e. fractures and negative impact on cognitive performance) and benefits (i.e. improvement in urinary incontinence, social engagement and overall QOL) associated with initiation of a BAM were assessed in elderly (65+) admitted for long-term care in the VA Community Living Centers. Descriptive statistics were used to compare BAM new-users and non-users at baseline; in addition, logistic regression was used to identify important predictors of BAM initiation. Treatment selection bias was addressed by using the propensity score matching method. After balancing the groups on baseline characteristics, the risk of fractures (hip fracture, any fracture) in relationship with BAM initiation was evaluated using Cox proportional hazard analysis. BAM impact on the cognitive status measured by the MDS-Cognitive Performance Scale (CPS) was evaluated through generalized estimated equations (GEE) method. Similarly, possible benefits measured through MDS were assessed via GEE. The final cohort included 1195 BAM new-users (with the majority being prescribed Oxybutynin immediate-release) and 22,987 non-users. Predictors of BAM initiation included demographic characteristics, bladder and bowel continence status, comorbidities, medication use, cognitive performance and functional status. Our study showed that BAM improved urinary continence (OR=1.27, 95%CI: 1.07-1.50) in those treated; social engagement as measured by MDS-Index of Social Engagement also improved in users, although at a level that is not clinically significant (difference in mean MDS-ISE=0.2074, 95%CI: 0.0550-0.3598). However, BAM initiation increased the risk of fractures (hip: HR=3.69, 95% CI: 1.46 - 9.34, p=0.0059; any fracture: HR=2.64. 95% CI: 1.37 - 5.10, p=0.0039). Our results showed no difference between new-users and non-users with regard to mean CPS and overall QOL. The purpose of the study was to clarify the proper role of medication use in the management of urinary incontinence in elderly in the VA CLC. The results raise questions about the continued use of Oxybutynin IR, the main BAM prescribed in this population. Given the increased risk for fractures in the context of potential improvement in urinary continence with no clinically significant improvement in social engagement, a wiser step might be to investigate the safety profile for newer BAM for situations when an addition to non-pharmacologic management for urinary incontinence is desired for elderly in long-term care.

<p>The thesis concerns the epidemiology, current and possible future treatment of urothelial cancer of the urinary bladder. The Swedish National Quality Registry for Bladder Cancer 1997-2001 was used to explore epidemiology, current therapies and outcome. More common in men, the incidence for Ta and T1 tumours peaks in the age range 70-79 years. There were differences in treatment activity between the reporting regions. An increasing activity was seen. Older patients received less intravesical treatment, which was also a tendency for women. The five year relative survival for all stages (Ta-T4) was 70%; 93% for Ta and 75% for T1. For Ta or T1 survival did not differ significantly between regions. Because the registry has only been running since 1997 a long term follow-up (ten years) of 250 patients comparing Bacillus Calmette-Guerin and Mitomycin-C, was performed. No differences regarding complementary treatment, progression or survival (overall or disease specific) were shown. Looking for new drugs, gemcitabine was tried for intravesical instillations. Patients were randomised to one of three dose schedules. The effect on a marker tumour lesion was evaluated after nine weeks. The overall complete response rate was 31% (9/29). Side effects were more common in women but generally mild; the most common was nausea. One patient stopped instillations (nausea and fever). No patients were excluded due to pathological changes in laboratory parameters. For metastasised disease, over-expression of the growth factor receptor HER2 on urothelial cancer cells was explored in primary tumours and metastases, aiming at radionuclide target therapy. With a new antigen retrieval procedure and evaluation protocol 80% of primary tumours overexpressed the receptor and 72% remained so in the metastases. In conclusion current therapies were increasingly used by clinicians. Superiority for BCG could not be proven. Prerequisites for new therapies have been explored and the way has been paved for future studies.</p>

The thesis concerns the epidemiology, current and possible future treatment of urothelial cancer of the urinary bladder. The Swedish National Quality Registry for Bladder Cancer 1997-2001 was used to explore epidemiology, current therapies and outcome. More common in men, the incidence for Ta and T1 tumours peaks in the age range 70-79 years. There were differences in treatment activity between the reporting regions. An increasing activity was seen. Older patients received less intravesical treatment, which was also a tendency for women. The five year relative survival for all stages (Ta-T4) was 70%; 93% for Ta and 75% for T1. For Ta or T1 survival did not differ significantly between regions. Because the registry has only been running since 1997 a long term follow-up (ten years) of 250 patients comparing Bacillus Calmette-Guerin and Mitomycin-C, was performed. No differences regarding complementary treatment, progression or survival (overall or disease specific) were shown. Looking for new drugs, gemcitabine was tried for intravesical instillations. Patients were randomised to one of three dose schedules. The effect on a marker tumour lesion was evaluated after nine weeks. The overall complete response rate was 31% (9/29). Side effects were more common in women but generally mild; the most common was nausea. One patient stopped instillations (nausea and fever). No patients were excluded due to pathological changes in laboratory parameters. For metastasised disease, over-expression of the growth factor receptor HER2 on urothelial cancer cells was explored in primary tumours and metastases, aiming at radionuclide target therapy. With a new antigen retrieval procedure and evaluation protocol 80% of primary tumours overexpressed the receptor and 72% remained so in the metastases. In conclusion current therapies were increasingly used by clinicians. Superiority for BCG could not be proven. Prerequisites for new therapies have been explored and the way has been paved for future studies.

Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. We demonstrated that curcumin inhibited 253JB-V and KU7 bladder cancer cell growth, and this was accompanied by induction of apoptosis and decreased expression of the proapoptotic protein survivin and the angiogenic proteins vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1). Since expression of survivin, VEGF and VEGFR1 are dependent on specificity protein (Sp) transcription factors, we also investigated the effects of curcumin on downregulation of Sp protein expression as an underlying mechanism for the apoptotic and antiangiogenic activity of this compound. Curcumin decreases expression of Sp1, Sp3 and Sp4 in blader cancer cells indicating that the cancer chemotherapeutic activity of curcumin is due, in part, to decreased expression of Sp transcription factors and Sp-dependent genes. Betulinic acid (BA) and curcumin are phytochemical anticancer agents, and we hypothesized that both compounds decrease EGFR expression in bladder cancer through downregulation of specificity protein (Sp) transcription factors. BA and curcumin decreased expression of EGFR, Sp1, Sp3, Sp4 and Sp-dependent proteins in 253JB-V and KU7 cells; EGFR was also decreased in cells transfected with a cocktail (iSp) containing small inhibitory RNAs for Sp1, Sp3 and Sp4 showing that EGFR is an Sp-regulated gene. Methyl 2-cyano-3,11-dioxo-18?-olean-1,12- dien-30-oate (CDODA-Me) is a synthetic triterpenoid derived from glycyrrhetinic acid which inhibits proliferation of KU7 and 253JB-V bladder cancer cells. CDODA-Me also decreased expression of specificity protein-1 (Sp1), Sp3 and Sp4 transcription factors. Similar results were observed for a structurally-related triterpenoid, methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me), which is currently in clinical trials for treatment of leukemia. Celastrol, a naturally occurring triterpenoid acid from an ivy-like vine exhibits anticancer activity against bladder cancer cells. Celastrol decreased cell proliferation, induced apoptosis and decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and several Sp-dependent genes like Fibroblast growth factor receptor 3 (FGFR3). In vivo studies using KU7 cells as xenografts showed that celastrol represents novel class of anticancer drugs that acts, in part, through targeting downregulation of Sp transcription factors.

Basioccipital foramen (bof) is found in four acropomatid species, including Apogonops anomalus, Doederleinia berycoides, Neoscombrops annectens, and Synagrops japonicus belonging to four genera. This structure is just near the fish¡¦s inner ear and to which the anterior diverticulae of the swim bladder in the species protrudes. This configuration is though to be closely related to enhance hearing capabilities and an important synapomorphic system to the phylogeny of acropomatids. The structural parameters of the sagittae (i.e., otolith area, otolith sulcus area, ratio of sulcus to area, otolith weight, hair cell density in otolithic macula, and the stereocilia number per hair cell bundle) were estimated, measured, and analyzed. The data of the parameters from the ¡¥bof-possessing¡¦ acropomatids are lower than that of the ¡¥non-bof¡¦ acropomatids. These values infer a probable poorer auditory capability of the ¡¥bof-possessing¡¦ acropomatids. COI, cytochrome b, and rhodopsin sequences of 12 species in five acropomatid genera (i.e., Acropoma, Doederleinia, Malakichthys, Neoscombrops, Synagrops) were analyzed to resolve the issue whether the configuration between ¡¥bof¡¦ and anterior diverticulae of swim bladder representing synapomorphic characters. The constructed Bayesian and maximum parsimony trees indicate that the ¡¥bof-possessing¡¦ acrpomatids do not form a clade. These results suggest that thses specialized structures (¡¥bof¡¦ and anterior swim bladder diverticulae) have developed more than once in Acropomatidae (i.e., a case of convergence).

Bladder cancer is a common malignancy affecting the genitourinary system. Although a large number of studies have been carried out on these areas for a long time, little is know about the molecular events which may involve in tumorigenesis. Until now, no profound immunohistological or molecular markers have been identified to define clinically relevant subsets of bladder cancer. The purpose of this thesis is to identify a novel bladder cancer carcinogenesis related genes. Chapter 1 attempts to illustrate the background, molecular markers, chromosomal abnormalities and genetic instability related to bladder cancer. In Chapter 2, various bioinformatics methodologies were used to annotate and identify candidate genes. Twenty-one genes were identified 1.5-fold up- or down-regulated in mRNA expression from RT4, TSGH8301 and J82, three different stages of bladder cancer cell lines by microarray chips (Dr. Liu, personal communications). Another eight candidate tumor suppressor genes were preliminarily identified from suppression subtractive hybridization (SSH) cDNA library of RT4 cell line based on an isoflavones-treated minus non-treated and further subjected to quantitative RT-PCR analyses to confirm the mRNA expression level in different stages of bladder cancer cell lines. Chapter 3 studies on the ANXA10 gene with special emphasis on its cloning, protein expression, subcellular localization and the preparation of polyclonal antibody. The result suggests that ANXA10 is a cytoplasmic protein in N18 cells. Chapter 4 analyzes the CDK2AP1 gene in mRNA and protein level at different bladder cancer cell lines and various specimens. In our preliminary observations, there are lost of CDK2AP1 expressions at invasive TCCs specimens when compared to noninvasive TCCs specimens. The mechanism of the tumor-associated loss of the CDK2AP1 expression is currently not clear. In Chapter 5, bladder cancer cell lines TSGH8301, UB37, TCCSUP and J82 in SCID mice xenograft model were established for further in vivo studies.

The mechanisms underlying the 6-hydroxydopamine (6-OHDA)-induced inflammatory response in the urinary bladder and prostate in anaesthetized male rats of Long- Evan strain were investigated. The magnitude of inflammatory responses were evaluated by morphometric analysis of the area density of India ink-labeled blood vessels in urinary bladder whole mounts and spectrophotometric analysis of Evans blue dye contents in urinary bladder and prostate. Moreover, scanning electron microscopy was employed to observe the venular endothelium in the urinary bladder wall and glandular epithelium in the prostate gland. Fifteen minutes after local application of 6-OHDA to the urinary bladder, 6-OHDA induced an increase of plasma leakage in a dose-dependent manner. It was revealed that area densities of India ink-labeled blood vessels in the rat urinary bladder whole mount were 5.65¡Ó1.72 % (N=6), 22.63¡Ó3.12 % (N=6), and 35.02¡Ó2.25 % (N=6) respectively, following a local injection of vehicle, 5 mg/kg 6-OHDA, and 10 mg/kg 6-OHDA. Using Evans blue dye as a tracer for spectrophotometric analysis, the results were similar. The Evans blue dye content was 80.53¡Ó60.74 ng/mg in the urinary bladder and 48.81¡Ó2.83 ng/mg in the prostate following injection of 5 mg/kg 6-OHDA (N=6). The Evans blue dye content was 157.73¡Ó4.45 ng/mg in the bladder and 65.52¡Ó4.25 ng/mg in the prostate following injection of 10 mg/kg 6-OHDA (N=6). Evans blue dye contents in the vehicle group (N=6) were much lower, 18.82¡Ó3.74 ng/mg in the urinary bladder and 18.50¡Ó2.47 ng/mg in the prostate, which were significantly smaller than the 6-OHDA treated group. Interestingly, the inflammatory responses were completely abolished by pretreating alone with dimethylthiourea (DMTU), a hydroxyl radical scavenger, and were moderately attenuated by pretreatment with L-732,138, a NK1 receptor antagonist. Under scanning electron microscope observation, 6-OHDA caused endothelial gaps formation in the venules of urinary bladder wall and triggered the release of secretory granules in the prostate gland cells. We concluded that 6-OHDA could induce inflammation in the urinary bladder and prostate gland involving free radical and tachykinin mechanisms.

The first topic of the thesis reveals a mini-invasive low-power measurement system for bladder pressure measurement. Not only can the mode of measurement be selected, the input range and amplification of instrumentation amplifier (IA) is also adjustable. The proposed system can measure the pressure in a bladder in a continuous mode. It also can monitor the pressure in a long-term mode with an automatic sleeping mechanism for power saving. The signal generated by the pressure sensor is sensed by an IA, which is then fed into the following ADC (analog-to-digital converter). The input range of the IA must be adjustable to keep the required linearity. The pressure range of the proposed system is found out to be 5 Psi with the maximum resolution of 1 cm-H2O, which covers the range of all of the known unusual bladder syndromes. The second topic is a self-disable sense technique for content addressable memory (CAM). The differential match-line sense circuit can be self-disabled to choke the charge current fed into the match line right after the comparison result is generated. Besides, the 13-T CAM cell provides the complete write, read, and comparison functions to refresh the data bit and verify its correctness before searching. The average energy consumption of the searching process is 1.872 fJ/bit/search according to thorough simulations.

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains viii, 147 p. : ill. Vita. Includes abstract. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 111-120).